Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH2:5][NH:4][CH2:3]1.[CH3:6][N:7]([CH3:29])[C:8]1[N:28]=[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25](O)=[O:26])=[O:18])=[CH:15][N:10]2[N:9]=1>>[CH3:6][N:7]([CH3:29])[C:8]1[N:28]=[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25]([N:4]3[CH2:5][CH:2]([F:1])[CH2:3]3)=[O:26])=[O:18])=[CH:15][N:10]2[N:9]=1
Reactant: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Reactant: FC1CNC1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)cn2n1

Procedure:
Using 3-fluoro-azetidine and 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Light yellow solid (160 mg, 68%). MS: m/z=387 (M+H+).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][CH:29]([N:31]1[N:35]=[N:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[N:32]1)[CH3:30])(C(C)(C)C)(C)C>C1COCC1>[Cl:42][C:38]1[CH:37]=[C:36]([C:33]2[N:34]=[N:35][N:31]([CH:29]([CH3:30])[CH2:28][CH2:27][OH:26])[N:32]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(CCO[Si](C)(C)C(C)(C)C)n1nnc(-c2cccc(Cl)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(CCO)n1nnc(-c2cccc(Cl)c2)n1
Yield: 91 %

Procedure:
TBAF was added to a solution of 2-(3-{[tert-butyl(dimethyl)silyl]oxy}-1-methylpropyl)-5-(3-chlorophenyl)-2H-tetrazole in THF (25 mL). The mixture was concentrated after 4 h and the crude was purified by flash column chromatography (SiO2, Heptane-EtOAc 1:1) to give 0.90 g (91%) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)CCl)[CH:2]=[CH2:3].[OH:13][C:14]1C=C(C=CC=1)C=O.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:7][C:6]=1[CH:14]=[O:13])[CH:2]=[CH2:3]
Reactant: O=Cc1cccc(O)c1
Reactant: C=CCOc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Product: C=CCOc1ccccc1C=O
Reaction time: 18 h

Procedure:
c:- (A) 3-Allyloxybenzyl chloride was obtained as follows: A mixture of 3-hydroxybenzaldehyde (6 g), allyl bromide (6.25 g), and potassium carbonate (8.82 g) in DENT (30 ml) was stirred for 18 hours, poured into water (100 ml) and extracted with diethyl ether (3×150 ml). The combined organic extracts were washed with water (2×150 ml) and brine (2×150 ml), dried (magnesium sulphate) filtered and evaporated to give 2-allyloxybenzaldehyde (7.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[Br:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O.O>[Br:9][C:3]1[C:2]([F:1])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:4]=1[F:8]
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(F)c1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of 2,6-difluorobromobenzene (125.5 g, 650 mmol) in 98% sulphuric acid (250 ml) was cooled in an ice-water bath and then treated with a 1:1 mixture of 98% sulphuric acid and fuming nitric acid (100 ml) added at such a rate that the internal temperature never exceeded 35° C. Once addition was complete the reaction was stirred at ambient temperature for 3 h then poured onto ice. This mixture was diluted with water (final volume 5 l), the resulting solid collected by filtration, washed with water, then dried under vacuum over phosphorus pentoxide, to afford 2-bromo-1,3-difluoro-4-nitrobenzene as a cream-coloured solid (145 g, 94%): δH (360 MHz, CDCl3) 7.10-7.15 (1H, m), 8.09-8.16 (1H, m).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:38])[NH:10][CH2:11][CH2:12][O:13][C:14](=[O:37])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:17]=2[CH3:36])[CH:4]=1.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(#N)C>[CH3:2][N:3]1[CH:8]=[CH:7][CH2:6][C:5]([C:9](=[O:38])[NH:10][CH2:11][CH2:12][O:13][C:14](=[O:37])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:17]=2[CH3:36])=[CH:4]1
Reactant: COc1ccc2c(c1)c(CC(=O)OCCNC(=O)c1ccc[n+](C)c1)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)OCCNC(=O)C1=CN(C)C=CC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
The indomethacin quaternary salt prepared in Example 95 (140 mg, 0.22 mmol), was dissolved in a minimum amount of water:acetonitrile (8:2). The water had been bubbled with nitrogen for 20 minutes prior to its use. Sodium bicarbonate (91 mg, 1.1 mmol) and sodium dithionite (110 mg, 0.65 mmol) were added to the solution while stirring at 0° C. The solution was then allowed to warm to room temperature. The reaction was continued for about 1 hour. Some of the product had precipitated during the reaction. This was dissolved in ethyl ether. The water layer was extracted several times with ether until no more yellow color transferred to the organic layer. The ether portions were combined and dried with magnesium sulfate, filtered and the ether was removed under reduced pressure. The resulting oil was dissolved in acetone and the solvent was removed (2×10 mL) under reduced pressure to form a dry foam. The final product weighed 92 mg. The yield was 82%; mp 60°-65° C. The product had the formula: ##STR126## as confirmed by UV, NMR and elemental analyses.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=O)[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:75][CH:76]([CH3:79])[CH2:77][NH2:78]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([NH:78][CH2:77][CH:76]([OH:75])[CH3:79])=[O:40])[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(O)CN
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of rac {1-[(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-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54 mmol) were added followed by 2-hydroxy-2-methyl-ethylamine (Aldrich, 20 mg, 0.27 mmol) and the mixture was stirred at rt for hers. The reaction was quenched with water and the mixture was extracted with methylene chloride (3×10 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 48 mg.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[CH3:43][O:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:25]=[C:26]([CH3:39])[C:27]([OH:31])=[C:28]([CH3:30])[CH:29]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:49]3[CH:48]=[CH:47][CH:46]=[C:45]([O:44][CH3:43])[CH:50]=3)[C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40]
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(N2C(=O)C(c3cc(C)c(O)c(C)c3)(c3cc(C)c(O)c(C)c3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.680 g, 1.13 mmol), 3-methoxyphenylboronic acid (0.343 g, 2.26 mmol), copper (II) acetate (0.205 g, 1.13 mmol), triethylamine (0.32 mL, 2.26 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite, and elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.417 g, 0.589 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.47 mL). Stir for 1 h. Add 1N aqueous HCl(10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.155 g (29%) of the title compound: mass spectrum (FAB): m/z=480(M+1); 1H NMR(DMSO-d6): δ8.23 (s, 2H), 7.46 (t, 1H), 7.31 (d, 1H), 7.23 (td, 1H), 7.10 (td, 1H), 7.05-7.02 (m, 1H), 6.98-6.95 (m, 2H), 6.81 (d, 1H), 6.73 (s, 4H), 3.79 (s, 3H), 2.07 (s, 12H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:48]=[CH:47][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[C:18]([C:23]([NH:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[O:24])[CH:19]=[CH:20][CH:21]=3)[C:16]([C:36](=[O:46])[C:37](=[O:45])[NH:38][C:39]3[CH2:40][O:41][C:42](=[O:44])[CH:43]=3)=[CH:15]2)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][NH:25][C:23]([C:18]1[C:17]2[C:16]([C:36](=[O:46])[C:37](=[O:45])[NH:38][C:39]3[CH2:40][O:41][C:42](=[O:44])[CH:43]=3)=[CH:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:48][CH:47]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cccc2c1c(C(=O)C(=O)NC1=CC(=O)OC1)cn2Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)c1cccc2c1c(C(=O)C(=O)NC1=CC(=O)OC1)cn2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
Trifluoroacetic acid (0.1 ml) is added to a stirred solution of tert-butyl 2-{[(1-(4-chlorobenzyl)-3-{oxo[(5-oxo-2,5-dihydro-3-furanyl)amino]acetyl}-1H-indol-4-yl)carbonyl]amino}ethylcarbamate of Example 9 (50 mg) in CH2Cl2 (1 ml). After stirring at room temperature for 3 h the solvent is removed by roto-evaporation and the residue is taken up with water, adjusting the pH at about 8-9 with 1N NaOH. The precipitate is collected by filtration and thoroughly washed to give N-(2-aminoethyl)-1-(4-chlorobenzyl)-3-{oxo[(5-oxo-2,5-dihydro-3-furanyl)amino]acetyl}-1H-indole-4-carboxamide (25 mg).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].Cl[CH2:7][C:8]1[CH:30]=[CH:29][C:11]([CH2:12][O:13][C:14]2[CH:15]=[C:16]([C:21]3([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:17]=[C:18]([F:20])[CH:19]=2)=[CH:10][CH:9]=1>>[F:20][C:18]1[CH:17]=[C:16]([C:21]2([O:27][CH3:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:15]=[C:14]([CH:19]=1)[O:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[CH:30][CH:29]=1
Reactant: CC(C)=NO
Reactant: COC1(c2cc(F)cc(OCc3ccc(CCl)cc3)c2)CCOCC1
Product: COC1(c2cc(F)cc(OCc3ccc(CON=C(C)C)cc3)c2)CCOCC1
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 1, acetone oxime was reacted with 4-[3-(4-chloromethylbenzyloxy)-5-fluorophenyl]-4-methoxytetrahydropyran to give acetone O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenoxymethyl]benzyl}oxime as a gum in 72% yield.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]([CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])[C:6](=[O:15])[CH:5]=1.[CH3:16]I>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][N:7]([CH2:10][CH:11]([CH3:14])[CH2:12][O:13][CH3:16])[C:6](=[O:15])[CH:5]=1
Reactant: CI
Reactant: CC(CO)Cn1ccc(Br)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)Cn1ccc(Br)cc1=O

Procedure:
NaH (60% in mineral oil, 57 mg) was added to a solution of 4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridin-2-one (0.53 g) in dimethylformamide (6 mL) chilled in an ice bath. After stirring the solution with cooling for 0.5 h, methyl iodide (110 μL) was added. The cooling bath was removed and the solution was stirred at room temperature overnight. Then, the solution was concentrated under reduced pressure and the residue was diluted with water. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (acetonitrile/water) to give the title compound as an oil. Yield: 70 mg (30% of theory); Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)#[CH:26].CN(C=O)C>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.[Cu]I.CCN(CC)CC>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:26]#[C:25][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(C=O)cc1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(C#Cc4ccc(C=O)cc4)n[nH]c3c1)C(=O)N2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 12.2 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (862 mg, 2 mmol), 4-ethynylbenzaldehyde (286 mg, 2.2 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol, 2 mmol %) and CuI (15.3 mg, 0.08 mmol, 4 mmol %) in a 50 mL of flask was added DMF (6 mL) and Et3N (10 mL). The resulting mixture was stirred at 100° C. (oil temp.) for 90 min. After removal of Et3N, H2O (20 mL) was added and the precipiates were collected by suction filtration. Crystals formed in the mother liquor were collected and dried to give the title compound (106 mg) as a yellow solid. The remaining residue was combined and purified by flash chromatography (gradient: EtOAc.hex 0 to 50% to 100%), followed by trituration with H2O to give the title compound (440 mg) as a yellow solid. Total 546 mg (yield 63%). 1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 10.44 (s, 1H), 10.05 (s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 3.29 (s, 3H), 3.22 (t, J=8.4 Hz, 1H), 2.40-2.33 (m, 1H), 1.99 (dd, J=8.8 Hz, 4.8 Hz, 1H); MS ESI 434.2 [M+H]+, calcd for [C27H19N3O3+H]+ 434.1.
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:13]=O)[CH2:2][CH3:3].[CH3:15][NH2:16].[BH4-].[Na+]>CO>[CH3:15][NH:16][CH2:13][C:5]1[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CN
Reactant: CCCc1c(C=O)oc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(CNC)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To 3-propyl-benzofuran-2-carbaldehyde (1.36 g, 72.2 mmol) was added methylamine (29 mL of a 2 M solution in methanol, 58 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. The mixture was concentrated under reduced pressure. The residue was taken up in ethanol (20 mL) and the solution was cooled in an ice-bath. NaBH4 (490 mg, 10.8 mmol) was added in one portion. The mixture was concentrated under reduced pressure and the residue taken up in 1 M NaOH. The mixture was extracted with Et2O (3×). The combined organics were washed, dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (1.68 g, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.54 (m, 1H), 7.49 (dd, J=7.2, 1.2 Hz, 1H), 7.25-7.20 (m, 2H), 3.76 (s, 2H), 2.65 (t, J=7.2 Hz, 2H), 2.30 (d, J=9.3 Hz, 3H), 1.99 (s, 1H), 1.66-1.58 (m, 2H), 0.94-0.86 (m, 3H); ESI MS m/z 204 (M+H)+.
Reaction SMILES: [C@H:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]([CH3:14])[C:12](=[O:15])[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:9]=1.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][N:13]1[C:12](=[O:15])[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:9]=[C:8]1[N:2]1[CH2:3][CH:4]2[CH2:7][C@H:1]1[CH2:6][N:5]2[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cn1c(N2CC3C[C@H]2CN3)nc(-c2ccncc2)cc1=O
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cn1c(N2CC3C[C@H]2CN3c2cccnc2)nc(-c2ccncc2)cc1=O
Yield: 46.5 %

Procedure:
A mixture containing 0.2 g (0.71 mmol) of (1S)-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one, 3.335 g (2.12 mmol) of 3-bromopyridine, 0.322 g (0.99 mmol) of cesium carbonate, 18 mg (0.028 mmol) of (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 6 mg (0.028 mmol) of palladium(II) acetate in 100 ml of anhydrous tetrahydrofuran under argon atmosphere is stirred under reflux for 18 h. The mixture is filtered. Water is added to the filtrate and the resulting solution extracted with chloroform. The combined extracts are washed with saturated aqueous ammonium chloride and evaporated. The crude product is purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 95/5 to give 119 mg of pure compound as a solid.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH2:18][CH:17]([C:32]([O:34]C)=[O:33])[CH2:16]2)=[O:14])[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1>CO>[N:7]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=3)[CH2:18][CH:17]([C:32]([OH:34])=[O:33])[CH2:16]2)=[O:14])[CH2:8][CH2:9][S:10][CH2:11][CH2:12]1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
7.74 g (69.0 mmol) of potassium tert-butoxide were added at RT to a solution of 2.97 g (6.90 mmol) of the compound from Example 44A in methanol (83 ml). The mixture was stirred at 60° C. overnight. For workup, the methanol was removed under reduced pressure, the residue was admixed with water and the mixture was acidified (pH 1) with aqueous 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried with magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 2.61 g (76% of theory, purity 84%)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[C:11]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH3:26])[CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=2[O:2]1.COC(=O)CC(=O)C1C=CC=C(OCCC)C=1.C1OC2C=CC(C=O)=CC=2O1>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](/[CH:10]=[C:11](/[C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH3:26])[CH:18]=3)\[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: CCCOc1cccc(C(=O)C(=Cc2ccc3c(c2)OCO3)C(=O)OC)c1
Agent: CCCOc1cccc(C(=O)CC(=O)OC)c1
Agent: O=Cc1ccc2c(c1)OCO2
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCCOc1cccc(C(=O)/C(=C/c2ccc3c(c2)OCO3)C(=O)OC)c1
Yield: 48 %

Procedure:
Methyl 3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)benzoyl]propenoate. To a solution of methyl-3-(Prop-1-yloxy)benzoylacetate (10 g, 4.2 mmol) in benzene (50 mL) was added 3,4-methylenedioxybenzaldehyde (6.36 g, 4.2 mmol) followed by piperidine (0.42 mL, 0.42 mmol) and glacial acetic acid (8 drops approx.). The mixture was refluxed for 2 h. and the volatiles removed in vacuo to give methyl (Z)-3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)benzoyl]propenoate (7.4 g, 48%) as an off white solid after trituration with methanol (m.p. 122°-123° C.). Anal. Calc. for C21H20O6 : C, 68.47; H, 5.47. Found: C, 68.81; H, 5.49.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[OH:14].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[Si:24]([O:14][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:2]=1[F:1])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)c1ccc(F)c(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 48 h
Yield: 66.8 %

Procedure:
To a solution of 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide (1.90 g, 9.55 mmol) in DMF (8 mL) was added imidazole (740 mg, 10.8 mmol) and TBDMSCl (1.62 g, 10.8 mmol) at room temperature. The reaction mixture was stirred for 48 h and quenched with saturated NaHCO3. The solution was extracted with ether (3×) and the combined ether portions washed with LiCl (10%), dried over Na2SO4, filtered and concentrated. The resulted colorless oil was purified by ISCO chromatography (120 g column) using hexanes/EtOAc (0-100% over 30 min) to give 3-(tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide (RT=10-12 minutes) as a colorless oil (2.00 g, 67% yield). LCMS: RT=2.06 min [M+H] 314.22 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.26 ppm, 2H, m; 7.02 ppm, 1H, m; 3.50 ppm, 3H, s; 3.31 ppm, 3H, s; 0.97 ppm, 9H, s, 0.16 ppm, 6H, s.