Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:24]([C:28]1[Se:32][C:31]([N+:33]([O-:35])=[O:34])=[C:30]([NH2:36])[CH:29]=1)([CH3:27])([CH3:26])[CH3:25].CN(C=O)C.[OH-].[Na+]>>[C:24]([C:28]1[Se:32][C:31]([N+:33]([O-:35])=[O:34])=[C:30]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cc(N)c([N+](=O)[O-])[se]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cc(C(C)(C)C)[se]c3[N+](=O)[O-])c2cc1OCCCN1CCOCC1

Procedure:
The reaction of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline with 5-(tert-butyl)-2-nitroselenophene-3-ylamine in the presence of DMF/NaOH as described in Example 1 gave title compound as a yellow color solid, mp 172-174° C. IR (KBr) vmax 3431, 2942, 2860, 1616, 1436, 1309, 1281, 1197, 1121, 1025, 863 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.67 (1H, s, exchangeable with D2O), 8.90 (1H, s), 8.83 (1H, s), 7.30 (1H, s), 7.25 (1H, s), 4.30 (2H, t, J=6.2 Hz), 4.03 (3H, s), 3.73 (4H, t, J=4.4 Hz), 2.61 (2H, t, J=7.2 Hz), 2.51 (4H, br s), 2.14 (2H, pentet, J=6.6 Hz), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3): δ 176.6, 156.0, 153.4, 152.8, 150.3, 148.4, 144.9, 130.1, 120.1, 109.9, 107.8, 99.8, 67.5, 67.0, 56.3, 55.4, 53.8, 37.9, 32.0, 26.1; LC-MS (positive ion mode): m/z 548, 550 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[N:4][CH:3]=1.C(#N)C.CN(C=O)C.C(Cl)(=O)C([Cl:24])=O.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1cc[nH]c2cc(Br)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Clc1ccnc2cc(Br)cnc12
Temperature: 95 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. A 350 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione (21.6 g, 150.0 mmol) and triethyl orthoformate (150 mL, 150.0 mmol). This was heated to 100° C., and stirred at this temperature for 2 hours. Reaction then cooled to 30° C. and 55-bromopyridin-3-amine (25.95 g, 150.0 mmol) added portion-wise. Reaction vessel resealed and mixture stirred at 100° C. for 3 hours. LC/MS shows completion. Reaction mixture was cooled to room temperature, diluted with hexane, filtered, and air dried to yield 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (41.5 g, 85% yield) as a yellow solid. MS [M+H]=327.0. Calc'd for C12H11BrN2O4=327.1. 2) 7-bromo-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.5 g, 32.1 mmol) and diphenyl ether (84.5 mL, 32.1 mmol). This was heated to 250° C. in heating mantle and allowed to stay at this temperature for 1 hour. Reaction mixture was cooled to room temperature and diluted with 300 mL of Hexanes. This was heated to 60° C. and triturated in this system for 3 hrs to afford 7-bromo-1,5-naphthyridin-4(1H)-one (6.05 g, 84% yield) as a crude brown solid. This was used without further purification. MS[M+H]=227.0. Calc'd for C8H5BrN2O=225.0. 3) 3-bromo-8-chloro-1,5-naphthyridine. 7-bromo-1,5-naphthyridin-4(1H)-one (23.8 g, 105.8 mmol), acetonitrile (192 mL, 105.8 mmol), and DMF (2.05 mL, 26.5 mmol) were placed in a 3-necked round bottom flask set up with a reflux condenser. Argon bubbled through. Reaction mixture brought to reflux (˜95° C.). Oxalyl chloride (28.7 ml, 328.1 mmol) was added dropwise via addition funnel over 40 minutes and reaction allowed to stir at this temperature for 16 hrs. Reaction mixture cooled to 0° C. and basified to pH ˜8 with aqueous sodium bicarbonate solution. Product extracted with DCM (500 mL) three times. Organic layers combined, dried over sodium sulfate and concentrated to afford brown solid. This was purified by ISCO silica gel chromatography to afford 3-bromo-8-chloro-1,5-naphthyridine (3.6 g, 14% yield) as fluffy tan solid. MS[M+H]=245.0@. Calc'd for C8H4BrClN2=243.5.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([OH:9])[C@H:3]1[OH:10].Cl.N[C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1.CCN(CC)CC>C(O)(C)C>[Cl:20][C:15]1[N:14]=[CH:13][N:18]=[C:17]([NH:1][C@@H:2]2[CH2:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([OH:9])[C@H:3]2[OH:10])[CH:16]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Temperature: 90 °C
Yield: 99 %

Procedure:
To a solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol.HCl (1.00 g, 5.44 mmol) and 2-amino-4,6-dichloropyrimidine (0.982 g, 5.99 mmol) in isopropyl alcohol (8 mL) was added Et3N (1.90 mL, 13.6 mmol). The reaction was heated to 90° C. for 1 h in an oil bath then cooled, filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash chromatography (20 to 50% MeOH/CH2Cl2) to afford the title compound as an off-white solid (2.025 g, >99%). LC/MS: Rt=0.81 min ES+ 260 (FA standard).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20](F)=[C:19]([C:24]#[N:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[C:24]([C:19]1[CH:18]=[C:17]([S:14]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[C:6]2[CH3:26])(=[O:16])=[O:15])[CH:22]=[CH:21][C:20]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)#[N:25]
Reactant: C1COCCN1
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(C#N)c2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(N2CCOCC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Example 54a) (60.7 mg, 0.157 mmol) in acetonitrile (3 ml) is added potassium carbonate (43.3 mg, 0.314 mmol) followed by morpholine (27.6 μl, 0.314 mmol). The reaction mixture is stirred at room temperature for 2 hours and then filtered and concentrated in vacuo to yield the titled compound as an orange oil which is used crude in the next step. (MH+ 455).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Cl)[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1)(=[O:27])=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[N:30][CH:31]=2)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(NS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (103 mg, 0.32 mmol) and 6-(methylsulfonamido)nicotinic acid, intermediate 15, (84 mg, 0.39 mmol) in CH2Cl2 (2 mL) and DMF (2 mL) is added TEA (0.18 mL, 1.29 mmol) and HATU (159 mg, 0.42 mmol) at room temperature. The crude is stirred at room temperature for 2 hrs. The crude is quenched with saturated NaHCO3, diluted in EtOAc. The organic layer is washed with six times with water, brine, dried over MgSO4, filtered, and concentrated. The crude is purified via RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-ethyl 4-(biphenyl-4-yl)-3-(6-(methylsulfonamido)nicotinamido)butanoate as a white solid (4.1 mg). HPLC retention time=1.61 minutes (condition A); MS (m+1)=482.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (t, J=7.2 Hz, 3 H), 2.56 (t, J=4.8 Hz, 2 H), 2.84-2.92 (m, 1 H), 3.05 (dd, J=13.6, 6.1 Hz, 1 H), 3.16 (s, 3 H), 4.08-4.18 (m, 2 H), 4.57-4.71 (m, 1 H), 7.03 (d, J=8.3 Hz, 1 H), 7.10 (d, J=8.3 Hz, 1 H), 7.22 (d, J=8.3 Hz, 2 H), 7.26-7.31 (m, 1 H), 7.33-7.40 (m, 2 H), 7.44-7.54 (m, 5 H), 7.98 (dd, J=8.8, 2.3 Hz, 1 H), 8.52 (s, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].CN(C)C=O.[H-].[Na+]>O>[CH3:12][C:11]1[O:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH2:6][O:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[CH2:2][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1ccccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
To a mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.04 g), methyl 2-(2-hydroxyphenyl)acetate (0.50 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.13 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.71 g, 53%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:5].Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[CH3:1])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccccc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccccc3C)cc2)cc1
Yield: 20 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-(2-methyl-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(2-methyl-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 20% of theory; m.p. <20° C
Reaction SMILES: [CH2:1]1[S:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C([Li])CCC.[CH3:13][C:14]1[CH:15]=[C:16]([C:20]2[O:21][C:22]([CH3:36])=[C:23]([CH2:25][O:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([CH2:33][CH:34]=[O:35])[CH2:28]3)[N:24]=2)[CH:17]=[CH:18][CH:19]=1.Cl>O1CCCC1.CCCCCC>[OH:35][CH:34]([CH:1]1[S:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH2:33][C@H:29]1[CH2:30][CH2:31][CH2:32][C@@H:27]([O:26][CH2:25][C:23]2[N:24]=[C:20]([C:16]3[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][CH:17]=3)[O:21][C:22]=2[CH3:36])[CH2:28]1
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC=O)C3)c(C)o2)c1
Reactant: O=C1CSC(=O)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC(O)C4SC(=O)NC4=O)C3)c(C)o2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
214 mg of thiazolidinedione are dissolved in 20 ml of tetrahydrofuran and, at −78° C., 1.4 ml of a 2.7 M solution of n-butyllithium in n-hexane are added. The mixture is stirred at −78° C. for 30 minutes, and 500 mg of {cis-3-[2-(3-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}acetaldehyde, dissolved in 10 ml of tetrahydrofuran, are then added. After 30 minutes of stirring at −78° C., the mixture is allowed to warm to room temperature. 20 ml of 1N hydrochloric acid are added and the mixture is extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 420 mg of 5-{1-hydroxy-2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione as a white solid. C23H28N2O5S (444.45), MS (ESI): 445 (M+H+)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Yield: 93.4 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl piperidin-3-ylcarbamate (695 mg, 3.5 mmol) followed by reduction to afford the desired product (847 mg, 93%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([O:18]CC)(=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+]>C(O)C>[CH2:15]([O:14][C:12](/[C:11](=[CH:7]/[C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)/[CH2:10][C:9]([OH:18])=[O:17])=[O:13])[CH3:16]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(C=O)o1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=C/c1ccc(C)o1)CC(=O)O
Temperature: 25 °C
Yield: 5.4 %

Procedure:
To a vigorously stirred solution of 5-methyl-2-furaldehyde (264 mL, 2650 mmol) and diethyl succinate (840 mL, 5050 mmol) in ethanol (1.820 L) at room temperature was added sodium ethoxide (0.93 L of a 21 weight % solution in ethanol) in one portion. The reaction mixture was then heated at reflux for 13 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was partitioned between ethyl acetate (1 L) and hydrochloric acid (1 L of a 2M aqueous solution). After separation, the aqueous layer was extracted with ethyl acetate (2×1 L). The combined organic extracts were then extracted with sodium hydrogen carbonate (2×1 L of a saturated aqueous solution). These aqueous extracts were combined and adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2×1 L). These organic extracts were combined and concentrated in vacuo to give desired (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid (I-1a: 34.34 g, 5%). The original organic extract was extracted with sodium hydroxide (2 L of a 2M aqueous solution). This aqueous extract was adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2×1 L). These organic extracts were combined and concentrated in vacuo to give additional desired materials (395.2 gram, 63%) as red liquid. 1H NMR (CDCl3, 300 MHz) δ ppm 7.48 (s, 1H), 6.57 (d, 1H), 6.09 (d, 1H), 4.24 (q, 2H), 3.87 (s, 2H), 2.32 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:30])=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2F)nc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2F)nc1
Yield: 163.4 %

Procedure:
Using a method similar to Example 371, (±)-6-[2-fluoro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile (compound of example 375, step 2) (0.225 g, 0.603 mmol), potassium carbonate (0.0425 g, 0.308 mmol), and 30% hydrogen peroxide solution (aq) (0.203 mL, 1.79 mmol) in dimethylsulfoxide (6.0 mL) provide 0.197 g (83%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C23H23FN3O2 392.1774, found 392.1760; 1H NMR (methanol-d4): 8.62 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=2.9, 8.8 Hz), 7.41-7.25 (m, 7H), 7.25-7.19 (m, 1H), 7.15 (d, 1H, J=8.3 Hz), 3.83 (d, 1H, J=13.2 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.51-3.41 (m, 1H), 3.18 (d, 1H, J=9.3 Hz), 3.02-2.94 (m, 1H), 2.86 (td, 1H, J=5.9, 8.8 Hz), 2.63 (t, 1H, J=8.8 Hz), 2.46-2.35 (m, 1H), 2.05-1.94 (m, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH2:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[CH3:20].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:7]([O:8][C:9]([N:21]([CH2:19][CH3:20])[CH:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:26][CH2:27]1)=[O:10])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
A 50% Cbz-Cl-toluene solution (20.87 ml, 61.40 mmol, 2.0 eq) was added dropwise at 0° C. to a mixture of tert-butyl 4-(ethylamino)piperidine-1-carboxylate (7.0 g, 30.70 mmol, 1.0 eq) and K2CO3 (12.71 g, 92.10 mmol, 3.0 eq) in DCM (100 ml) and the mixture was stirred for 14 hours at RT. The reaction mixture was diluted with DCM (200 ml), washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 20% ethyl acetate in hexane). Yield: 63% (7.0 g, 19.33 mmol)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1Br)([CH3:3])[CH3:2].C([Li])CCC.[C:19](=[O:21])=[O:20]>Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[C:19]([OH:21])=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)C)c1C(=O)O
Temperature: -29 °C
Reaction time: 1 h

Procedure:
2,6-Diisopropylbromobenzene (21.58 g, 0.0895 mol) was cooled to -23° C. under nitrogen and 2.5 M n-butyl lithium in hexanes (36 mL) was added dropwise as the temperature further cooled to -29° C. When the addition was complete, the reaction mixture was warmed to 0° C. and was stirred 1 hour at zero and was then poured onto a large excess of crushed dry ice. The mixture was stirred with a glass rod. When the dry ice had sublimed, hydrochloric acid (1N, 200 mL) was added and the mixture was extracted with ethyl ether, the ether washed with brine, dried (magnesium sulfate), filtered, and concentrated to a yellow oil. The oil was taken up in ether (200 mL), the ether solution extracted with sodium hydroxide solution (1N, 200 mL), the layers separated, the aqueous layer made acidic with 1.5N hydrochloric acid, brine added, and the aqueous layer extracted with ether (200 mL). The ether layer was washed with brine (50 mL), dried (magnesium sulfate), filtered and concentrated to an oil which solidified on standing, 13.42 g, 72.7%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([CH3:10])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(C)nc1
Reactant: COC(OC)N(C)C
Product: Cc1ccc(C(=O)C=CN(C)C)cn1

Procedure:
As for Example 1, 3-acetyl-6-methylpyridine is refluxed with N,N-dimethylformamide dimethylacetal to yield 3-dimethylamino-1-(6-methyl-3-pyridyl)-2-propen-1-one. The preceding compound is heated at reflux temperature for 6 hours with 3-amino-4-chloropyrazole in glacial acetic acid to give the product of the example.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[S:18][C:19]([CH2:22]O)=[CH:20][CH:21]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[S:18][C:19]([CH2:22][N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]3)=[CH:20][CH:21]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CO)s1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)s2)CC1

Procedure:
N-(1-{5-[2-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-ethyl]-thiophen-2-ylmethyl}-piperidin-4-yl)acetamide is prepared as example 28.1 from 70 mg (0.21 mmol) 4-benzyloxy-1-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-1H-pyridin-2-one (preparation 11d) and 58 mg (0.41 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].N1C=CC=CC=1>CCO>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12](=[N:30][OH:31])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(=NO)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of the ketone 483 (2.47 g, 6.6 mmol) in EtOH (35 mL) is added hydroxylamine hydrochloride (1.83 g, 26.4 mmol) followed by pyridine (2.13 mL, 26.4 mmol). The mixture is stirred at 80° C. for 8 h. The reaction mixture is cooled, the solvent is evaporated, and the residue dissolved in EtOAc, washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with heptane:EtOAc (7:3) gives 1.95 g of the product 484. 1H NMR (CDCl3) δ 7.55 (d, 2 H), 7.50-7.10 (m, 10 H), 7.00-6.70 (m, 2 H), 6.50-6.35 (m, 1 H), 5.30-5.00 (m, 2 H), 3.80 (d, 3 H); MS: m/z 391 (M++1).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:22]([NH:26][NH2:27])[N:23]=[N:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[N:24][N:23]3[C:1](=[O:2])[NH:27][N:26]=[C:22]3[C:21]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:18][CH:19]=1
Reactant: NNc1nncc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(F)cc3)cnn12
Temperature: 66 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (1.27 g, 7.86 mmol) in THF (20 mL) was added a suspension of 1-(5-(4-fluorophenyl)4-(pyridin-4-yl)pyridazin-3-yl)hydrazine (442 mg, 1.57 mmol) in THF (5 mL). After addition, the reaction mixture was heated to 66° C. After 20 min., the reaction mixture was cooled to RT and the reaction mixture was then concentrated under reduced pressure. The residue was diluted with water. The resultant mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 7-(4-fluorophenyl)-8-(pyridine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (440 mg, 91%) as a yellow solid. LC/MS (method A): RT=1.27 min, (M+H)+=308.