Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:5]([C:50]([O:52]CC)=[O:51])=[CH:4][N:3]=1.O.[OH-].[Li+].[ClH:58]>CO.C1COCC1.O>[ClH:58].[CH3:1][C:2]1[N:7]=[C:6]([N:8]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:5]([C:50]([OH:52])=[O:51])=[CH:4][N:3]=1
Reactant: CCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nc(C)ncc1C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nc(C)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 1B (0.6 g, 0.842 mmole) was dissolved in 4 ml of methanol and 6 ml of THF. A solution of 180 mg of lithium hydroxide monohydrate in 1.5 ml of water was added and the mixture was refluxed for 5 hours. After cooling, 1 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated under vacuum and 2 ml of water and 3 ml of ether was added to the residue. An oil which was insoluble in both layers formed. The oil was separated and crystallized from acetonitrile to provide 0.289 g of the desired product. M.p. 155°-158° C. 1H NMR (CD3OD) δ0.95 (t, 3H, J=7 Hz), 1.30 (m, 2H), 1.69 (m, 2H), 2.60 (s, 3H), 3.70 (m, 2H), 5.08 (m, 2H), 7.10 (d, 2H), 7.20 (s, 2H), 7.55 (d, 2H), 7.5-7.7 (m, 4H), 8.55 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66])=[CH:59][CH:58]=1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:56][C:57]2[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66])=[CH:61][CH:62]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80.6 mg, 0.172 mmol) in dichloromethane (3 ml) were added DIPEA (89.0 mg, 0.685 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (106 mg, 0.437 mmol). The mixture was stirred for 20 mins under argon before methyl 3-(4-aminophenyl)propanoate (33.4 mg, 0.186 mmol) was added. After 2 hrs, the reaction mixture was diluted with dichloromethane, washed with sat. NaHCO3, water and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral methyl 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoate (104.2 mg, 96%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 628.19. found: 628.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]1)=O)[O:7]2.FC1C=CC=C2C=1CCC(C(O)=O)O2.C(N1CCNCC1)C1C=CC=CC=1>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH2:19]1)[O:7]2
Reactant: O=C(C1CCc2c(F)cccc2O1)N1CCN(Cc2ccccc2)CC1
Agent: O=C(O)C1CCc2c(F)cccc2O1
Agent: c1ccc(CN2CCNCC2)cc1
Product: Fc1cccc2c1CCC(CN1CCN(Cc3ccccc3)CC1)O2

Procedure:
By carrying out the preparation as in Example 1, but using, at the start, 1-[(5-fluorochroman-2-yl) carbonyl]-4-benzylpiperazine resulting from the condensation of 5-fluorochroman-2-carboxylic acid with N-benzylpiperazine, the title compound is obtained.
Reaction SMILES: CS([C:4]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N+:21]3([O-])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[N:5]=1)=O.[CH:28]([NH2:31])([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C.S([O-])(O)=O.[Na+].N>O.CC(N(C)C)=O>[O:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:6]3[N:5]=[C:4]([NH:31][CH:28]([CH3:30])[CH3:29])[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=3)=[CH:15][CH:16]=2)[CH2:22][CH2:23]1
Reactant: CS(=O)c1nc(Nc2ccc(C[N+]3([O-])CCOCC3)cc2)ncc1C(N)=O
Reactant: CC(C)N
Agent: N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc(Nc2ccc(CN3CCOCC3)cc2)ncc1C(N)=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 450 mg of 4-methylsulfinyl-2-({4-[(N-oxidomorpholin -4-yl)methyl]phenyl}amino)pyrimidine-5-carboxamide, 0.29 ml of isopropylamine, 0.24 ml of diisopropylethylamine and 5 ml of DMA was stirred at 80° C. for 3 hours. The reaction mixture was cooled down to room temperature, mixed with 8 ml of 5% sodium hydrogen sulfite, followed by stirring for 1 hour. The reaction mixture was adjusted to pH 9 by adding 0.5 ml of concentrated aqueous ammonia, diluted with water and then extracted with chloroform. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol:aqueous ammonia), and the resulting pale brown oil was crystallized from ethyl acetate to obtain 50 mg of 2-{[4-(morpholinomethyl)phenyl]amino}-4-(2-propylamino)pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[O:5]1.[CH2:19](Cl)[O:20][CH3:21].O>CN(C=O)C>[CH3:19][O:20][CH2:21][O:17][C:14]1[CH:15]=[CH:16][C:11]([B:6]2[O:5][C:4]([CH3:18])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 0.17 h

Procedure:
NaH (60% in oil, 4.00 g) was added portionwise at 0° C. to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (11.00 g) in DMF (125 mL). After stirring for 10 min, MOMCl (7.60 mL) was added dropwise, and the mixture was stirred for 1 h. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (8.86 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH2:13][C:12]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:29][CH2:30][CH2:31][NH2:32].N1C(C)=CC=CC=1C>C(O)(C)C>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([C:12]3[NH:32][CH2:31][CH2:30][CH2:29][C:13]=3[C:14](=[O:23])[N:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Reactant: NCCCBr
Agent: Br
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: O=C1C2=C(NCCC2)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Temperature: 80 °C

Procedure:
To a solution of 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione (Intermediate 1A.4-1, 300 mg, 0.85 mmol) in isopropanol (4.3 ml) were added 3-bromopropylamine hydrobromide (205 mg, 0.94 mmol) and 2,6-lutidine (0.22 ml, 1.87 mmol). The reaction vessel was sealed and heated at 80° C. for 3 days. The reaction was concentrated in vacuo and partitioned between dichloromethane and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-5% methanol (10% NH4OH)/dichloromethane) to yield 1-benzyl-6′-(3-fluorophenyl)-1′,2′,3′,4′-tetrahydrospiro[piperidine-4,7′-pyrrolo[3,4-b]pyridin]-5′(6′H)-one. LCMS (M+H) 392.1. 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 6H), 7.03 (td, J=8.2, 2.0 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.92 (dt, J=9.9, 2.1 Hz, 1H), 3.46 (s, 2H), 3.33 (m, 2H), 2.52 (t, J=6.1 Hz, 41H), 2.33 (t, J=6.2 Hz, 2H), 2.06 (quint, J=6.9 Hz, 2H), 1.84 (m, 4H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[N+:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[C:19]([CH:5]([C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[Cl:2])[N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:18]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: Clc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: Oc1c(C(c2ccccc2Cl)N2CCCCC2)cc(Cl)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(2-chloro-benzylidene)-piperidinium chloride and 4-chloro-1-naphthol.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].O>CCCCCC>[C:2]1([CH:1]([OH:8])[C:10]([F:12])([F:11])[F:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 88 %

Procedure:
Benzaldehyde was reacted with trifluoromethyltrimethylsilane as in Example 10. After a reaction time of 5 hours, 20 ml of water were added, and the reaction mixture was heated briefly to 80° C. 50 ml of hexane were then added. The reaction mixture was then extracted twice with 100 ml of water, and the resultant organic phase was dried over Na2SO4. On distillation of the crude product, 15.4 g (88% yield) of 1-phenyl-2,2,2-trifluoroethanol (boiling point 68°-69° C./6 mbar) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14][NH:15][CH3:16])[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1.O1CCCC1.C(N(CC)CC)C.[CH2:29]([C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH2:38][CH3:39])[C:32]=1[C:40](=[O:44])[C:41](Cl)=[O:42])[CH3:30]>O>[CH2:29]([C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH2:38][CH3:39])[C:32]=1[C:40](=[O:44])[C:41]([N:15]([CH3:16])[N:14]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:42])[CH3:30]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Reactant: CNN=C(CS(C)(=O)=O)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(CS(C)(=O)=O)c1ccc(F)cc1
Yield: 60.8 %

Procedure:
To a 30 ml volume two-necked flask, 1-[1-(4-fluorophenyl)-2-methylsulfonylethylidene]-2-methylhydrazine (5-2-4) (0.90 g) and anhydrous tetrahydrofuran (5 ml) were added under a nitrogen atmosphere, and added triethylamine (0.37 g) under cooling. To the mixture, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a) (0.88 g) was added dropwise below 0° C., and stirred under ice-cooling for 2 hours. The reaction mixture was added to water, and extracted with tert-butyl methyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (tert-butyl methyl ether) to give 1.0 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-[1-(4-fluorophenyl)-2-methylsulfonylethylidene]-1-methylhydrazine ((4-64)-(1)-39).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([OH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH3:19]I.[H-].[Na+]>C1COCC1>[F:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][CH3:19])[CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1CF
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](CF)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl (2S,4R)-2-(fluoromethyl)-4-hydroxypyrrolidine-1-carboxylate (500 mg, 1.97 mmol) in THF (6.6 mL) at 0° C. was added methyl iodide (0.43 mL, 3.44 mmol) followed by sodium hydride (104 mg, 4.34 mmol). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice, and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl (2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidine-1-carboxylate. MS ESI calc'd. for C14H18FNO3 [M+H]+ 268. found 268.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[C:27]([C:28]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]=[C:9]3[O:8][CH:5]2[CH2:6][CH2:7][C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]2)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC1(C)CCC(Oc2nccc3c(N)cccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(Oc2nccc3c(NC(=O)c4c(Cl)ccc(CNC(=O)C(C)(C)C)c4F)cccc23)CC1
Yield: 33.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-((4,4-dimethylcyclohexyl)oxy)isoquinolin-5-amine (Intermediate-28, 70 mg, 0.25 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 89 mg, 0.31 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (97 mg, 0.75 mmol) in CH2Cl2 (3 mL) to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.89 (s, 1H), 8.19 (t, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.04 (d, J=5.7 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.48 (d, J=6.0 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 5.28 (m, 1H), 4.34 (d, J=5.4 Hz, 2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.53 (m, 2H), 1.34 (m, 2H), 1.15 (s, 9H), 1.00 (s, 3H), 0.97 (s, 3H); MS (m/z): 540.10 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][CH:3]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)ccc3N21
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)ccc3N21
Temperature: 90 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A mixture of (R)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #10, Step E, 5.0 g, 16.88 mmol), (2-fluorophenyl)boronic acid (3.54 g, 25.32 mmol), K2CO3 (4.67 g, 33.78 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.76 g, 3.37 mmol) in dioxane (60 mL) and water (10 mL) was stirred at 90° C. for 2 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give (R)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.5 g, 46%) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.51 (m, 1H), 7.43-7.13 (m, 6H), 4.83 (q, J=6.4 Hz, 1H), 4.69-4.60 (d, J=13.2 Hz, 2H), 1.33 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10](=[CH:14][O:15][CH2:16][CH3:17])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([O:25][CH2:26][CH3:27])=[CH:23][CH3:24])[CH3:20].CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:10]2[C@@H:14]([O:15][CH2:16][CH3:17])[C@H:23]([CH3:24])[C:22]([O:25][CH2:26][CH3:27])([O:21][CH2:19][CH3:20])[O:13][C:11]=2[CH3:12])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(Cl)cc1
Reactant: CC=C(OCC)OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCO[C@@H]1C(C(=O)Nc2ccc(Cl)cc2)=C(C)OC(OCC)(OCC)[C@H]1C
Temperature: 25 °C
Reaction time: 40 h
Yield: 31.1 %

Procedure:
N-(4'-Chlorophenyl)-2-ethoxymethylene-3-oxobutanamide (1.3 g) was stirred in toluene (10 ml) whilst 1,1-diethoxyprop-1-ene (2 g) was added dropwise. The mixture was stirred at room temperature for 40 hours and evaporated to dryness. The residual gum was purified by medium pressure liquid chromatography on K60 silica using ethyl acetate/petroleum ether b.p. 60°-80° C. 15/85 v/v as eluting solvent to give two stereoisomers. The first isomer after trituration with n-hexane gave trans-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (0.6 g), m.p. 104°-106° C. The n.m.r. spectrum (deuterochloroform) showed the --CH(OEt)-- signal at 4.0 ppm (doublet of quartets 1H, J=3 Hz and 1 Hz), consistent with the trans-configuration. The second isomer, after trituration with n-hexane, gave cis-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (0.1 g), m.p. 125°-7° C. The n.m.r. spectrum (deuterochloroform) showed the --CH(OEt)-- signal at 4.5 ppm (doublet of quartets, 1H, J=7 Hz and 1 Hz) consistent with the cis-configuration.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[Na+].[Na].F[C:13]1[C:18]([F:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1>CS(C)=O.O>[F:19][C:18]1[C:13]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:14][CH:15]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:17]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Hydroquinone (4.4 g, 0.04 mole) was dissolved in 65 ml of dimethylsulfoxide and powdered sodium hydroxide (1.4 g, 0.035 mole) was added in one portion and the mixture stirred under nitrogen atmosphere for 10 minutes to convert to the sodium salt. 2,3-Difluoro-5-(trifluoromethyl)pyridine (6.0 g, 0.033 mole) was then added and the mixture was stirred at 50° C. for 1.5 hours then warmed to 60° C. for a moment, let cool for 15 minutes and then poured into 500 ml of cold water. Additional sodium hydroxide (~3 g in water) was added to convert the desired product to its sodium salt. The insoluble bis-derivative was then removed by extraction with hexane. The clear aqueous phase was separated, cooled and acidified with concentrated hydrochloric acid. The solid which separated was collected on a filter, washed, dried on a vacuum funnel and taken up in hot hexane. After treating with decolorizing carbon, filtering, concentrating and cooling the white crystalline product separated. Yield: 2.6 g. M.P. 97.5-98.5.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[NH:14])=[CH:5][CH:4]=1.[C:15](=O)([O-])[OH:16].[Na+].Cl.O(N)C>CO>[CH3:15][O:16][N:14]=[C:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:6]1[CH:7]=[CH:8][C:3]([NH2:2])=[CH:4][CH:5]=1
Reactant: O=C([O-])O
Reactant: N=C1CCCN1c1ccc(N)cc1
Agent: CON
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C1CCCN1c1ccc(N)cc1
Temperature: 70 °C

Procedure:
2.68 g (12.7 mmol) of 1-(4-aminophenyl)pyrrolidin-2-ylideneamine, hydrochloride, are dissolved in 70 ml of methanol, 9.49 g (113 mmol) of sodium hydrogencarbonate and 4.06 g (48.6 mmol) of methoxylamine, hydrochloride, are added, and the mixture is heated at 70° C. for 48 hours. The reaction mixture is evaporated, and the residue is taken up in acetone. The insoluble components are filtered off, and the filtrate is evaporated. The residue is chromatographed on a silica-gel column with ethyl acetate as eluent, giving 1-(4-aminophenyl)pyrrolidin-2-one O-methyl oxime as a brownish solid; ESI 206.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:19]([CH:20]=O)[C:18]=1[OH:25])[CH:15]=[CH2:16]>>[CH2:14]([C:17]1[C:18]([OH:25])=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1)[CH:15]=[CH2:16]
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: C=CCc1cccc(C=O)c1O
Product: C=CCc1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(3-Allyl-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-allylsalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.58-2.64 (m, 4H), 3.38 (s, 2H), 3.58-3.63 (m, 4H), 3.89 (s, 2H), 5.06-5.15 (m, 2H), 5.39 (s, 1H), 5.97-6.06 (m, 1H), 6.73-6.77 (m, 1H), 6.85-6.89 (m, 1H), 6.99-7.08 (m, 1H), 7.84 (s, 1H), 10.65 (br s, 1H), 12.31 (br s, 1H). Mass spectrum (ES) MH+=327.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:40]([C:37]1[CH:36]=[CH:35][C:34]([CH:28]([O:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCCCCC(Br)c1ccc(CC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC(Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.1 %

Procedure:
A mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butyrate (176 mg), 1-(1-bromohexyl}-4-isobutylbenzene (223 mg) and potassium carbonate (207 mg) in N,N-dimethylformamide (4 ml) was stirred at room temperature for 6 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (3:1) to give ethyl 4-[3-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol-1-yl]-butyrate (279 mg) as an oil.