Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCOC.CC1OC(C=CC2C=C3CCCN4CCCC(=C34)C=2)=CC(=C(C#N)C#N)C=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:59])=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:59])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Agent: CC1=CC(=C(C#N)C#N)C=C(C=Cc2cc3c4c(c2)CCCN4CCC3)O1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 186.7 %

Procedure:
To a solution of tert-butyl-4-carbamoylpiperidine-1-carboxylate (2.65 g, 11.62 mmol) in a DME/DCM 2:1 mixture (78 mL), Lawesson reagent (2.35 g, 5.81 mmol, 0.5 eq) was added and the mixture was stirred at r.t. overnight. The solvent was removed and the residue was taken up with ethyl acetate and washed with saturated aqueous K2CO3. The organic layer was separated, dried over Na2SO4 and concentrated to dryness. The residue was triturated with diethyl ether and dried to give 2.65 g (92%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:12])[CH:10]=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]([CH3:12])[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CC(C=O)=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc(F)cc1)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 113 g (0.69 mole) of 3-(4-fluorophenyl)-2-methyl-2-propen-1-al in 800 ml ethanol at 10° C. was added in portions 13.1 g (0.345 mole) of sodium borohydride. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The mixture was cooled in an ice bath while 350 ml of 1N hydrochloric acid was added dropwise to give a final pH of ~7. The mixture was diluted with 500 ml water and extracted three times with methylene chloride. The organic extracts were dried and concentrated and the residue distilled to give 56.1 g (49%) of colorless liquid, b.p. 68°-70° C. (0.15 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:14]3=[N:15][C:16]([CH3:27])=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[C:13]3[C:12]([CH3:28])=[CH:11]2)=[C:5]([CH3:29])[CH:4]=1.C(N(CC)C(C)C)(C)C.[NH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][C:46]#[N:47])[CH2:41][CH2:40]1.C(OCC)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:29])[C:6]([N:10]2[C:14]3=[N:15][C:16]([CH3:27])=[CH:17][C:18]([N:39]4[CH2:44][CH2:43][CH:42]([CH2:45][C:46]#[N:47])[CH2:41][CH2:40]4)=[C:13]3[C:12]([CH3:28])=[CH:11]2)=[C:7]([CH3:9])[CH:8]=1
Reactant: N#CCC1CCNCC1
Reactant: COc1cc(C)c(-n2cc(C)c3c(OS(=O)(=O)C(F)(F)F)cc(C)nc32)c(C)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C)c(-n2cc(C)c3c(N4CCC(CC#N)CC4)cc(C)nc32)c(C)c1
Temperature: 150 °C
Yield: 56.1 %

Procedure:
A mixture of crude trifluoromethanesulfonic acid 1-(4-methoxy-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl ester (1.1 g), N,N-diisopropylethylamine (0.65 g) and piperidin-4-yl-acetonitrile (1.6 g) was heated at 150° C. in a sealed tube for 7 hours. After cooling to room temperature, ethyl acetate and water were poured into the mixture, and separated. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=3/1) to obtain {1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile (0.58 g) as a pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[F:14][C:15]1[CH:32]=[CH:31][C:18]2[S:19][C:20]([CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)O)=[C:21]([CH3:22])[C:17]=2[CH:16]=1>>[F:14][C:15]1[CH:32]=[CH:31][C:18]2[S:19][C:20]([CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:4]3[C:3](=[O:7])[C:2]([CH3:1])([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5]=3[OH:6])=[C:21]([CH3:22])[C:17]=2[CH:16]=1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: Cc1c(C(O)c2ccccc2)sc2ccc(F)cc12
Product: Cc1c(C(C2=C(O)C(C)(c3ccccc3)C2=O)c2ccccc2)sc2ccc(F)cc12

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 427.5 ([M−H]−).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:20])=O.[OH-].[Na+]>CO.O>[Br:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH:6]([CH3:20])[NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)C(C)CNC(C)C2
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (21 mg, 0.055 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (10 mL), the combined organic phases were washed with brine (10 mL), dried with Na2SO4 and concentrated to give 11 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.29 (s, 1H), 6.64 (s, 1H), 3.88 (s, 3H), 3.02 (m, 2H), 2.89 (dd, J=9, 14 Hz, 1H), 2.80 (m, 1H), 2.67 (d, J=14 Hz, 1H), 2.53 (dd, J=10, 13, 1H) 1.30 (d, J=7 Hz, 3H), 1.19 (d, J=6 Hz, 3H). MS calculated for C13H18BrNO+H: 284, observed: 284.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])(=[O:4])=[O:3].[H][H]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:13])([F:14])[F:15])[NH2:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1cc(N)ccc1OC(F)(F)F
Yield: 91.3 %

Procedure:
3-Methylsulfonyl-4-trifluoromethoxynitrobenzene (17.5 g) was dissolved in methanol (400 mL) followed by addition of palladium on carbon (10%, 50% water, 3.2 g). The reaction mixture was hydrogenated for 17 hours at 1 atm of hydrogen, filtered and concentrated in vacuo to give 14.3 g of 3-methylsulfonyl-4-trifluoromethoxyaniline.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CC(C)=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[O:5][CH2:6][C:2]([CH3:14])([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: ClCCCBr
Reactant: CC1(C)COC(c2ccc(O)cc2)=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)COC(c2ccc(OCCCCl)cc2)=N1
Yield: 97 %

Procedure:
A mixture of 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenol ax7 (5 g, 26 mmol, 1 eq), potassium carbonate (7.19 g, 52 mmol, 2 eq), and 1-bromo-3-chloropropane (2.8 ml, 29 mmol, 1.1 eq) in acetone (120 ml) is stirred at reflux for 36 h. The mixture is then concentrated; the residue is dissolved in dichloromethane, and washed with a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate and concentrated under vacuum to obtain 2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10 as a white solid (6.75 g).
Reaction SMILES: [H-].[Na+].[CH2:3](P(=O)(O)O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH:31]=O.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1/[CH:31]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Reactant: O=P(O)(O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(/C=C/c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Sodium hydride (60 wt % oil, 52 mg) was dissolved in anhydrous tetrahydrofuran (1 ml), and a solution (0.5 ml) of benzylphosphonic acid (114 mg) in tetrahydrofuran was added dropwise to the solution at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 30 min, and a solution (0.5 ml) of 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (100 mg) in tetrahydrofuran was then added dropwise thereto. The reaction mixture was stirred at room temperature for one hr, and water (1 ml) was then added dropwise thereto to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (100 mg, yield 80%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([OH:22])[CH2:11][CH2:12][N:13]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[N:15]=[C:14]2Cl)=[CH:4][CH:3]=1.[H-].[Na+]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[O:22][C:14]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:13]3[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cn(CCC(O)COc2ccc(Br)nc2)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(Br)nc1)CC2
Yield: 87 %

Procedure:
Ring closure of alcohol 137 with NaH (1.6 equiv.) as in Example 2AA followed by chromatography of the product on silica gel, eluting with 0-0.5% MeOH/CH2Cl2 (foreruns) and then with 0.5-0.75% MeOH/CH2Cl2, gave additional 138 (87%) as a pale yellow solid (see above).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1COCC1.C[Mg]Br.O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]([OH:12])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: C[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cc(Br)ccc1OCc1ccccc1

Procedure:
2-Benzyloxy-5-bromobenzaldehyde (5 g) was dissolved in anhydrous diethyl ether (20 mL) and THF (20 mL) and stirred at ambient temperature under argon while a solution of methyl magnesium bromide in ether (7.4 mL, 3M solution in ether) was added dropwise over 5 minutes. A white precipitate formed. After 30 minutes the mixture was poured onto a mixture of ice and water (300 mL). The aqueous mixture was extracted with ethyl acetate (3×250 mL), the organic extracts were washed with brine (100 mL) and dried (MgSO4). After removal of the solvent the residual pale yellow oil was purified by MPLC (eluting with dichloromethane on silica) to give 1-(2-benzyloxy-5-bromophenyl)-ethanol, (5.19 g, mp 76.7° C.).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.[NH2:45][C:46]1[C:51]([NH2:52])=[N:50][C:49](Br)=[CH:48][N:47]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:48]2[N:47]=[C:46]([NH2:45])[C:51]([NH2:52])=[N:50][CH:49]=2)=[N:6]1
Reactant: Fc1ccccc1Cn1nc(I)c2cccnc21
Reactant: Nc1ncc(Br)nc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: C1COCCO1
Product: Nc1ncc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C

Procedure:
Under argon, 425 mg (1.20 mmol) of the compound from Example 33A were initially charged in 1,4-dioxane (11 ml), and the reaction mixture was purged with argon for 10 min. Thereafter, 0.91 ml (1.80 mmol) of hexabutylditin and 250 mg (1.32 mmol) of 2,3-diamino-5-bromopyrazine were added. Subsequently, 422 mg (0.60 mmol) of bis(triphenylphosphine)palladium(II) chloride were added and the reaction mixture was heated to reflux overnight. Thereafter, the mixture was cooled to RT and filtered through Celite, and the filtrate was concentrated. The residue was admixed with methanol, and the solids were filtered off and discarded. The filtrate was taken up in methanol-dichloromethane, absorbed onto diatomaceous earth and purified on silica gel (eluent: cyclohexane-ethyl acetate 2:1, 1:1). This gave 151 mg (31% purity, 11% of theory) of the title compound. The crude product was converted further without further purification.
Reaction SMILES: O[C:2]1([C:25]2[C:26]([OH:34])=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:3]1=[O:24])[N:11]=[CH:10][CH:9]=[CH:8]3.C1(C(C2C=CC=CC=2)N2C3C=C4OCCOC4=CC=3C(O)(C3C(O)=CC4OCCC=4C=3)C2=O)C=CC=CC=1>>[OH:34][C:26]1[C:25]([CH:2]2[C:6]3=[C:7]4[C:12](=[CH:13][CH:14]=[C:5]3[N:4]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:3]2=[O:24])[N:11]=[CH:10][CH:9]=[CH:8]4)=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1
Reactant: COc1ccc(CN2C(=O)C(O)(c3cc4c(cc3O)OCC4)c3c2ccc2ncccc32)cc1
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCC2)OCCO3
Product: COc1ccc(CN2C(=O)C(c3cc4c(cc3O)OCC4)c3c2ccc2ncccc32)cc1

Procedure:
Following the procedure as described in PREPARATION 74C and making non-critical variations using 1-hydroxy-1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one to replace 6-(diphenylmethyl)-8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one, 1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one was obtained (37%) as a colorless solid: MS (ES+) m/z 438.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:46][CH3:47])[CH3:45])=O>>[CH2:46]([N:44]([CH3:45])[CH2:42][CH2:41][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[C@@H:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[CH:3][C:2]=1[F:1])[CH3:47]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: CCN(C)C(=O)CCl
Product: CCN(C)CCOc1ccc(CN(c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 45.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-ethyl-N-methylacetamide (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.5 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH3:19])=[CH:7]2.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>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>[CH3:19][C:8]1[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:25](=[O:27])[CH3:26]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2cccc(Br)c2nc1Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2cc(C)c(Oc3ccccc3)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
A solution of 8-bromo-3-methyl-2-phenoxyquinoline (505.5 mg, 1.609 mmol), tributyl(1-ethoxyvinyl)stannane (Synthonix, Inc., Wake Forest, N.C.; 0.598 mL, 1.770 mmol), and Pd(PPh3)4 (93 mg, 0.080 mmol) in toluene (8.0 mL) was sparged with argon and then stirred under N2 at 100° C. for 16 h. The mixture was cooled to 25° C. and concentrated onto silica gel. Chromatographic purification (silica gel, 0-20% EtOAc/hexanes) furnished 1-(3-methyl-2-phenoxyquinolin-8-yl)ethanone (326.0 mg, 1.176 mmol, 73% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (1H, s), 7.90 (1H, dd, J=7.2, 1.4 Hz), 7.82 (1H, dd, J=8.0, 1.2 Hz), 7.37-7.47 (3H, m), 7.23-7.25 (1H, m), 7.19 (2H, d, J=8.1 Hz), 2.55 (3H, d, J=0.6 Hz), 2.28 (3H, s). m/z (EST, +ve) 278.1 (M+H)+.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.O=[C:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:45]2[CH2:46][CH2:41][CH2:42][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC(=Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirring solution of (4-fluorophenylmethyl)-triphenylphosphonium chloride (17.68 g, 43.5 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (14.6 mL, 36.5 mmol). The reaction was warmed to 0° C. for 1 hr and t-Butyl 3-oxo-1-piperidinecarboxylate (3.46 g, 17.4 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred at room temperature for 1 hr and the heated to reflux for 16 hr. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The reaction was extracted with ethyl acetate three times (100 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, hexane:ethyl acetate 9:1) to yield 3.82 g of a mixture of E and Z isomers as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.22-7.14 (m, 2H), 7.04-6.98 (m, 2H), 6.36 (s, 0.33H), 6.28 (s, 0.67H), 4.14 (s, 1.34H), 4.00 (s, 0.66H) 3.50 (t, J=5, 2H), 2.47 (t, J=5, 0.66H), 2.39 (t, J=5, 1.34H), 1.75-1.68 (m, 1.34H), 1.65-1.57 (m, 0.66H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1sc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)nc1C

Procedure:
This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 4-biphenylsulfonyl chloride as described for EXAMPLE 30 with tile exception that it was not recrystallized. Yield 96 mg, 24%: 1H NMR (DMSO) δ 7.8-7.95 (m, 4H), 7.65-7.75 (m, 2H), 7.35-7.55 (m, 3H), 4.23 (q, 2H); 2.39 (s, 3H), 1.26 (t, 3H); MS-ES (neg) m/z 401.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])=[CH:11][CH2:10]1.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH:43]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:43][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)[CH2:25][CH2:26]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])=[CH:11][CH2:10]1
Reactant: O=Cc1ccccn1
Reactant: CC1CC=C(c2cc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC1CC=C(c2cc(C3CCN(Cc4ccccn4)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
This compound was prepared according to the procedure in Example 21 from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide (as prepared in Example 17) and pyridine-2-carbaldehyde. 1H-NMR (400 MHz, DMSO-d6): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.52 (m, 1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.74 (m, 1H), 4.56 (s, 2H), 3.40 (m, 2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.48-2.22 (m, 3H), 2.18-2.06 (m, 4H), 1.98-1.82 (m, 3H), 1.52 (m, 1H), 1.02 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C28H32N6O, 481.2 (M+H), found 481.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[CH:19]=[N+]=[N-])[CH3:16]>C1(C)C(C)=CC=CC=1>[CH2:15]([O:17][C:18]([CH:19]1[CH:10]2[CH:11]1[C:12](=[O:13])[N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]2=[O:14])=[O:22])[CH3:16]
Reactant: O=C1C=CC(=O)N1c1ccc(Cl)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1C2C(=O)N(c3ccc(Cl)cc3)C(=O)C12
Yield: 34.8 %

Procedure:
A solution of 19.4 g (93 mmol) of 1-(4-chloro-phenyl)-pyrrole-2,5-dione in 120 ml of xylene was treated with 19.4 ml (187 mmol) of ethyldiazoacetate and refluxed during 12 hrs. Evaporation of the solvent and chromatography on silica gel with toluene and then a gradient of toluene/AcOEt from 95:5 to 90:10 gave 9.5 g(35%) of the title compound. Off white solid. MS: 294 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1I
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: Fc1ncccc1N1CCOCC1
Temperature: 150 °C

Procedure:
A microwave reaction vessel was charged with 2-fluoro-3-iodopyridine (1.0211 g, 4.579 mmol), morpholine (0.3989 mL, 4.579 mmol), Pd2(dba)3 (0.2633 g, 0.2748 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.2232 g, 0.5495 mmol), and sodium t-butoxide (1.1363 g, 13.74 mmol) in toluene (15 mL). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 150° C. for 20 min (125 watts, Powermax™ feature on, ramp time 5 min). The solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(2-fluoropyridin-3-yl)morpholine.