Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH:33]2[CH2:38][CH2:37][CH:36]([P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:35][CH2:34]2)=[C:26]2[C:30]=1[C:29](=[O:31])[N:28]([CH3:32])[CH2:27]2>>[CH2:41]([O:40][P:39]([CH:36]1[CH2:37][CH2:38][CH:33]([C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[O:19][CH3:20])[N:3]=3)=[C:30]3[C:26]=2[CH2:27][N:28]([CH3:32])[C:29]3=[O:31])[CH2:34][CH2:35]1)(=[O:46])[O:43][CH2:44][CH3:45])[CH3:42]
Reactant: CCOP(=O)(OCC)C1CCC(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: COc1ccccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Product: CCOP(=O)(OCC)C1CCC(c2ccc(Nc3nc(Nc4ccccc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1

Procedure:
The title compound was prepared according to the procedure for Example 102 using 4-chloro-N-(2-methoxyphenyl)-5-(trifluoromethyl)pyrimidin-2-amine (7.2 mg, 0.024 mmol) and diethyl [4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexyl]phosphonate (Compound 193A, 9.0 mg, 0.024 mmol). The reaction mixture was purified by MDP (basic buffer) to give a white solid. The material was further purified by silica gel chromatography (ISCO Combi-flash system, eluting with 0-8% MeOH/DCM), affording the title compound as a white solid, 5 mg. (4:1 mixture, cis and trans unassigned). 1H NMR (CDCl3): 1.40 (t, J=7.1 Hz, 6H), 1.11 (t, J=7.6 Hz, 3H), 1.70-1.84 (m, 4H), 2.09-2.28 (m, 5H), 2.58 (m, 1H), 3.23 (s, 3H), 3.94, 3.95 (2xs, 3H), 4.14-4.23 (m, 4H), 4.39, 4.43 (2xs, 2H), 6.95-7.02 (m, 2H), 7.10 (m, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.93 (m, 1H), 8.26 (m, 1H), 8.38 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 10.64 (s, 1H). MS (ES+): m/z=648.33 [MH+]. HPLC: tR=4.53 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([F:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([Mg]Br)[CH:23]=[CH2:24]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@@H:8]([F:21])[CH2:9][CH2:24][CH:23]=[CH2:22])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](F)c2cccc(Br)c2)cc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC[C@H](F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of toluene-4-sulfonic acid (S)-2-(3-bromophenyl)-2-fluoro-ethyl ester (5 mmol) in THF at room temperature is treated dropwise with a 1M solution of allylmagnesium bromide, stirred at room temperature for 5 h, quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to afford 1-bromo-(S)-3-(1-fluoropent-4-en-1-yl)benzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: O=Cc1ccc(F)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C=O)cc3)c2)CC1
Yield: 60 %

Procedure:
Using 3.0 g (6.6 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester and 4-fluorobenzaldehyde (1.66 g, 13.3 mmol) and following the procedure of Example 42(b) afforded 2.2 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (1H, m), 3.68 (1H, m), 6.75 (1H, d), 7.25 (4H, m), 7.50 (2H, s), 7.82 (2H, d), 7.95 (2H, d), 8.38 (1H, d), 9.94 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1)=O>C(#N)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:14]=[C:11]3[CH:10]=[CH:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:13][N:12]3[CH:16]=2)=[CH:20][C:21]=1[N+:26]([O-:28])=[O:27]
Reactant: O=C(CBr)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: Nc1ccc(-c2ccccc2F)nn1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3nc(-c4ccccc4F)ccc3n2)ccc1Br
Yield: 37.9 %

Procedure:
A stirred solution of 6-(2-fluorophenyl)pyridazin-3-amine (2.22 g, 11.7 mmol) and 2-bromo-1-(4-bromo-3-nitrophenyl)ethanone (3.78 g, 11.7 mmol) in acetonitrile (100 mL) is heated at 80° C. for 12 hours. The mixture is concentrated to dryness and then purified via chromatography using CH2Cl2 to afford the title compound (1.83 g, 37%) as a yellow solid: Rf 0.46 (CH2Cl2); LCMS (m/z)=413.3, 415.3 [M+H]+, tR=3.19 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]([O-])([O-])OCC>>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:9])=[CH:7][N:6]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1ccc(Cl)nc1
Product: CNc1ccc(Cl)nc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To 5.0 g (0.039 mole) of 5-amino-2-chloropyridine was added 40 ml of ethyl orthoformate and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 50 ml of EtOH. After addition of 1.8 g of sodium borohydride, the mixture was stirred at 70-80° C. for 3 hours. The reaction mixture was concentrated and after addition of 50 ml of iced water and 5 ml of concentrated hydrochloric acid, the mixture was adjusted to pH 7-8 with NaHCO3 and extracted with AcOEt (50 ml×3). The AcOEt layers were pooled,washed with water and dried over MgSO4. The AcOEt was distilled off and hexane was added to the crystalline residue. The crystals are collected by filtration, washed with hexane and dried to give 5.1 g of the title compound as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]([OH:24])=O)=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.C([N:35](CC)CC)C.N>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22](=[O:24])[NH2:35])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(=O)O)c12
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(N)=O)c12
Temperature: 5 °C
Yield: 77.6 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-5-fluoro-1,2-benzisoxazole (0.31 g) in tetrahydrofuran (20 ml) was added isobutyl chlorocarbonate (0.14 g) and triethylamine (0.11 g) with stirring at 5° C., and the mixture was then stirred for 15 minutes. Ammonia-saturated tetrahydrofuran solution (saturated at room temperature, 5 ml) was added to the reaction mixture and stirred for 15 minutes. The reaction mixture was poured into ice water (40 ml), extracted with diethylether (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give title compound (0.24 g, 78% yield) as a colorless powder.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:40](=[O:41])[N:6]2[C:7]([C:27]([O:29]CC3C=CC([N+]([O-])=O)=CC=3)=[O:28])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O.[Na+:47].[Na+].[Na+].[H][H]>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:40](=[O:41])[N:6]2[C:7]([C:27]([O-:29])=[O:28])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+:47]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (128.5 mg) was dissolved in 6.7 ml of THF and 6.7 ml of 1/15 M sodium phosphate buffer (pH 6.6) to prepare a solution, and 130 mg of 10% Pd-C was added to the solution. The air in the reaction vessel was replaced by hydrogen, and the contents of the reaction vessel were stirred at room temperature for 2 hr. The catalyst was removed by filtration through Celite, followed by washing with water. The filtrate was washed with ethyl acetate and was then concentrated under the reduced pressure to a volume of about 2 ml. The concentrate was purified by column chromatography on Cosmosil 40C18-PREP (5% aqueous methanol solution) to give 40.9 mg of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:11]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([N:22]([CH2:35][CH3:36])[CH2:23][CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH3:21]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:11]=2[C:12]=1[C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:22]([CH2:35][CH3:36])[CH2:20][CH3:21])=[CH:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc2oc(Cc3ccccc3)cc12
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(Cc3ccccc3)oc3cccc(OC)c23)cc1

Procedure:
Acylation of 2-benzyl-4-methoxybenzofuran with 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride as described in Example 6 gives 2-benzyl-3-[4-(2-diethylaminoethoxy)benzoyl]-4-methoxybenzofuran.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].IC.[C:15](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:2]=1[NH:1][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)ccc1N
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CNc1ccc(Cl)cc1C(=O)OC
Reaction time: 48 h
Yield: 12.7 %

Procedure:
A mixture of methyl 2-amino-5-chlorobenzoate (1.0 g, 5.4 mmol), iodomethane (0.75 ml, 12.0 mmol), potassium carbonate (1.7 g, 12.4 mmol), and acetonitrile (20 ml) was stirred for 48 hours. The mixture was filtered through a pad of celite under suction and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate-hexane (1:19) to provide 5-chloro-2-methylaminobenzoic acid methyl ester (137 mg, 13% yield) followed by 5-chloro-2-dimethylaminobenzoic acid methyl ester (809 mg, 70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=O)[CH2:11]Br)[S:7][CH:6]=1)=[O:4].S(=O)(=O)(O)O.[CH:19]([NH2:21])=[O:20]>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:21]=[CH:19][O:20][CH:11]=2)[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Reactant: NC=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1csc(-c2cocn2)c1
Temperature: 150 °C

Procedure:
5-(2-Bromo-acetyl)-thiophene-3-carboxylic acid methyl ester (0.60 g, 2.28 mmol) was suspended in formamide (10 mL) then sulfuric acid (1 mL) was added and the tube purged with nitrogen then sealed. The mixture was heated at 150° C. by microwave irradiation for 15 minutes. The resultant solution was diluted with HCl (1 N) and water and extracted with ethyl acetate (×3). The organic phase was dried over sodium sulfate and evaporated then purified by chromatography on a silica II cartridge, eluting with 1:1 DCM: cyclohexane to afford 5-oxazol-4-yl-thiophene-3-carboxylic acid methyl ester as a pale yellow solid (0.197 g). LCMS m/z 210.14 [M+H]+ R.T.=3.64 min (Analytical Method 9).
Reaction SMILES: [CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][C:5]1[CH:6]=[C:7]2[C:28]3[CH:27]=[CH:26][S:25][C:24]=3[C:20]3[S:21][CH:22]=[CH:23][C:19]=3[C:8]2=[CH:9][C:10]=1[CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2].C([Li])(C)(C)C.[CH3:38][Sn:39](Cl)([CH3:41])[CH3:40]>C(OCC)C>[CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][C:5]1[CH:6]=[C:7]2[C:28]3[CH:27]=[C:26]([Sn:39]([CH3:41])([CH3:40])[CH3:38])[S:25][C:24]=3[C:20]3[S:21][C:22]([Sn:39]([CH3:41])([CH3:40])[CH3:38])=[CH:23][C:19]=3[C:8]2=[CH:9][C:10]=1[CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCC(CC)Cc1cc2c(cc1CC(CC)CCCC)c1ccsc1c1sccc21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCC(CC)Cc1cc2c(cc1CC(CC)CCCC)c1cc([Sn](C)(C)C)sc1c1sc([Sn](C)(C)C)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A dry 100-mL three-neck flask was flushed with N2 and was charged with 5,6-bis(2-ethylhexyl)naphtho[2,1-b:3,4-b′]dithiophene (0.50 g, 1.1 mmol) and diethyl ether (Et2O) (11 mL, 0.10 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 1.3 M solution of tert-butyllithium in hexanes (2.3 mL, 3.0 mmol) was added drop-wise via deoxygenated syringe. After 30 minutes of stirring at −78° C., the solution was chilled to 0° C. and stirring was continued for 5 minutes, at which point the reaction mixture was cooled back to −78° C. A 1 M solution of trimethyltin chloride (4.4 mL, 4.4 mmol) in hexanes was added to the reaction flask drop-wise and stirring continued for 30 minutes at −76° C. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. As the reaction was completed, cool DI water (10 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 50 mL of cool water and extracted with MTBE (100 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified by precipitation into methanol from a THF solution to yield pale yellow oil (0.73 g, 84%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1ccccc1Cl
Reactant: CS(=O)(=O)c1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Product: Clc1ccccc1CNc1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of [3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 50 supra) (200 mg, 0.50 mmol) and 2-chlorobenzylamine (281 mg, 1.99 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol 50:1 to 20:1) to afford the crude product (110 mg). Then the crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford {3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 58 mg, 25.1%). 1H NMR (300 MHz, CD3OD): δ 8.72 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 7.59 (d, 1H, J=6.9 Hz), 7.46-7.28 (m, 5H), 4.75 (brs, 2H), 4.17 (brs, 2H), 3.93 (brs, 4H), 3.59-3.28 (m, 5H). LC-MS: [M+H]+ 466.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[C:3]=1[CH3:12].O.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:11][C:9]1[CH:8]=[CH:7][C:5]2[S:6][C:2]([C:14]#[N:15])=[C:3]([CH3:12])[C:4]=2[CH:10]=1
Reactant: Cc1c(Br)sc2ccc(Cl)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1c(C#N)sc2ccc(Cl)cc12
Temperature: 80 °C

Procedure:
A mixture of 2-bromo-5-chloro-3-methylbenzo(b)thiophene (1.00 g, 3.82 mmol), zinc cyanide (247 mg, 2.10 mmol), and Pd(PPh3)4 (440 mg, 0.38 mmol) in DMF (15 mL) was heated to 80° C. for 16 hours, added to water (50 mL), and extracted with 30% ethyl acetate/hexanes (3×100 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)CCC>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cnccn3)ccc1Oc1c(F)cc(O)cc12
Temperature: 110 °C

Procedure:
Pd(PPh3)4 (0.506 g, 0.438 mmol), (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (1.6 g, 4.38 mmol), and 2-(tributylstannyl)pyrazine (2.426 g, 6.57 mmol) were combined in 10 ml of DMF and heated in the microwave at 110° C. for two hours. The solution was diluted with ethyl acetate (50 mL) and washed twice with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified via silica gel column chromatography (RediSep 40 g column) using 10-100% 90/10/1 (CH2Cl2/MeOH/ammonia) in CH2Cl2 to afford (S)-2-amino-4′-fluoro-7′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a white solid. MS m/z=365.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([CH:10]3[O:15][CH2:14][CH2:13][N:12](CC4C=CC=CC=4)[CH2:11]3)=[N:9][C:5]=2[CH:4]=1.Cl.C(Cl)Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([CH:10]3[O:15][CH2:14][CH2:13][NH:12][CH2:11]3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2[nH]c(C3CNCCO3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
To a solution of 5-(methyloxy)-2-[4-(phenylmethyl)-2-morpholinyl]-1H-benzimidazole (2.0 g, 6.18 mmol), and hydrogen chloride (0.451 g, 12.37 mmol) in CH3OH (50 mL) stirred under nitrogen at room temperature was added palladium on carbon (0.066 g, 0.618 mmol). The reaction mixture was stirred under hydrogen at 25° C. for 3 hours. CH2Cl2 was added and the mixture was filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with 90:10 CH2Cl2/CH3OH to afford the title compound (500 mg). LC-MS (ES) m/z=234 [M+H]+.
Reaction SMILES: Cl.[F:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:28]=[CH:29][C:22]=12.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C>[F:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:21]2[N:26]=[CH:25][N:24]=[C:23]3[N:27]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:28]=[CH:29][C:22]=23)[CH2:8][CH2:7]1
Reactant: N[C@H]1CC[C@H](OCC(F)c2ccccc2F)CC1
Reactant: Clc1ncnc2c1cnn2C1CCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Fc1ccccc1C(F)CO[C@H]1CC[C@H](Nc2ncnc3c2cnn3C2CCCCO2)CC1
Temperature: 80 °C

Procedure:
A mixture of 0.52 g trans-4-[2-fluoro-2-(2-fluorophenyl)ethoxy]-cyclohexanamine hydrochloride, 0.46 g of 4-chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine, and 1 g of powdered sodium carbonate in 25 mL of 2-propanol was heated to 80° C. under nitrogen overnight. The mixture was cooled, filtered and the solid washed with 3×50 mL portions of 10% methanol in chloroform. The combined extracts were concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 50%-100% ethyl acetate in hexane gave 0.82 g of product as a white solid: MS (m+1)=458.4.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[Cl-].[NH4+]>C(OCC)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Br:1])[OH:5])=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-bromobenzaldehyde (1 ml) was dissolved in diethyl ether (20 ml) and cooled to −78° C. 4-chlorophenylmagnesium bromide (1M diethyl ether solution, 9 ml) was added thereto and the reaction mixture was stirred for one hour at the same temperature. Saturated ammonium chloride aqueous solution was added thereto and the water layer was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by column chromatography to obtain the title compound (2.50 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:32][CH2:31][CH2:29][OH:30])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:26])[F:27])[CH:3]=1
Reactant: NCCO
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 11.70 (1H, br), 10.33 (1H, m), 8.49 (1H, s), 7.70 (1H, d, J=9 Hz), 7.56 (2H, m), 7.32 (1H, s), 4.91 (1H, br t), 4.32 (2H, s), 3.56 (2H, m), 3.45 (2H, m); ES− MS: 424 (M−1, 100).