Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[F:22][C:23]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[F:22][C:23]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:26]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)c1cccc(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1cccc(F)c1F
Yield: 45.3 %

Procedure:
Preparation of example 97 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), 2,3-difluoro-benzoic acid (24 mg, 0.154 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.154 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 2:1 hexane:acetone increasing to 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (24 mg, 0.058 mmol) as a yellow powder in 45% yield.
Reaction SMILES: [C:1]([NH3+:5])([CH3:4])([CH3:3])[CH3:2].[C:6]12([CH2:16][O:17][C:18]([C:20]([F:25])([F:24])[S:21]([O-:23])=[O:22])=[O:19])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.ClC1C=C(C=CC=1)C(O)=[O:31]>C(Cl)(Cl)Cl>[C:1]([NH3+:5])([CH3:4])([CH3:3])[CH3:2].[C:6]12([CH2:16][O:17][C:18]([C:20]([F:25])([F:24])[S:21]([O-:31])(=[O:23])=[O:22])=[O:19])[CH2:15][CH:10]3[CH2:9][CH:8]([CH2:14][CH:12]([CH2:11]3)[CH2:13]1)[CH2:7]2
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: O=C(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)S(=O)[O-]
Agent: CC(C)(C)[NH3+]
Solvent: ClC(Cl)Cl
Product: O=C(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Within a 1-L three-neck flask, 153 g (purity 86%, 345 mmol, 1.0 eq) of the (adamantane-1-ylmethyl)oxycarbonyldifluoromethanesulfinic acid tert-butylammonium salt obtained in Example 5-a was dissolved in 600 g of chloroform. To the resulting solution, 89 g (362 mmol, 1.05 eq) of 70% m-chlorobenzoic acid was slowly added at 0° C. This reaction solution was stirred for 1 hour at room temperature. After that, it was confirmed by 19F NMR of the reaction solution that: the (adamantane-1-ylmethyl)oxycarbonyldifluoromethanesulfonic acid tert-butylammonium salt was totally consumed; and there was no bromodifluoroacetic acid adamantane-1-ylmethyl ester detected as a by-product. The thus-obtained organic layer was washed with 200 g of 10% aqueous sodium sulfite solution, washed with 500 g of saturated sodium hydrogencarbonate solution and washed twice with 500 g of water. After distillation of chloroform from the washed organic layer, the solid residue was dissolved in a mixed solvent of chloroform, ethyl acetate and diisopropyl ether and then recrystallized. With this, 122 g of target (adamantane-1-ylmethyl)oxycarbonyldifluoromethanesulfonic acid tert-butylammonium salt was obtained. The purity of the target compound was 99%; and the yield of the target compound was 89%. No fluorine ion (F−) was detected from any liquid waste of this step. Further, 380 ppb of sodium ion (Na+) was detected from the (adamantane-1-ylmethyl)oxycarbonyldifluoromethanesulfonic acid tert-butylammonium salt obtained in this step.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:32][CH2:31][Br:30])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: O=C(C[C@@H](c1ccc(OCCBr)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 7.5 (200 mg, 0.51 mmol), 1,2-dibromoethane (0.88 mL, 10 mmol), potassium carbonate (210 mg, 1.5 mmol) and tetrabutylammonium bromide (16 mg, 51 μmol) in water (6.0 mL) was heated to reflux and stirred for two hours. The mixture was then cooled to room temperature and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by medium pressure chromatography (silica gel, 20 to 100% EtOAc:hexanes) to obtain 47.1 (100 mg). MS ESI (pos.): m/e 500.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:10]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(OCC)N(C)C
Product: CN(C)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 27.4 g. of o-nitrotoluene and 31.2 g. of 95% N,N-dimethylformamide diethyl acetal was heated under a nitrogen atmosphere in a 165° oil bath for 22 hours with continuous distillation of the ethanol formed in the reaction through a distillation head and descending condenser.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C([C:18]1[O:22][N:21]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:19]=1)=O>C1COCC1.CCCCCC.C(O)(=O)C.CO>[CH:23]([C:20]1[CH:19]=[C:18]([CH:8]2[O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5]2)[O:22][N:21]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cc(C=O)on1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1cc(C2CC(=O)CC(=O)O2)on1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
At -10° C., 61.5 g of methyl acetoacetate was dripped into 16.5 g of sodium hydride in 350 ml of THF. The mixture was cooled to -60° C. and 344 ml of 1.6 molar n-butyllithium solution in hexane was added. After all had been added, the mixture was stirred for 30 minutes at -60° C., and then 69.5 g of 5-formyl-3-isopropylisoxazole in 50 ml of THF was quickly dripped in at -60° C. The mixture was stirred for 30 minutes and then 10 ml of methanol followed by 30 g of acetic acid was added. After 10 minutes, the mixture was poured onto 500 g of ice, heated to room temperature, and stirred for 1 hour. The aqueous phase was extracted three times with methylene chloride, brought--with cooling--to a pH of 4.5 with dilute hydrochloric acid, and extracted with methylene chloride. The extract was washed with 5% strength sodium bicarbonate solution and water, dried with sodium sulfate, and the solvent was stripped off in a rotary evaporator. The residue was crystallized by stirring with methyl tert-butyl ether, followed by suction filtration. There was obtained 15 g of pure product.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.C(OC(Cl)=O)C(C)C>O1CCCC1.C(N(CC)CC)C>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CSc2ccc(CO)cc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The acid (a) in tetrahydrofuran (50 ml) and triethylamine (4.7 ml) was cooled to 0° C. and isobutylchloroformate (4.02 ml) was added dropwise and the solution was stirred at 0° C. for 2 hours, when it was filtered into a stirred solution of sodium borohydride (3.14 g) in ice/water (50 ml). The mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature. It was acidified with 2M hydrochloric acid, evaporated to half volume, and the resulting product was collected, washed with water and dried in vacuo, to give a white solid (4.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].CC1C=CC(S(O[CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[S:29]([C:32]2[CH:40]=[CH:39][C:38]3[N:37]4[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][N:44]=[C:36]4[C:35]4(OCCC[O:47]4)[C:34]=3[CH:33]=2)(=[O:31])=[O:30])(=O)=O)=CC=1.CN(C=O)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[S:29]([C:32]2[CH:40]=[CH:39][C:38]3[N:37]4[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][N:44]=[C:36]4[C:35](=[O:47])[C:34]=3[CH:33]=2)(=[O:31])=[O:30])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C2(OCCCO2)C2=NCC(C)(C)CN23)cc1
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C(=O)C2=NCC(C)(C)CN23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a solution of 4-methoxy-phenol (0.420 mmol) in THF (3 mL) was added NaH (60% dispersion in mineral oil) (0.015 g, 0.063 mmol) and the reaction was stirred at rt for 1 hr. {(2S)-1-[(3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate (0.12 g, 0.21 mmol) in THF (2 mL)/DMF (2 mL) was then added and the reaction heated overnight at 100° C. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70). The resulting product was dissolved in CH2Cl2 (3 mL) and methanesulfonic acid (2 mL) was added and the solution was stirred at 50° C. overnight. The reaction mixture was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70) to give the title compound as a light yellow foam (0.031 g, 38%). NMR (400 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 484.1 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].O>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(I)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Yield: 81 %

Procedure:
2-Amino-5-iodopyridine (1.0 g) and 2-bromo-4′-cyanoacetophenone (1.02 g) were dissolved in ethanol (30 mL), and sodium hydrogencarbonate (382 mg) was added to the solution, followed by refluxing for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was left to cool. The precipitated matter was recovered through filtration and dried, to thereby yield the title compound (1.27 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19]>>[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCNCC1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nc2)cc1
Product: CC(C)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: [N+]([C:4]1C=C(C2C3N=CC=CC=3C(=O)NN=2)C=C[CH:9]=1)([O-])=O.[N+:21]([C:24]1[CH:25]=[C:26]([C:30]2[C:31]3[CH:40]=[CH:39][CH:38]=[N:37][C:32]=3[C:33](=[O:36])[NH:34][N:35]=2)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[C:26]([C:30]2[C:31]3[CH:40]=[CH:39][CH:38]=[N:37][C:32]=3[C:33](=[O:36])[N:34]([CH2:4][CH3:9])[N:35]=2)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)c2cccnc12
Reactant: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Product: CCn1nc(-c2cccc([N+](=O)[O-])c2)c2cccnc2c1=O

Procedure:
Following the procedures of Example 8A and substituting for 8-(3-nitrophenyl) pyrido[2,3-d]pyridazin-5-one with 5-(3-nitrophenyl)-pyrido[2,3-d]pyridazin-8-one there is obtained 5-(3-nitrophenyl)-7-ethylpyrido[2,3-d]pyridazin-8-one.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al].[Li].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:1]([CH:8]([CH2:9][OH:10])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [Al]
Agent: [H-]
Solvent: CCOCC
Product: OCC(CO)Cc1ccccc1
Yield: 65.1 %

Procedure:
A solution of diethyl benzylmalonate (107 g, 0.43 mol) in 300 ml dry diethyl ether was added under nitrogen to a suspension of 24.5 g (0.65 mol) lithium aluminium hudride (LiAlH4) in 220 ml dry ether so to maintain a gentle reflux. The reaction mixture was refluxed for 2 more hours after the addition was completed. The excess of LiAlH4 was destroyed by addition of 50 ml ethyl acetate, followed by 50 ml water and finally by 600 ml 15% sulfuric acid. The ether phase was extracted by a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent left a white solid that was purified by recrystallization in ether. An amount of 45.8 g (0.28 mol) of 2-benzyl-1,3-propanediol was obtained (yield=64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH3:17].[CH2:18]([O:20][C:21](=[O:35])[CH2:22][O:23][C:24]1[C:33]2[C:28](=[C:29](O)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:18]([O:20][C:21](=[O:35])[CH2:22][O:23][C:24]1[C:33]2[C:28](=[C:29]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:15][CH2:16][CH3:17])[CH:5]=3)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:19]
Reactant: CCOC(=O)COc1cccc2c(O)cccc12
Reactant: CCCc1cc(CCCCCO)ccc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(CCCCCOc2cccc3c(OCC(=O)OCC)cccc23)ccc1OC
Yield: 79.5 %

Procedure:
To a stirred suspension of 5-(4-methoxy-3-propylphenyl)pentanol (2.48 g), ethyl(5-hydroxy-1-naphthalenyloxy)acetate (2 g), and triphenylphosphine (3.2 g) in dry tetrahydrofuran (30 ml) under nitrogen was added diethyl azodicarboxylate (1.65 ml) slowly so that the temperature did not rise above 50°. After 3 hours the solution was evaporated, and the residue was chromatographed on silica with a mixture of dichloromethane and light petroleum (bp 40°-60°) (4:6) to give the sub-title ester (3 g), mp 70° (from ethanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.C[NH:14]C1C=CC=CC=1>>[NH2:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=1
Reactant: CNc1ccccc1
Reactant: Clc1ccc2cc(Br)ccc2n1
Product: Nc1ccc2ccccc2n1

Procedure:
6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and N-methylaniline (2 mL) were heated at 120° C. for 16 hours. Extraction from 2M NaOH into DCM and drying on Na2SO4 gave the crude 2-aminoquinoline. This was converted, via Methods 3 and 5, to compound 205 (88 mg, 31%). [M−H]−=277.0 m/z. Activity: B
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4]/[C:5](/[C:21]1O[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:24][N:25]=1)=[CH:6]\[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]2)=[C:9]([O:19][CH3:20])[CH:8]=1.C([O-])(=O)C.[NH4+:37]>C(O)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[N:37]=[C:21]3/[C:5](=[CH:6]/[C:7]4[CH:12]=[CH:11][C:10]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:9]([O:19][CH3:20])[CH:8]=4)/[CH2:4][CH2:3][CH2:2][N:25]3[N:24]=2)=[CH:27][CH:28]=1
Reactant: [NH4+]
Reactant: COc1cc(/C=C(\CCCCl)c2nnc(-c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C2\CCCn3nc(-c4ccc(F)cc4)nc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
A solution of 2-{4-chloro-1-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}butyl}-5-(4-fluorophenyl)-[1,3,4]oxadiazole (85 mg) and ammonium acetate (290 mg) in acetic acid (3 mL) was heated under reflux for 10 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Methylene chloride and a 1 N sodium hydroxide solution were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 34 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[N:8][C:9]([C:12]([NH:14][C@H:15]3[CH2:19][CH2:18][N:17]([C:20]4[C:21]5[N:22]([CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:24][N:25]=4)[CH2:16]3)=[O:13])=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:6]2[CH:7]=[N:8][C:9]([C:12]([NH:14][C@H:15]3[CH2:19][CH2:18][N:17]([C:20]4[C:21]5[N:22]([CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:24][N:25]=4)[CH2:16]3)=[O:13])=[N:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(C2=CCCC2)cn1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(C2CCCC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.8 %

Procedure:
To a solution of (S)-5-(cyclopent-1-en-1-yl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.07 g, 0.19 mmol, 1 eq) in 1 mL of MeOH was added 10% Pd/C (0.02 g, 0.02 mmol, 0.1 eq). The reaction mixture was equipped with a H2 balloon and stirred for 3 hr at room temperature. The contents were filtered and the purified by HPLC to afford (S)-5-cyclopentyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.005 g, 0.013 mmol, 7%). 1H NMR (400 MHz, CD3OD) δ 8.83 (s, 2 H), 7.78 (q, J=1.1 Hz, 1 H), 7.73 (d, J=5.8 Hz, 1 H), 7.57 (d, J=3.9 Hz, 1 H), 6.94 (dd, J=2.7, 4.7 Hz, 1 H), 6.86 (d, J=5.9 Hz, 1 H), 5.00-4.80 (m, 1 H), 4.50-3.50 (br, 4 H), 3.20-3.10 (m, 1H), 2.60-2.48 (m, 1 H), 2.48-2.38 (br, 1 H), 2.22-2.12 (m, 2 H), 1.95-1.60 (m, 6 H); MS: (ES) m/z calculated for C21H24N6O [M+H]+ 377.2, found 377.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:16]=2[O:17][CH2:18][CH2:19][OH:20])[C:11](O)=[O:12])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:45]=[CH:44][C:33]([C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:35])=[CH:32][CH:31]=1>>[OH:20][CH2:19][CH2:18][O:17][C:16]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][C:10]([C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:45][CH:44]=2)=[O:12])=[CH:14][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1
Reactant: COc1ccc(C(=O)OCCCCCCN)cc1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Product: COc1ccc(C(=O)OCCCCCCNC(=O)c2cc(-c3cccc(Cl)c3)c(OCCO)c(-c3cccc(Cl)c3)c2)cc1

Procedure:
The product was prepared as a colorless, viscous oil (0.675 g, 71%) from 3,5-bis(3-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid (0.605 g, 1.5 mmol) and 4-methoxybenzoic acid, 6-aminohexyl ester (0.565 g, 2.25 mmol) using a procedure similar to step 3 of example 164; 1H NMR (400 MHz, DMSO-d6) 1.33–1.46 (m, 4H), 1.50–1.58 (m. 2H), 1.65–1.73 (m, 2H), 3.10–3.15 (m, 2H), 3.22–3.30 (m, 4H), 3.80 (s, 3H), 4.21 (t, J=6.6 Hz, 2H), 4.44 (t, J=6.6 Hz, 1H), 6.99–7.03 (m, 2H), 7.45–7.52 (m, 4H), 7.57–7.61 (m, 2H), 7.69 (s, 2H), 7.85–7.91 (m, 4H), 8.56 (t, J=5.5 Hz, 1H); IR (film) 3350, 2940, 1710, 1640, 1605, 1540, 1510, 1275 cm−1; mass spectrum [(+)ESI], m/z 636 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[NH2:15].[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[C:5](=[C:4]([O:3][CH3:2])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)[NH2:15]
Reactant: COc1ccc(C(=O)O)c(N)c1OC
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(OC)c(OC)c1N
Yield: 82 %

Procedure:
Hydrogen chloride was passed into a solution of 3,4-dimethoxyanthranilic acid (100 g., 0.51 mole) in 1.5 liters methanol for 40 minutes. The reaction mixture was refluxed for 4 days while introducing hydrogen chloride gas intermittently. The solvent was removed in vacuo, and the residual white solid was dissolved in 500 ml. water, cooled and basified to pH 10 with sodium hydroxide solution. After cooling for an additional hour, the cream color product (87.0 g., 82% yield) was filtered. Recrystallization from methanol furnished pure product, M.P. 66°-67° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: OCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][P:26]([O:36]CC2C=CC=CC=2)([O:28]CC2C=CC=CC=2)=[O:27])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][P:26]([OH:28])([OH:36])=[O:27])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1OP(=O)(O)O
Reaction time: 0.67 h
Yield: 97.1 %

Procedure:
To a Parr hydrogenation flask containing 3.7 mg of 10% Pd/C was added a solution of 50 mg (0.080 mmol) of 3-[(5-chloro-2-[[bis[phenylmethyl]phosphono]oxy]phenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one dissolved in 2 mL of ethyl acetate and 5 mL of ethanol. The mixture was hydrogenated at 40 psi for 40 minutes, filtered through celite and the filtrate was concentrated to give 35 mg of 3-[(5-chloro-2-[phosphonooxy]phenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one as a white solid: m.p. 173-176° C. MS 449 (M--H)-.