Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].IC.[C:26]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:26][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C
Reaction time: 16 h

Procedure:
A solution of ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate (1.0 g, 3.23 mmol) and iodomethane (2.5 mL, 40.2 mmol) in DMF (25 mL) was treated with Cs2CO3 (3.26 g, 10 mmol) and stirred for 16 h. The reaction was quenched by addition of water and the solid was collected and dried to yield ethyl 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate (I13064-48) as a yellowish solid (1.1 g, 100%): 1H NMR (DMSO-d6) δ 1.03 (t, J=7.0 Hz, 3 H), 4.09 (s, 3 H), 4.18 (q, J=7.0 Hz, 2 H), 7.40-7.55 (m, 5 H), 7.90 (d, J=9.2 Hz, 1 H), 8.23 (dd, J=9.2, 2.3 Hz, 1H), 8.32 (d, J=2.3 Hz, 1 H); MS (EI) m/z 325.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]S.COC(OC)CCl.[Na].[CH2:16]([SH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([S:23][C:3]([O:6][CH3:7])([O:2][CH3:1])[CH3:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: SCc1ccccc1
Reactant: COC(CS)OC
Agent: COC(CCl)OC
Agent: [Na]
Product: COC(C)(OC)SCc1ccccc1

Procedure:
Several processes for making 2-mercaptoacetaldehyde dimethylacetal (I, R1 =R2 =CH3) are reported by Parham et al., J. Am. Chem. Soc. 75, 2065-2069 (1953). These processes involve reaction of 2-chloroacetaldehyde dimethyl acetal with (1) benzylmercaptan sodium salt to produce benzyl-(1,1-dimethoxy ethyl)sulfide which was then reduced with sodium/ammonia to the desired acetal; (2) sodium sulfide to form 1,1,1',1'-tetramethoxyethyl disulfide followed by reduction of said disulfide using sodium/ammonia or lithium aluminum hydride; and (3) sodium polysulfide to give a mixture of polysulfides which was reduced with sodium/ammonia. A fourth process described in said reference comprises the action of potassium hydrosulfide on diethyl or dimethyl bromoacetal to produce the corresponding dialkyl mercaptoacetal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([CH2:31][CH2:32][C:33](O)=[O:34])(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:33](=[O:34])[CH2:32][CH2:31][C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: O=C(O)CCC(=O)c1ccccc1
Solvent: CCCCO
Product: O=C1CCC(c2ccccc2)=NN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 11.6 %

Procedure:
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (2 g) in n-Butanol (40 mL) was added of 1.14 g of 3-benzoylpropionic acid. The mixture was heated at reflux. After 3 h, the mixture was cooled at 0° C. and the 4-({4[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-phenyl-butyric acid (2.19 g, 72%) was recovered by filtration. Mp 144–146° C., 1H NMR (DMSO-d6).12.0 (1H, OH), 10.4 (1H, s, NH), 10.1 (1H, s, NH), 8.77 (1H, d, 5 Hz), 8.42 (1H, d, 5 Hz) 8.12 (1H, s), 8.06 (1H, s), 7.80 (3H, m), 7.6 (1H, d, 5 Hz) 7.53 (1H, d, 5 Hz), 7.45 (3H, m), 7.34 (1H, t, 8 Hz), 7.08 (1H, m) 3.4 (2H, m), 2.95 (2H, m), MS (ES+) 473 (MH+, 100),. MS (ES−) 471 (M−1, 100). To a solution of 4-({4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-phenyl-butyric acid (0.48 g) in tetrahydrofuranne (40 mL) was additionned N,N′-dicyclohexylcarbodiimide (0.23 g) and 1-Hydroxybenzotriazole (0.1401 g). The solution was stirred at reflux for 2 h then the solvent was evaporated. The crude was chromatographied, eluting with ethyl acetate to gave the title compound as a solid (0.3366 g, 78%). Mp 165–167° C., 1H NMR (CDCl3) 9.6 (1H,s, NH), 8.76 (1H, d, 5 Hz), 8.59 (1H, d, 5 Hz), 8.21 (1H, s), 7.86 (4H, m), 7.44 (4H, m), 7.26 (2H, m), 7.01 (1H, m), 3.18 (2H, t, 8 Hz), 2.87 (2H, t, 8 Hz). 13C NMR (CDCl3) 166.3, 162.4, 160.4, 159.8, 154.8, 152.9, 150.1, 146.7, 140.9, 135.7, 134.9, 130.5, 130.3, 129.0, 126.7, 122.9, 120.1, 119.6, 118.8, 117.55, 109.6, 28.4, 23.6. MS (ES+) 455 (MH+, 100), 909 (2 MH+, 10).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[CH2:8][CH2:7]1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CON
Reactant: CN1CCC(=O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCN(C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (0.88 g, 10.6 mmol) was added to a solution of Example 17A (1.55 g, 9.6 mmol) in pyridine (20 mL) and the mixture stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure and ethyl acetate (200 mL) was added. The organic layer was washed twice with water (200 mL) and brine, dried over sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.76 (t, J=6.61 Hz, 2H), 2.83 (s, 3H), 3.11 (t, J=6.61 Hz, 2H), 3.87 (s, 3H), 6.69 (t, J=7.46 Hz, 1H), 6.75 (d, J=8.48 Hz, 1H), 7.22 (td, J=7.80, 1.70 Hz, 1H), 7.73 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 191.07 (M+H)1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[O:16]([CH:8]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][N:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(OC(Oc2ccccc2)c2ccccn2)cc1

Procedure:
To a solution of 10.42 grams (g) (0.032 mole (m)) of 6-chloro-2-(diphenoxymethyl)pyridine, 8.02 g (0.079 m) of triethylamine in 200 milliliters (ml) of absolute ethanol in a Parr shaker bottle was added 0.5 g of 5 percent palladium on charcoal. Hydrogen was passed over the liquid surface using a Parr hydrogenator until ~3 pounds (0.3 m) had been consumed. The reaction mixture was filtered and the solvent removed by evaporation under reduced pressure. The residue was poured into a solution of 50 ml of water and 50 ml of 10 percent sodium hydroxide. This solution was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and the solvent stripped away under vacuum. The residue was heated at 0.02 millimeters of mercury to 110° C. to remove lower boiling impurities. The above named product was recovered as a pale yellow oil in a yield of 6.8 g and was ~99 percent pure. The Nuclear Magnetic Resonance spectrum (NMR) confirmed the product. The product has a refractive index of n25/d=1.5946 and upon analysis was found to have carbon, hydrogen and nitrogen contents of 77.78, 5.56 and 4.92 percent, respectively, as compared with the theoretical contents of 77.98, 5.24 and 5.05 percent, respectively, as calculated for the above named compound (Compound 1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[N:25]=[C:26]=[O:27])[CH2:22]2>C(Cl)Cl.C(N(CC)CC)C>[CH:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][CH:15]([CH2:22]3)[CH:16]1[NH:25][C:26]([N:1]1[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]1)=[O:27])[CH2:18]2
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (20 mg, 0.108 mmol) and 2-adamantyl isocyanate (18 mg, 0.10 mmol) were combined in CH2Cl2 and stirred overnight at ambient temperature. An additional 5 mg (0.028 mmol) of 2-adamantyl isocyanate and 2 drops of triethylamine were added and the mixture again stirred overnight at ambient temperature. The mixture was chromatographed directly on a silica gel column eluted with CH2Cl2 followed by 0.5% and 1% methanol in CH2Cl2. The product fractions were combined and evaporated to dryness in vacuo, and the residue was crystallized from petroleum ether to provide the title compound as a solid: (mp 189°-191°).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:15]=1[CH:31]([CH3:33])[CH3:32].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:15]=3[CH:31]([CH3:33])[CH3:32])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(Br)cnc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (94 mg, 0.416 mmol), 4-chloro-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline (125 mg, 0.416 mmol) and 4.0M solution of HCl in 1,4-dioxane (0.10 mL, 0.416 mmol) in NMP (0.6 mL) and heating in the microwave for 5 h at 150° C. After purification 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline was obtained as a colorless film. Mass Spectrum (ESI) m/e=491 [(M+1) (79Br)] and 493 [(M+1) (81Br)].
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([N:2]4[CH2:5][CH2:4][CH2:3]4)=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]
Reactant: C1CNC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
Azetidine hydrochloride (104 mg, 1.11 mmol) and triethylamine (0.155 ml, 1.11 mmol) were added to a dimethylformamide (1 ml) solution of phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (116 mg, 0.222 mmol) synthesized in Production example 5-2; and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a solvent mixture of ether-hexane=1:1; and the resultant solid was filtered off to yield the title compound (50 mg) as crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH2:11])=[O:10])=[CH:5][CH:4]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:16][CH2:17][C:18]1[N:11]=[C:9](/[CH:8]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:13][CH:12]=2)[O:10][CH:20]=1
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(CCl)CCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
4-(Trifluoromethyl)cinnamamide (1 g, 4.65 mmol) and 1,3-dichloroacetone (1.1 g, 8.66 mmol) were added to toluene (5 ml) and the mixture was refluxed under heating for 8 hours. Ethyl acetate (20 ml) was added, and the mixture was washed with water (20 ml) twice and concentrated under reduced pressure. To the residue was added methanol (4 ml) and the mixture was stirred at room temperature. The crystals were filtrated and dried under reduced pressure to give 4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (733 mg, yield 55%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)CCC.N#N>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ccncc1
Temperature: 80 °C

Procedure:
A solution of 3-(3-bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (70 mg, 0.19 mmol) and 4-(tri-n-butylstannyl)pyridine (107 mg, 0.29 mmol) in N,N-dimethylacetamide (3 ml) was degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) and copper(I) iodide (15 mg, 0.079 mmol) was added and the mixture heated at 80° C. for 6 h. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and water, separated and the aqueous re-extracted with dichloromethane. The combined organics were washed with brine, dried (MgSO4) and evaporated. The residue was purified using preparative thin-layer chromatography on silica gel, using 30% ethyl acetate/dichloromethane as the eluent, to give a yellow solid. Further purification using preparative thin-layer chromatography on silica gel, eluting with 2% methanol/dichloromethane, afforded 3-[4-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a cream solid: δH (360 MHz, DMSO) 7.52 (1H, d, J 7), 7.63 (1H, dd, J 10 and 8), 7.71-7.73 (2H, m), 7.90 (1H, ddd, J 9, 5 and 2), 8.04 (1H, dd, J 7 and 2), 8.33 (1H, s), 8.72 (2H, m), 9.37 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>CC#N>[F:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:8]([C:7]2[C:2]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:3][C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:5][C:6]=2[CH3:19])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCOCC2)nc(N2CCCC2)c1C(=O)NCc1cccc(F)c1
Temperature: 140 °C
Yield: 58.6 %

Procedure:
To a solution of 254 mg (0.7 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in MeCN (0.5 ml) were added 115 μl (1.4 mmol) pyrrolidine and 290 μl (2.1 mmol) NEt3. The RM was heated in the microwave to 120° C. for 30 min and subsequently to 140° C. for 45 min. Then the mixture was filtered through celite and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 2:1), followed by crystallization (hexane/EtOAc) provided 164 mg (0.41 mmol, 59%) N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-pyrrolidin-1-yl-pyridine-3-carboxylic acid amide (example 24). [M+H]+ 399.2.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][C:16]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[NH:33][N:32]=[N:31][N:30]=5)=[CH:25][CH:24]=4)[NH:20]C(=O)N[C:17]3=[O:22])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-:34].[Na+].Cl>>[NH2:20][C:16]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:25][CH:24]=1)([CH2:15][CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17]([OH:22])=[O:34]
Reactant: [OH-]
Reactant: O=C1NC(=O)C(CC2c3ccccc3Oc3ccccc32)(c2ccc(-c3nnn[nH]3)cc2)N1
Agent: Cl
Agent: [Na+]
Product: NC(CC1c2ccccc2Oc2ccccc21)(C(=O)O)c1ccc(-c2nnn[nH]2)cc1

Procedure:
5-(9H-xanthen-9-ylmethyl)-5-[4-(1H-tetrazol-5-yl)phenyl]hydantoin (3.2 g, 7.6 mmol) was heated with aqueous sodium hydroxide (2M, 23 ml) at 130° C. for 2 days following the procedure described in Example 1 (vi). The reaction mixture was acidified with aqueous hydrochloric acid and the product isolated by filtration to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:4]([CH3:16])[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH3:16])=[C:5]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1NS(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)c(N)cc1NS(C)(=O)=O
Yield: 96.2 %

Procedure:
A mixture of Intermediate 79A (175 mg, 0.66 mmol), zinc (432 mg, 6.61 mmol), ammonium chloride (354 mg, 6.61 mmol) in ethanol (10 mL) and water (5.0 mL) was heated to reflux for 30 min. The reaction mixture was concentrated, suspended in ethyl acetate and filtered. The filtrate was washed with water, aqueous NaHCO3 and brine, dried over MgSO4 and concentrated to give Intermediate 79 (149 mg, 96%) as a white solid. HPLC: Rt=0.453 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=235 [M+H]+. Intermediate 79 was used in the synthesis of Example 243.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[C:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]([C:13]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)=[O:14])=[CH:4][CH:3]=1.FC(F)(F)C(O)=[O:27]>CN(C=O)C>[CH3:12][O:11][C:9]([C:6]1[C:5]([C:13]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)=[O:14])=[CH:4][CH:3]=[C:2]([CH2:1][OH:27])[N:7]=1)=[O:10]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1c(C(=O)c2ccc3c(c2)OCO3)ccc(C)[n+]1[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(CO)ccc1C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a DMF(15 ml) solution of 6-methyl-3-(3,4-methylenedioxyphenylcarbonyl)-2-methoxycarbonylpyridine N-oxide(1.56 g,4.95 mmol) was added anhydrous trifluoro acetic acid(7 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 h. After removal of the excess anhydrous trifluoro acetic acid the residue was partitioned between water and AcOEt. The organic layer was washed with a saturated aqueous solution of NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure to give 6-hydroxymethyl-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-2-carboxylic acid methyl ester(1.72 g).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:11])[CH3:10]>C(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH3:1])=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:11])[CH3:10]
Reactant: CNC1CCCCC1
Reactant: CC(=O)Nc1ccc(CBr)cc1C(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(CN(C)C2CCCCC2)cc1C(C)(C)C

Procedure:
48 gm of N-methyl-cyclohexylamine were added to 56 gm of 4-acetylamino-3-tert.butyl-benzyl bromide in 500 ml of chloroform, and the mixture was refluxed for 1.5 hours. Subsequently, the reaction mixture was extracted three times with water, and the organic phase was evaporated. The residue was purified column-chromatograhically on silicagel with chloroform/methanol (5:1), and 4-acetylamino-3-tert.butyl-N-cyclohexyl-N-methyl-benzylamine hydrochloride, m.p. 240-243° C (decomp.), was crystallized from a solution of the purified base in absolute ethanol/ether by addition of absolute ethanolic hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[N+]([C:15]1C=CC=C[C:16]=1[OH:21])([O-])=O.C(OC(=O)C)(=O)C>C(O)(=O)C.O=[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:16](=[O:21])[CH3:15])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared from the commercially available 2-fluoro-4-nitrophenol according the procedure of Burckhalter, J. H. et al. (J. Am. Chem. Soc. 1948, 70, 1363). Nitrophenol (5.73 g, 36.5 mmol) and acetic anhydride (3.72 g, 36.5 mmol) were dissolved in acetic acid (20 mL) and PtO2 (150 mg) was then added. The reaction mixture was shaken under H2 atmosphere (50 psi) at RT for 24 h. The precipitate which formed was collected by vacuum filtration and the filter paper was washed with acetic acid (25 mL). The combined filtrate and washing was concentrated in vacuo to give the title compound (2.0 g). The solid that remained on the filter paper was treated with MeOH to dissolve the product and the Pt2O filtered off. The filtrate was concentrated in vacuo and the solid obtained was triturated with 1:1 EtOAc/hexanes (200 mL) to give a second crop of the title compound (1.8 g, 62% overall). 1H NMR (DMSO-d6) δ 9.83 (s, 1H), 9.51 (s, 1H), 7.50 (dd, 1H, J=13.6, 2.5 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (dd, 1H, J=9.3, 9.3 Hz), 1.98 (s, 3H); MS (ESI+) m/z 170.23 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.[NH2:26][C:27]1[O:31][N:30]=[C:29]([CH2:32][CH3:33])[CH:28]=1>>[CH2:32]([C:29]1[CH:28]=[C:27]([NH:26][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[O:31][N:30]=1)[CH3:33]
Reactant: CCc1cc(N)on1
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)Cl)cc3)c2cc1OC
Product: CCc1cc(NC(=O)Cc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)on1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 19, 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetyl chloride was reacted with 5-amino-3-ethylisoxazole. There was thus obtained the title compound in 55% yield; 1H NMR: (DMSOd6) 1.16 (t, 3H), 2.56 (q, 2H), 3.76 (s, 2H), 3.97 (s, 3H), 3.99 (s, 3H) 6.16 (s, 1H), 7.27 (d, 1H), 7.39 (s, 1H), 7.41 (d, 2H), 7.55 (s, 1H), 8.54 (s, 1H); Mass Spectrum: M+H+ 435.