Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[O:5][C:4](=O)[CH:3]=1.S([O-])([O-])(=O)=O.[OH:30][NH3+:31].O[NH3+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:30][N:31]1[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: Cc1cc(COc2ccc(Oc3ccc(Cl)cc3)cc2)oc(=O)c1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(COc2ccc(Oc3ccc(Cl)cc3)cc2)n(O)c(=O)c1

Procedure:
171.4 g (0.5 mole) of 4-methyl-6-[4-(4-chlorophenoxy)phenoxymethyl]-2-pyrone in 50 ml of toluene were heated to 80° C. Then 59.9 g (0.36 mole) of hydroxylammonium sulfate and 38.3 g (0.36 mole) of sodium carbonate were added. 10 minutes later a further 59.9 g (0.36 mole) of hydroxylammonium sulfate and 38.3 g (0.36 mole) of sodium carbonate were added. After about 4 hours the heating was removed and, at about 40° C., 500 ml of methylene chloride were added. The dissolved reaction product was then filtered off from the insoluble salts. The filtrate was then dried over sodium sulfate, and the methylene chloride was evaporated off. When the residue was stirred with 500 ml of ethyl acetate, the reaction product crystallized out. For final purification, the 1-hydroxy-4-methyl-6-[4-(4-chlorophenoxy)phenoxymethyl]-2-pyridone was recrystallized from dimethylformamide. Yield 80.5 g (45%); melting point 168°-170° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][NH:30]2)[CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:27]1
Reactant: CN1CCN(C[C@@H]2CCCN2)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Product: CN1CCN(C[C@@H]2CCCN2CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-(+)-2-[(4-methyl-1-piperazinyl) methyl]pyrrolidine to give colorless crystals, mp. 182°-185° C. (D) (from ethyl acetate/methanol 99:1 v/v); [α]D20 =-11.2° (ethanol).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:12]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=3[N:14]=2)[C:6]([F:27])=[CH:5][C:3]=1[NH2:4].[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>>[F:1][C:2]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:12]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=3[N:14]=2)[C:6]([F:27])=[CH:5][C:3]=1[NH:4][C:31]([NH:30][CH2:28][CH3:29])=[O:32]
Reactant: C[C@H]1COCCN1c1nc(-c2cc(F)c(N)cc2F)nc2c1CCN(C)C2
Reactant: CCN=C=O
Product: CCNC(=O)Nc1cc(F)c(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)cc1F
Yield: 11 %

Procedure:
Method as example 85 using (S)-2,5-difluoro-4-(7-methyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline and ethyl isocyanate as starting material. The solvent was removed in vacuo and purified twice by flash chromatography using 0-20% DCM/MeOH as eluent yielding the title compound (6.2 mg, 0.013 mmol, 11%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:11].[ClH:12]>>[Cl:12][C:6]1[CH:5]=[CH:4][N+:3]([O-:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: Cl
Product: Cc1cc(Cl)cc[n+]1[O-]
Yield: 75 %

Procedure:
2-methyl-4-nitropyridine 1-oxide (5.0 g, 32 mmol, 1.0 eq) was dissolved in concentrated HCl (80 mL) and refluxed for 3 days. The reaction was cooled and the excess concentrated HCl was removed in vacuo. The viscous oil was neutralized with 10% K2CO3 and extracted with CH2Cl2 (5×). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 3.49 g (75%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J=7.0 Hz, 1H), 7.66 (d, J=3.0 Hz, 1H), 7.40 (dd, J=7.0, 3.0 Hz, 1H), 2.32 (s, 3H); ES-MS [M+1]+: 144.2.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[C:3]=1[CH:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]1[NH:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23]C(=O)C)=[CH:18][CH:17]=[CH:16][CH:15]=2.[Li+].[OH-]>CO>[OH:1][C:2]1[CH:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:4](=[O:10])[C:3]=1[CH:11]([C:12]1[NH:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][OH:23])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)OCCc1c(C(C2=C(O)C(C(C)C)NC2=O)c2ccccc2)[nH]c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1NC(=O)C(C(c2ccccc2)c2[nH]c3ccccc3c2CCO)=C1O

Procedure:
A solution of acetic acid 2-{2-[(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-phenyl-methyl]-1H-indol-3-yl}-ethyl ester (40 mg) and LiOH (8.5 mg ) in MeOH (0.5 ml) was stirred at 22° C. for 30 min and evaporated. The residue was partitioned between 0.1 N aqueous HCl and AcOEt and the organic layer was dried and evaporated. The residue was chromatographed on silica using CH2Cl2/MeOH (10:3) to give the title compound as an orange foam. MS: 391.1 ([M+H]+).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[NH2:27]>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][N:21]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: Nc1cnccn1
Product: O=C(Nc1cnccn1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (50 mg, 0.17 mmol) and 2-pyrazinamine (CAN 5049-61-6, 20 mg, 0.21 mmol) as starting materials; off white solid (15 mg, 23.7%). MS (ESI): 365.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH:22]([OH:24])[CH3:23])[N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32]>C(Cl)Cl.O1CCOCC1>[ClH:32].[ClH:32].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH:22]([OH:24])[CH3:23])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(O)c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of tert-butyl 1′-benzyl-4-(1-hydroxyethyl)spiro[indoline-3,4′-piperidine]-1-carboxylate (0.045 g, 0.11 mmol) in DCM (2 mL) was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to yield 1-(1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)ethanol dihydrochloride (0.047 g, 100%), which was used without further purification. LCMS (APCI+) m/z 323.2 [M+H]+; Rt=2.38 min
Reaction SMILES: [C:1]([O:5][P:6]([C:13]([F:43])([F:42])[C:14]1[CH:41]=[CH:40][C:17]([CH2:18][CH:19]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:46][C:47]([F:57])([F:56])[C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=1.CCOCC>CN(C=O)C>[C:9]([O:8][P:6]([C:13]([F:43])([F:42])[C:14]1[CH:41]=[CH:40][C:17]([CH2:18][C:19]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:47]([F:46])([F:56])[F:57])=[CH:55][CH:54]=2)([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(Cc2ccc(C(F)(F)F)cc2)(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
To a solution of the product from Example 18, Step 1 (94 mg, 0.15 mmol) in DMF (2 mL) at 0° C. was added NaH (5.5 mg, 80% in oil). After 15 min., 4-(trifluoromethyl)benzyl bromide (44 mg, 0.18 mmol) was added. After 2 h at 0° C., the mixture was given a standard aqueous/Et2O work-up, and the residue was purified by flash chromatography (1:10 EtOAc/hexane) to give a syrup (53 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18][CH3:19])=[N:14][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][O:27]C3CCCCO3)=[CH:22][CH:21]=2)[C:9]1=[O:34]>Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18][CH3:19])=[N:14][CH:15]=2)[N:10]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=2)[C:9]1=[O:34]
Reactant: CSc1ncc2c(n1)N(c1ccc(COC3CCCCO3)cc1)C(=O)N(c1ccccc1Br)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)N(c1ccc(CO)cc1)C(=O)N(c1ccccc1Br)C2
Yield: 85 %

Procedure:
A solution of 0.945 mg (1.75 mmol) of 3-(2-bromophenyl)-3,4-dihydro-1-[4-(tetrahydropyran-2-yloxymethyl)phenyl]-7-methylthio-pyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of saturated hydrogen chloride in ethyl acetate was stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate (10 ml) then washed with water (10 ml) and saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated to give 0.68 g (85%) of 3-(2-bromophenyl)-3,4-dihydro-1-[4-(hydroxymethyl)phenyl]-7-methylthio-pyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow gum. [Mass spectrum (ESI) MH+ =457].
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:6][O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[CH3:24][O:25]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=1)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:6][O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCc1ccccc1)(COC(C)=O)COC(C)=O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC(CCc1ccc(C=O)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-acetamido-1, 3-diacetoxy-2-(2-phenylethyl)propane (10 g) in anhydrous dichloromethane (150 ml) were added titanium tetrachloride (15.4 ml) and dichloromethyl methyl ether (5.63 ml) under a nitrogen atmosphere at −15° C. The mixture was stirred at room temperature for 2 hours, poured into ice water and extracted with chloroform. The chloroform layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; diisopropyl ether: ethyl acetate =1:1) to give the title compound (5.1 g) as a white solid, melting point 98-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([OH:21])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([O:21][C:7](=[O:8])[CH3:6])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1)(=[O:1])[CH3:3]
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC(C)=O)cc3)c(C)c2c1OC(C)=O
Yield: 176.8 %

Procedure:
A solution of 2-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1 gm; 3 mmoles) in pyridine (15 mL) and acetic anhydride (3 mL) was stirred at 50° C. for 15 minutes. The volatiles were removed in vacuo leaving a residue that crystallised on cooling. It was slurried with hexane, filtered, washed with hexane, and air dried to yield 1.1 gm (87%) of 2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran, mp. 119°-120° C.
Reaction SMILES: [C:1]([OH:5])#[C:2][CH2:3][CH3:4].I[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[OH:5][CH2:1][CH2:2][C:3]#[C:4][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1
Reactant: CCC#CO
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#CCCO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of butyn-1-ol (0.76 g, 0.11 mol) and methyl 4-iodophenylacetate (1.5 g, 0.0054 mol) in acetonitrile (10 mL) at 0° C., triethylamine (1.5 mL, 0.01 mol) was added, followed by the addition of bistriphenylphosphine palladium chloride (0.25 g, 0.36 mmol) and CuI (0.025 g). The reaction mixture was stirred at 0° C. under an argon atmosphere for 30 minutes and at room temperature for 3 hours. The dark colored reaction mixture was concentrated under reduced pressure, and the residue was partitioned between 5% citric acid (50 mL) and EtOAc (50 ML). The organic phase was washed with 5% citric acid (3×15 mL), water, dried (Na2SO4), filtered, and concentrated. The resulting material was purified by silica gel flash column chromatography eluting with 35% EtOAc in hexane to afford methyl 4-(4-hydroxy-1-butynyl)phenylacetate (1 g, 85%) as a dark colored liquid. FAB-MS m/z=219 (M+H), HRMS calcd. for C13H15O3 (M+H), 219.1021, found 219.1008. Calcd for C13H14O3 : C, 71.54, H 6.46; found: C, 71.04, H, 6.41.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[C:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:28]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1b using 5-cyclohex-1-enyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (Example 2b) and 3-(trifluoromethyl)-1,2,4-oxadiazole-5-methanamine (944905-93-5) as starting materials; MS (ESI) 451.2 (M+H)+.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[F:30][C:31]1[CH:32]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][NH:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:37][C:35]1[CH:34]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][N:39]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)C1

Procedure:
64 mg (0.17 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 70 mg (0.16 mmol) (S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine, 40 μL (0.23 mmol) DIPEA and 65 mg (0.17 mmol) HATU in 0.80 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.[NH:18]([C:20]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:24](=[O:35])[N:23]([CH3:36])[C:22](=[O:37])[CH:21]=1)[NH2:19]>CCOC(C)=O>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:10]([CH:11]=[N:19][NH:18][C:20]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:24](=[O:35])[N:23]([CH3:36])[C:22](=[O:37])[CH:21]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: O=C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(NN=Cc3ccc(-c4ccccc4)cc3)cc(=O)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A solution of 4-phenylbenzaldehyde (395 mg, 2.17 mmol) in EtOAc is slowly added into a dry ice cooled slurry of 6-hydrazinyl-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (200 mg, 0.724 mmol) in EtOAc. After the addition, the reaction mixture is stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and the residue is triturated with MeOH, followed by filtration to give 256 mg product as pale yellow solids (Yield: 80.3%). 1H NMR (400 MHz, DMSO-d6) δ 3.17 (s, 3H), 3.71 (s, 3H), 5.22 (s, 2H), 5.59 (s, 1H), 6.91 and 7.21 (AB, J=7.2 Hz, 4H), 7.37-7.81 (m, 9H), 8.36 (s, 1H), 10.67 (s, 1H). MS (FAB) m/z 441.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([O:23]C)=[O:22])[CH:16]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1.O>[F:25][C:26]([F:35])([F:36])[O:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:2]2[C:3]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=3)=[O:13])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:32][CH:33]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cc(NC(=O)c2nc3ccccc3nc2Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cc(NC(=O)c2nc3ccccc3nc2Oc2ccc(OC(F)(F)F)cc2)ccn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
A solution of methyl 4-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (2.6 g, 7.59 mmol), 4-(trifluoromethoxy)phenol (982.5 μL, 7.59 mmol) and K2CO3 (3.14 g, 22.76 mmol) in NMP (52.00 mL) was stirred at 70° C. for two hours and at room temperature for 12 hours. 120 ml of water were added and the reaction mixture was heated to 80° C. for 60 minutes. The reaction mixture was cooled to 45° C., aqueous HCl (1.0 N) was added until a precipitate formed. This mixture was stirred for 10 minutes, and then it was filtered. The filter cake was washed with an excess of water until the pH paper showed neutral and then it was washed with an excess of hexanes. The residue was dispersed in 120 ml of ethyl acetate, stirred for 15 minutes then it was filtered. The filter cake was washed with 10 ml ethyl acetate, 10 ml dichloromethane and dried overnight to give 44344-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid (33) (2.2 g, 61%) as a light tan-colored solid. ESI-MS m/z calc. 470.08, found 471.3 (M+1)+; Retention time: 1.51 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.67 (d, J=5.5 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.22 (dd, J=8.4, 1.6 Hz, 1H), 7.99 (dd, J=5.5, 2.2 Hz, 1H), 7.93-7.77 (m, 3H), 7.52 (s, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[OH-].[OH-].[Na+].Cl.[N+:18]([CH3:21])([O-:20])=[O:19]>O.CO>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:21][N+:18]([O-:20])=[O:19]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(C=C[N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Compound 2 was prepared according to the procedure of A. Kalir et al. [Isr. J. Chem. 5: 129-136 (1967)]. To a 100-mL round bottom flask, 6.674 g of powdered 3-methoxy-2-nitrobenzaldehyde (98%, Aldrich) (36.87 mmol), 2.1 mL of nitromethane (39 mmol), and 15.5 mL of methanol were added. This suspension was cooled to approximately 5° C., and 5.6 mL of 9.5N aqueous hydroxide (53 mmol) was added. An additional 1 mL of nitromethane, 9.5N aqueous sodium hydroxide, and methanol was added. The reaction mixture was stirred for 1 hr at approximately 5° C. Over the course of the hour an additional 5 mL of methanol was added. After 1 hr the precipitate was dissolved in 25 mL of water. This solution was added to 20 mL of 10% aqueous hydrochloric acid. The resulting precipitate was extracted with three 100-mL portions, one 50-mL portion, and finally one 25-mL portion of diethyl ether. The ether extracts were combined, dried with MgSO4, and filtered. The ether was removed by rotary evaporation and the residue was refluxed for 5 min in 31 mL of acetic anhydride and 3.566 g of anhydrous sodium acetate. The solution was allowed to cool and then was diluted with water. The precipitate was collected. Recrystallization from hot methanol with a recovery of a second crop of crystals from the mother liquor yielded 5.891 g (71%) of 2 as yellow crystals: 1H NMR (CDCl3) δ 3.94 (s, 3H, OCH3), 7.19 (d, 2H, J=8.3 Hz), 7.50 (m, 2H), 7.85 (d, 1H, J=13.7 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:11]=[C:12]([C:19](=[O:21])[CH:20]=2)[C:13]([O:15]COC)=[O:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>C(O)C>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=3)[CH:11]=[C:12]([C:19](=[O:21])[CH:20]=2)[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COCOC(=O)c1cn(-c2ccc(OCOC)cc2)c(-c2ccc(N(C)C)cc2)cc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COCOc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2ccc(N(C)C)cc2)cc1
Yield: 83.4 %

Procedure:
In 1 ml of ethanol was dissolved 0.08 g of methoxymethyl 6-(4-dimethylaminophenyl)-1-(4-methoxymethyloxyphenyl)-4-oxo-1,4-dihydronicotinate at room temperature, and 1 ml of a 10% by weight aqueous sodium carbonate solution was added to the resulting solution. The resulting mixture was subjected to reaction at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals were collected by filtration, washed with 5 ml of water, and dried to obtain 0.06 g of 6-(4-dimethylaminophenyl)-1-(4-methoxymethyloxyphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 150°-152° C.