Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH:7]([N:25]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[C:13]1=[O:24])([CH3:4])([CH3:3])[CH3:2].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(#N)C>[C:1]([O:5][C:6](=[O:39])[CH:7]([NH2:25])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[C:13]1=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(=O)n(CCCCC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)n(CCCCC(N)C(=O)OC(C)(C)C)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A solution of the title C compound, 2-(benzhydrylideneamino)-6-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl)hexanoic acid t-butyl ester (2.15 g) in 80 mL of acetonitrile is treated with 8 mL of water and p-toluenesulfonic acid hydrate (0.800 g, 4.21 mmol), and the clear solution is stirred at 25° C. for 16 h. The solvent is evaporated under reduced pressure, and the residue is partioned between 150 mL of diethyl ether and 100 mL of 0.1N aqueous HCl. The aqueous phase is added dropwise to 1N aqueous NaOH (15 mL, 15.0 mmol) to precipitate an oily solid which is extracted into two 60 mL portions of methylene chloride. The organic extracts are combined, dried over anhydrous MgSO4, and concentrated. Chomatography on silica gel (eluant; ethyl acetate) affords 448 mg (30%) of 2-amino-6-(1-methyl-2,4-dioxo-1,4-di-hydro-2H-quinazolin-3-yl)hexanoic acid t-butyl ester as a colorless oil: NMR(CDCl3) 1.46 (s, 9H), 1.51-1.79 (m, 6H), 3.32 (dd, 1H, J=7.0, 5.4), 3.61 (s, 3H), 4.11 (t, 2H, J=7.4), 7.20 (d, 1H, J=8.3), 7.25-7.29 (m, 1H), 7.69 (td, 1H, J=8.6, 1.5), 8.23 (dd, 1H, J=7.9, 1.5); IR 1702, 1656; MS 362 (M++1).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[Br:11][C:12]1[C:17]([NH2:18])=[C:16]2[O:19][CH2:20][O:21][C:15]2=[CH:14][CH:13]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>CN(C=O)C.O>[Br:11][C:12]1[C:17]([NH:18][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[C:16]2[O:19][CH2:20][O:21][C:15]2=[CH:14][CH:13]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Nc1c(Br)ccc2c1OCO2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3c(Br)ccc4c3OCO4)ncnc2cc1OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 0.626 ml) was added to a solution of 6-bromo-2,3-methylenedioxyaniline (0.135 g) in DMF (2 ml) and the mixture was stirred at ambient temperature for 30 minutes. A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (0.1 g) in DMF (3.5 ml) was added and the resultant mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using an 80:17:3 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.045 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.4 (m, 1H), 1.7 (m, 3H), 1.85 (m, 2H), 2.3 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.55 (m, 2H), 4.05 (s, 3H), 4.3 (m, 2H), 6.15 (s, 2H), 7.05 (d, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 515 and 517; Elemental Analysis: Found C, 55.74; H, 5.30; N, 10.76. C24H27BrN4O4 requires C, 55.93; H, 5.28; N, 10.87%.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]2)[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([C:43]4([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]4)[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)C1(c2cc(Br)ccn2)CC1
Product: C[C@@H](c1ccc(-c2ccnc(C3(S(C)(=O)=O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 84 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-2-(1-methanesulfonyl-cyclopropyl)-pyridine following a procedure analogous to that described in Example 1. Yield: 84% of theory; LC (method 1): tR=1.86 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[O:5][C:6]1[N:7]=[C:8]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:9]2[N:14]=[C:13]([C:15]3[CH:29]=[C:28]([CH3:30])[C:18]([O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[C:17]([CH3:31])[CH:16]=3)[O:12][C:10]=2[N:11]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[O:5][C:6]1[N:7]=[C:8]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[C:17]([CH3:31])[C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:28]([CH3:30])[CH:29]=3)[O:12][C:10]=2[N:11]=1
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(Oc4cccc(Cl)c4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Oc4cccc(Cl)c4)nc3o2)cc(C)c1OCC(=O)O
Yield: 55.8 %

Procedure:
Analogously to example 1 (j), the reaction of 62 mg of tert-butyl {4-[5-(3-chlorophenoxy)-7-isobutyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate with trifluoroacetic acid gave 31 mg (45%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26].C(N)C(C)C>>[NH2:28][C:25]([CH3:27])([CH3:26])[CH2:24][NH:23][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(N)CN
Solvent: CC(C)CN
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Yield: 73.6 %

Procedure:
7-Benzyloxy-4-chloro-3-nitroquinoline (14.5 g, 46.0 mmol), prepared as described in Parts A-D of Example 1, was treated according to the general method described in Part E of Example 1. 1,2-Diamino-2-methylpropane (5.29 mL, 50.6 mmol) was used in lieu of isobutylamine. After the work-up, the crude product was passed through a layer of silica gel (eluting sequentially with chloroform and 96:4 chloroform:methanol) to provide 12.4 g of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.CN(C=O)C.CC(C)([O-])C.[K+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
In a 250 ml round bottom flask, under a nitrogen atmosphere, was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (5.0 g, 18.6 mmol) from Example I(1), step 1b, tert-butyl 4-aminobenzoate (3.95 g, 20.5 mmol), and DMF (30 ml). The solution was cooled to 0° C. and 1.0 M potassium tert-butoxide in THF (46 ml) was added dropwise via syringe over 30 minutes. The reaction was allowed to stir at room temperature for 30 minutes and then warmed to 50° C. for 2 hrs and then concentrated in vacuo to remove THF. The resulting solution was taken up in ethyl acetate, washed with H2O (3×300 ml) and then brine (1×50 ml). The organic layers were combined, dried over Na2SO4 and filtered. Following solvent evaporation, 6.0 g of crude product was obtained. Further purification was done via triteration with 3:1 diethyl ether/heptane to give 2.2 g of tert-butyl 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoate as a brown solid after filtration.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]1=[O:13].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CCO>[O:13]=[C:3]1[CH:2]([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1
Reactant: CCOC(=O)C1CCC(Br)C(=O)C1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCC(Sc2ccccc2)C(=O)C1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of ethyl 4-bromo-3-oxocyclohexanecarboxylate (3.73 g, 15 mmol) in EtOH (30 mL) at 80° C. was added a solution of benzenethiol (1.65 mL, 15 mmol) and NaOH (0.6 g, 15 mmol) in EtOH (100 mL). The suspension was stirred for 1 hour, then was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with water then brine, then was dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel afforded 2.56 g (61%) of the title compound as a yellow oil: MS (−) 277 (M−H)−.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)=[O:7])C.Cl>>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[N:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][N:10]=2)=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(-c2ncc(C(=O)O)cn2)cc1

Procedure:
NaOH aqueous solution was added to ethyl-2-(4-butyloxyphenyl)-5-pyrimidinecarboxylate (VI), followed by heating the mixture, adding hydrochloric acid, filtering off the resulting precipitates, and drying to obtain 2-(4-butyloxyphenyl)-5-pyrimidinecarboxylic acid (VII). This compound (VII) (1.0 g, 3.7 mmols), 4-dimethylaminopyridine (0.2 g), N,N'-dicyclohexylcarbodiimide (1.7 g) and 3-chloro-4-fluorophenol (0.7 g) were dissolved in dichloromethane (30 ml), followed by agitating the solution for 5 minutes, further agitating at room temperature overnight, filtering off the resulting precipitates, washing the dichloromethane phase with 2N-hydrochloric acid, then with 2N-NaOH aqueous solution and further with water till the washing water became pH 7, drying over magnesium sulfate, concentrating under reduced pressure, and recrystallizing the residual white solids from methanol to obtain the objective 3-chloro-4-fluorophenyl-2-(4-butyloxyphenyl)-5-pyrimidinecarboxylate (0.5 g). This compound had a crystalline-smectic point (C-S point) of 152.3° C. and a smectic-clearing point (S-I point) of 165.4° C. The elemental analysis values of this compound were as follows: C: 62.9%, H: 4.5%, N: 7.0% (calculated values in terms of C21H18ClFN2O3 --C: 62.92%, H: 4.53%, N: 6.99%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](=[C:10]1[CH2:14][CH2:13][C:12]2([CH2:19][CH:18]([CH3:20])[C:17](=[O:21])[CH:16]([CH3:22])[CH2:15]2)[CH2:11]1)([CH3:9])[CH3:8].[H-]>CCOCC>[C:7](=[C:10]1[CH2:14][CH2:13][C:12]2([CH2:15][CH:16]([CH3:22])[CH:17]([OH:21])[CH:18]([CH3:20])[CH2:19]2)[CH2:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)=C1CCC2(C1)CC(C)C(=O)C(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)=C1CCC2(C1)CC(C)C(O)C(C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (0.19 g, 5 mmol) in anhydrous ether (10 mL) was added 2-isopropylidene-7,9-dimethylspiro[4.5]decan-8-one (1.6 g, 7.3 mmol), prepared according to Example 23, in ether (3 mL) under nitrogen. The mixture was stirred at room temperature for 2 hours and then excess hydride decomposed by addition of wet ether. The solution was filtered, dried (Na2SO4) and concentrated on a rotary evaporator. Kugelrohr distillation gave 1.4 g, bp 150° C./0.5 mm, of the alcohol having the structure: ##STR36##
Reaction SMILES: [CH2:1]1[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])[C:8](=[O:9])[N:4]2[C:3]([C:19]([OH:21])=[O:20])=[C:2]1[CH2:22][OH:23].[C:24](OC(=O)C)(=[O:26])[CH3:25].[OH-].[Na+]>>[CH3:25][C:24]([O:23][CH2:22][C:2]1[CH2:1][S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])[C:8](=[O:9])[N:4]2[C:3]=1[C:19]([OH:21])=[O:20])=[O:26]
Reactant: O=C(O)CCCC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCCC(=O)O)[C@H]2SC1
Yield: 74000 %

Procedure:
To an aqueous solution of desacetyl glutaryl 7ACA (4 ml, 0.20 mmoles) chilled in an ice bath is added 0.4 ml acetic anhydride (4.2 mmoles) dropwise and 20% sodium hydroxide (9.75 mmoles) is pumped in to maintain the reaction pH at 7.0±1. After all of the acetic anhydride is added and the pH stabilizes, by HPLC there is now 0.148 moles of glutaryl 7ACA (yield is 74%). There is 4.5% of desacetyl glutaryl 7ACA remaining along with 10% of a compound tentatively identified as the cyclic glutarimide 7ACA derivative.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([Br:1])[CH:14]=3)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccc(-c2nc3c(F)cccc3s2)cc1
Reactant: BrBr
Solvent: ClCCl
Product: Nc1ccc(-c2nc3c(F)cccc3s2)cc1Br
Reaction time: 0.17 h

Procedure:
Bromine (0.8 mmol) was added to a solution of the 4-fluoro-2-(4′-aminophenyl) benzothiazole prepared as described in Example 3 (0.8 mmol) in dichloromethane (20 ml) at 10° C. The resulting solution was stirred for 10 min, then poured into water/ice (10 ml). The organic layer was removed and washed with 10% sodium thiosulfate (10 ml), water (10 ml) and evaporated. The product was purified by column chromatography (dichloromethane) to leave a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:12][C:13](C)([O-])[CH3:14].[K+]>>[CH2:14]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:13]#[CH:12]
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Product: C#CCn1cnc2ccccc21

Procedure:
The procedure for Example 648 was used, substituting pyrrolidin-2-one for 1H-benzimidazole and sodium hydride for potassium tert-butoxide to provide Example 649. MS (ESI): m/z 124 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([NH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([NH:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCCCCCN
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCNc1ccc(C(=O)OC)cc1
Yield: 85.8 %

Procedure:
According to the general procedure B, Methyl 4-chlorobenzoate (85 mg, 0.50 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 2 mol % of Pd(dba)2, 4 mol % of Ph5FcP(t-Bu)2, K3PO4 (260 mg, 1.23 mmol) in toluene at 100° C. for 20 h to give the title compound (101 mg, 86%) as a solid: 1H-NMR (500 MHz, CDCl3): δ 7.90 (d, 2H, J=8.8 Hz), 6.54 (d, 2H, J=8.8 Hz), 4.17 (bs, 1H), 3.85 (s, 3H, —COOMe), 3.15 (dd, 2H, J=7.0 and 12.3 Hz), 1.62 (m, 2H), 1.40 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H, J=6.9 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 167.31, 152.13, 131.47, 117.85, 111.22, 51.38, 43.30, 31.50, 29.21, 26.68, 22.52, 13.94. GC/MS(EI): m/z 235 (M+), 164. Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C, 71.54; H, 8.84; N, 5.79.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].C(=O)([O-])O.[K+]>CC(C)=O.O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(CNC(=O)c1ccc(I)cc1)OC

Procedure:
A solution of 4-iodobenzoyl chloride (100 g, 375.6 mmol) in 300 mL of acetone was added to a solution of aminoacetaldehyde dimethylacetal (41.4 g, 1.05 equiv.) and potassium hydrogen carbonate (39.5 g, 1.05 equiv.) in 270 mL of acetone and 450 mL of water. After completion of the reaction, acetone was removed under reduced pressure at no more than 35° C. to induce crystallization. The crystal slurry was filtered, washed and dried in vacuo at <50° C., to give 120 g (95 M %, HPLC area % 96) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:25])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(-c3cccc(Cl)c3)ccc2F)c1

Procedure:
The phenyl bromide (141) (100 mg, 0.26 mmol) was coupled to 3-chloro-phenylboronic acid (40 mg, 0.26 mmol) using Method E. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13](OCC(O)=O)(=[O:15])[CH3:14].[OH:21]/[N:22]=[C:23](/[C:25]1[CH:26]=[CH:27][C:28]([CH3:39])=[C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:30]=1)\[NH2:24].[Li+].[OH-].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C1COCC1.CO.O>[OH:15][CH2:13][C:14]1[O:21][N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:39])=[C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH:30]=2)[N:24]=1
Reactant: Cc1ccc(/C(N)=N/O)cc1NC(=O)OC(C)(C)C
Reactant: CC(=O)OCC(=O)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
CDI (1.76 g, 10.78 mmol) was added portion-wise to a stirred solution of 2-acetoxyacetic acid (1.27 g, 10.78 mmol) in NMP (5 mL). After 10 minutes, (Z)-tert-butyl 5-(N′-hydroxycarbamimidoyl)-2-methylphenylcarbamate (35) (1.43 g, 5.39 mmol) was added in one portion and stirred for another hour at room temperature. The solution was then heated via microwave at 125° C. for 15 minutes. The solution was partitioned with EtOAc and water. The organic phase was separated, dried over Na2SO4 and concentrated to give a residue which was dissolved in THF/MeOH/H2O (3:2:1, 5 mL) and followed by addition of 6N LiOH (5.4 mL). The resulting mixture was stirred for 10 minutes. Then aqueous 2M NaHCO3 (30 mL) was added and the solution was extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated to give a residue which was purified over silica gel to afford tert-butyl (5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)carbamate (137). MS m/z 306.0 (M+1)+.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:5]=[C:6]([CH:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:11][CH3:12])[CH:7]=[CH:8][CH:9]=1>CO>[CH3:1][NH:2][CH2:12][CH2:11][CH:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: CN
Reactant: CCC(Oc1ccccc1OC)c1cccc(Cl)c1
Solvent: CO
Product: CNCCC(Oc1ccccc1OC)c1ccccc1

Procedure:
A reaction mixture consisting of 200 ml. of methylamine, 225 ml. of methanol and 75 g. of 3-chloro-1-(o-methoxyphenoxy)propylbenzene was heated in an autoclave for 12 hours at 140° C. The reaction mixture was cooled, and the solvent was removed by evaporation. The semisolid residue was mixed with concentrated aqueous sodium hydroxide. The resulting mixture was extracted several times with ether. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine, formed in the above reaction, was insoluble in the alkaline solution and was extracted therefrom with ether. The ether extracts were combined, and the combined extracts washed with water and dried. The ether was removed therefrom in vacuo leaving the amine as a dark colored residue. The residue was dissolved in ether and 1 equivalent of oxalic acid in methanol added slowly. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate formed an insoluble precipitate which was collected by filtration, and the filter cake washed with ether and dried. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate melted at 150°-152° C. The NMR spectrum of the compound was consistent with the expected structure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[N:15]1[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]1.[OH-].[K+].Br[CH2:26][CH2:27][F:28]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[N:15]1[C:20](=[O:21])[N:19]([CH2:26][CH2:27][F:28])[C:18](=[O:22])[CH:17]=[N:16]1
Reactant: FCCBr
Reactant: CC(C)Oc1cc(-n2ncc(=O)[nH]c2=O)c(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(-n2ncc(=O)n(CCF)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
To a stirred mixture of 0.084 g (0.0035 mole) of sodium hydride in 20 mL of tetrahydrofuran was added a solution of 1.0 g (0.003 mole) of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (Compound 51, Example III, Step F) in 5 mL of tetrahydrofuran. The resulting mixture was stirred at room temperature for one hour. Tetrabutylammonium bromide (0.5 g, 0.002 mole) and potassium hydroxide (0.5 g, 0.009 mole) were added, and the mixture was heated at 60°-70° C. for approximately 1.5 hours. While maintaining the temperature at 60° C., a solution of 0.5 g (0.004 mole) of 1-bromo-2-fluoroethane in 5 mL of tetrahydrofuran was added. After complete addition, the mixture was allowed to cool to room temperature and was stirred for approximately 18 hours. The mixture was partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure produced an oil. The oil was subjected to column chromatography on silica gel, eluting with ethyl acetate:n-heptane (1:1). Evaporation of the appropriate fractions provided a solid which was recrystallized from ethyl acetate:n-heptane to give 0.4 g of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-4-(2-fluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione, Compound 26 in the tables.