Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CN(C)c1ccc(Nc2nc(Cl)ncc2Cl)c(S(=O)(=O)N(C)C)c1
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N(C)C)cc4S(=O)(=O)N(C)C)n3)cc21

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan solid (0.077 g, 64%). MP: 240-243° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.90 (s, 1H), 8.15 (d, J=9.1 Hz, 1H), 8.07 (s, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.30-7.19 (m, 2H), 7.14 (d, J=3.0 Hz, 1H), 6.93 (br s, 1H), 6.85 (dd, J=9.2 Hz and 2.9 Hz, 1H), 3.75-3.62 (m, 2H), 3.02 (s, 6H), 2.72 (s, 6H), 2.37-2.26 (m, 2H), 2.10-1.95 (m, 2H), 1.32 (s, 6H), 1.17 (t, J=7.1 Hz, 3H). MS: 586.24 (MH)+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 47.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 27 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 569 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([CH3:22])[C:12]=3[CH3:23])[CH2:9][C:8]3([CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]2=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:3]=2)[C:8]2([CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH2:9]1
Reactant: Cc1nc2c(Cl)cccc2c(N2CC3(CCOCC3)c3ncc(Br)cc32)c1C
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)cccc2c(N2CC3(CCOCC3)c3ncc(N4CCOCC4)cc32)c1C

Procedure:
Prepared according to procedure N by stirring 6′-bromo-1′-(8-chloro-2,3-dimethylquinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]-pyridine] (25 mg, 0.054 mmol), morpholine (4.75 μL, 0.054 mmol), Pd2dba3 (5 mg, 5.4 μmol) and XPhos (5.2 mg, 10.9 μmol) in toluene (2.0 mL) at reflux for 14 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(8-chloro-2,3-dimethyl-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 7.78 (1H, dd, J=7.4, 1.4 Hz), 7.58-7.62 (2H, m), 7.32-7.36 (1H, m), 5.68 (1H, d, J=2.3 Hz), 4.11-4.20 (2H, m), 3.95-4.00 (1H, m), 3.85-3.91 (1H, m), 3.74 (4H, dd, J=5.3, 4.5 Hz), 3.52-3.62 (2H, m), 2.92-3.05 (4H, m), 2.84 (3H, s), 2.33-2.42 (2H, m), 2.31 (3H, s), 1.73-1.87 (2H, m). Mass Spectrum (ESI) m/e=465.2 (M+1).
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[CH:10]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])[CH:12]=1
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(Cl)ccc1F
Reaction time: 15 h

Procedure:
To a mixture of acetone (22 ml), sodium hydroxide (0.83 g) and water (55 ml) was added dropwise at room temperature a solution of 5-chloro-2-fluorobenzaldehyde (3.5 g) in acetone (20 ml), and the mixture was stirred at the same temperature for 15 hours. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(5-chloro-2-fluorophenyl)-3-buten-2-one (4.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Cl:21])[N:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Cl:21])[N:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: COc1cc(Cl)nc(N)n1
Product: COc1cc(Cl)nc(NC(=O)c2cc(Cl)ccc2O)n1
Yield: 2.2 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:18][C:19]2[N:20]([CH3:30])[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].NC1C=CC(C#N)=C([F:40])C=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:18][C:19]2[N:20]([CH3:30])[N:21]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:23]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([F:40])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: N#Cc1ccc(N)cc1F
Reactant: CCc1cccc(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)cc2)c1
Product: CCc1cccc(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)c(F)c2)c1

Procedure:
According to the procedure for the preparation of Intermediate 370.4, 4-amino-2-fluorobenzonitrile (46 mg, 0.34 mmol) gave 75 mg of Intermediate 373.1 as a white solid. LCMS 412.30 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1Cl.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1[S:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Sc1ccccc1
Reactant: Nc1nc(-n2cccn2)nc(Cl)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(-n2cccn2)nc(Sc2ccccc2)c1Br

Procedure:
To a solution of 0.1 g (0.36 mmol) of 5-bromo-6-chloro-2-(1H-pyrazol-1-yl)pyrimidin-4-amine (Intermediate 5) in 4 ml of THF, 74 μl (0.73 mmol) of thiophenol and 0.178 g (0.55 mmol) of Cs2CO3 were added. The mixture was allowed to react under microwave conditions 15 min. at 100° C. Afterwards the reaction mixture was put on 10 ml of cool water. The formed white precipitate was filtered, washed several times with cold water and dried.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:21][N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[C:17]([CH:20]=1)[C:18]#[N:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:21][N:22]2[CH2:23][CH:24]([OH:26])[CH2:25]2)=[C:17]([CH:20]=1)[CH2:18][NH2:19]
Reactant: N#Cc1cc(Cl)ccc1CN1CC(O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1cc(Cl)ccc1CN1CC(O)C1
Yield: 70 %

Procedure:
1M LAH in ether (11.25 mL, 11.25 mmol) was added to a stirred solution of 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzonitrile (1.67 g, 7.50 mmol) in THF (70 mL) at 0° C. After 1 h the reaction was quenched with EtOAc (5 ml) and concentrated. The residue was stirred with ether (150 mL) and this was then treated successively with water (0.43 mL), 15% NaOH (0.43 mL) and water (1.29 mL). After stirring for 15 min the mixture was filtered and evaporated to give 5-Chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzylamine (1.19 g) as a gum: 1H NMR (CDCl3, 400 MHz) δ 2.99 (m, 2H), 3.64 (m, 2H), 3.75 (s, 2H), 4.38 (d, J=5.3 Hz, 2H), 4.50 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.21 (dd, J=2.2, 9.7 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][N:13]=1)[CH3:2].CC1(C)C(C)(C)OB([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[C:16]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)[CH:15]=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OS(=O)(=O)C(F)(F)F)ccn1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(N)cc2)ccn1
Yield: 70.1 %

Procedure:
Compound II (52 mg, 0.109 mmol), Pd(PPh3)4 (12 mg, 0.011 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (48 mg, 0.218 mmol) and potassium carbonate (60 mg, 0.44 mmol) were stirred in toluene (3 mL) and water (1.5 mL) at 120° C. under microwave irradiation (300 W) for 30 min. The reaction mixture was then poured onto brine (50 mL) and extracted with EtOAc (2×20 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 0:100) to furnish III as a brown oil (32 mg, 70%).
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:31]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
In a similar manner as described for example 33, 45.8 mg of methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[4-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]#[C:19][Si](C)(C)C)[N:17]=2)=O)=[C:8]([CH3:24])[C:7]([O:25][CH3:26])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:26][O:25][C:7]1[C:8]([CH3:24])=[C:9]2[C:4]([C:1]([OH:3])=[CH:2][C:11]([C:13]3[S:14][CH:15]=[C:16]([C:18]#[CH:19])[N:17]=3)=[N:10]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C#C[Si](C)(C)C)cs2)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C#Cc1csc(-c2cc(O)c3ccc(OC)c(C)c3n2)n1
Temperature: 80 °C
Yield: 52 %

Procedure:
To a suspension of compound 208b (8.71 g, 1 eq.) in tert-butanol (240 mL) was added potassium tert-butoxide (5.32 g, 2.1 eq.). The heterogeneous mixture was stirred and heated to 80° C. The solvent was then evaporated and water was added to the resulting black residue. The pH of the mixture was brought to 6 with 1N HCl. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuo. The solid was purified by chromatography on silica gel to give compound 209b as an orange solid in 52% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.45 (s, 3H), 3.25 (s, 1H), 3.99 (s, 3H), 6.89 (br s, 1H), 7.06 (d, J=9.09 Hz, 1H), 7.72 (s, 1H), 8.26 (d, J=9.09 Hz, 1H), 9.50 (br s, 1H); MS (ESI, EI+) m/z=297 (MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[Br:15][C:16]1[CH:20]=[N:19][N:18]([CH3:21])[C:17]=1[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]([CH3:36])([N+:33]([O-])=O)[CH3:32])[NH2:25].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:33][C:31]([CH3:36])([CH3:32])[CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:24]([NH:25][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)=[CH:23][C:22]=1[C:17]1[N:18]([CH3:21])[N:19]=[CH:20][C:16]=1[Br:15]
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(OC(F)(F)F)c2)ccc1OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
3-Trifluoromethoxybenzoyl chloride (12 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (21 mg, 81%) as a TFA-salt. LCMS m/z (%)=529.3 (M+H 81Br 76.1%), 527.5 (M+H 79Br 64.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 3 H), 1.18 (s, 3 H), 3.67 (s, 3 H), 3.84 (d, J=9.85 Hz, 1 H), 4.00 (d, J=9.85 Hz, 1H), 7.30 (d, J=9.09 Hz, 1 H), 7.60-7.65 (m, 1 H), 7.67 (s, 1 H), 7.68-7.73 (m, 2 H), 7.85-7.93 (m, 4 H), 7.95 (dd, J=8.97, 2.65 Hz, 1 H), 8.01 (d, J=7.83 Hz, 1 H), 10.48 (s, 1 H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:44]2[C:43](=[CH:45][CH2:46][OH:47])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]>C1COCC1.O>[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([O:47][CH2:46][CH:45]=[C:43]2[C:44]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:62][CH:63]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]
Reactant: OCC=C1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3-c3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0°C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 2-fluoren-9-ylidene-ethanol (0.208 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature, and stirring continued for 72 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (3×20 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to a yellow gum. This was then purified by column chromatography on silica gel (15% Et2O in petroleum eluent) to give ethyl 2-ethoxy-3-[4-(2-fluoren-9-ylidene-ethoxy)-phenyl]-propionate as a yellow gum; 0.28 g (60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8](=[O:13])[CH:9]([CH3:12])[CH2:10]2
Reactant: CC(CO)C(=O)c1ccc(F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1Cc2cc(F)ccc2C1=O

Procedure:
A mixture of 18.2 g. (0.10 mole) of 4'-fluoro-3-hydroxy-2-methylpropiophenone and 12 g. of phosphorous pentoxide in 100 ml. of xylene is refluxed for one hour. The reaction is cooled, water is added and the xylene layer is washed with aqueous sodium hydroxide and water. The organic layer is then concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O1CCOCC1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:31]4[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[N:29][CH:30]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nn3c(-c4ccc(C#N)nc4)cnc3s2)cc1OC
Temperature: 120 °C
Yield: 26.6 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.10 g, 0.3 mmol, 1 eq), dioxane (5 mL), 2-cyanopyridine-5-boronic acid pinacol ester (0.155 g, 0.64 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.018 g, 0.1 eq), potassium carbonate (0.178 g, 1.3 mmol, 5 eq), and water (2 mL) was heated in the microwave oven (120° C., 30 min) and was left to cool to RT. A precipitate formed that was filtered off (0.048 g) and washed with a mixture of Et2O and little MeOH to afford the desired product (white solid, 0.029 g, 31%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=5.37 min, [M+H]+ m/z 364.1; 1H NMR (300 MHz, DMSO) d 9.47-9.39 (m, 1H), 8.68 (dd, J=8.3, 2.3, 1H), 8.23-8.10 (m, 2H), 7.60 (dd, J=8.3, 2.3, 1H), 7.51 (d, J=2.1, 1H), 7.17 (d, J=8.5, 1H), 3.91 (s, 3H), 3.87 (s, 3H);
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[N:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[N:13]([CH3:14])[CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Clc1cc(-c2ncc[nH]2)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1ccnc1-c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 2,4-Dichloro-6-(1-dimethylsulfamoylimidazole-2-yl)pyrimidine 83 (246 mg, 0.76 mmol) in 10 mL of 1.5 N HCl was refluxed for 1 h. After cooling to RT, the pH was adjusted to 8.5 with aq NaHCO3 and the product was extracted into CH2Cl2. After drying the CH2Cl2 layer was evaporated to give 110 mg of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine. A mixture of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine (121 mg, 0.56 mmol), K2CO3 (100 mg, 0.72 mmol) and CH3I (2.280 g, 1 mL, 16 mmol) in 15 mL of dry acetone was refluxed for 48 h. After cooling to RT, the solvent was evaporated and the residue was partitioned between water and CH2Cl2. The CH2Cl2 layer was washed successively with water and brine, and then the solvent was evaporated to give 75 mg of 2,4-dichloro-6-(1-methylimidazole-2-yl)pyrimidine 86.
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[P:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:38])[CH:5]1[CH:39]([OH:41])[CH3:40])[CH:2]=[CH2:3].[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl>[CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])=[P:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:38])[CH:5]1[CH:39]([O:41][C:42](=[O:44])[CH3:43])[CH3:40])[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC1C(C(C)O)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C=CCC1C(C(C)OC(C)=O)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of one cis and two trans-isomers of 4-allyl-3-(1-hydroxyethyl)-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one (5.0 g) in dry dichloromethane (150 cm3) was treated with 4-N,N-dimethylaminopyridine (1.22 g) followed by acetic anhydride (2.27 g) and the solution was stirred overnight at room temperature. The solution was evaporated under reduced pressure and the residue was chromatographed using high performance liquid chromatography, eluting with a 6:4 ethyl acetate/60°-80° petroleum ether mixture. This gave one cis and two trans-isomers of 4-allyl-3-(1-acetoxyethyl)-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one. The yields were the cis isomer (1.10 g, 21%) one trans isomer (0.28 g, 5%) and the other trans isomer (1.23 g, 23%). The cis-isomer crystallised (m.p. 156°-160° decomp). The infra-red spectra of all three isomers were identical; νmax (CHCl3) 3000, 1730, 1635 and 1610 cm-1.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH:38]1[O:42][C:41](=[O:43])[NH:40][CH2:39]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][CH:38]3[O:42][C:41](=[O:43])[NH:40][CH2:39]3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C1NCC(CCl)O1
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(CC2CNC(=O)O2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=599.0 (M+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 5-chloromethyl-2-oxazolidinone.