Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8](Cl)=[O:9])=[O:4].[NH2:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12>C(OCC)(=O)C.C1OC1C>[Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:9])=[O:4]
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Agent: CC1CO1
Solvent: CCOC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c4cccs4)[C@H]3SC2)s1

Procedure:
A solution of 2-dichloroacetoxyimino-2-(thien-2-yl)acetyl chloride (0.585 g.) in ethyl acetate (5 ml.) was added to a stirred suspension of diphenylmethyl 7β -amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylate (1 g.) in ethyl acetate (10 ml.) and propylene oxide (1 ml.) at 20°. After 30 minutes all the solid had dissolved. The solution was washed with 2N-hydrochloric acid, saturated sodium bicarbonate solution, water and brine, dried and concentrated to give crude diphenylmethyl 7β-[2-dichloroacetoxyimino-2-(thien-2-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylate (syn-isomer) as a solvated foam (1.567 g.) λmax. (EtOH)267.5 nm (e11 240), τ values (CDCl3) include 3.00 (singlet, -CHPh2), 3.75 (singlet; CHCl2) and 7.35 (singlet; CH3).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[S:20]1[CH2:25][CH2:24][CH2:23][S:22][CH:21]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[H-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]([O:11][C:10]([NH:9][CH2:8][C:7]1[CH:17]=[C:3]([CH:4]=[CH:5][C:6]=1[O:18][CH3:19])[CH2:2][C:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:20][CH2:25][CH2:24][CH2:23][S:22]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C1SCCCS1
Reactant: COc1ccc(CBr)cc1CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)SCCCS1
Reaction time: 8 h

Procedure:
1.76 g of t-butyl N-[5-(bromomethyl)-2-methoxybenzyl]carbamate and 0.76 ml of ethyl 1,3-dithian-2-carboxylate were dissolved in anhydrous N,N-dimethylformamide. A solution of 220 mg of 60% sodium hydride in 18 ml of toluene was added under ice-cooling, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 1.70 g of the title compound from the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16]2)=[C:4]([F:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:25][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CN(C)C(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)N(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of (3S)-3-{[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-N,N-dimethyl-1-pyrrolidinecarboxamide (0.146 mmol) in dioxane (2 mL) was treated with 4-methoxyphenylboronic acid (0.165 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 2 h. The solution was cooled to room temperature. The dioxane layer separated from the aqueous layer and was removed via pipette and passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (4 mL). All dioxane filtrates were combined and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (26 mg, 39%). MS(ES)+ m/e 440.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.Br[CH2:14][CH2:15][O:16][CH2:17][CH3:18]>CC#N>[CH2:15]([O:16][CH2:17][CH2:18][C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CCOCCBr
Solvent: CC#N
Product: CCOCCc1c[nH]c2cc(N)ccc12

Procedure:
3-(2-Ethoxy-ethyl)-1H-indol-6-ylamine (B-16) was synthesized following the general scheme above starting from 6-nitroindole and 1-bromo-2-ethoxy-ethane. Overall yield (15%). HPLC ret. time 1.56 min, 10-99% CH3CN, 5 min run; ESI-MS 205.1 m/z (MH+).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:16])[NH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.C[O:29][C:30](=[O:41])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[NH2:32].C(N(C(C)C)CC)(C)C.[OH-].[Na+].Cl>CN(C=O)C.C(O)(=O)C.CO>[CH:1]1([NH:7][C:8](=[O:16])[NH:9][CH2:10][CH2:11][CH2:12][C:13]([NH:32][CH:31]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=2)[C:30]([OH:41])=[O:29])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCNC(=O)NC1CCCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCNC(=O)NC1CCCCC1)NC(Cc1ccc(O)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of 632 (0.45 g, 2.0 mmol) and 1-ethyl-3-(3-(dimethylamino)-propyl) carbodiimide (0.5 g, 2.2 mmol) in 15 mL of DMF, 0.53 g (2.3 mmol) of tyrosine methyl ester and 2.4 mmol of diisopropylethylamine were added. The mixture was heated at 60° C. for 6 h. Then, 50 mL of 0.1 N NaOH were added and the mixture was left at room temperature overnight. The reaction mixture was then acidified with concentrated HCl and extracted twice with a 2:1 mixture of chloroform:methanol. The organic phases were pooled, dried and evaporated. The residue was purified by chromatography on a silica column (5×4 cm). Elution with a 75:25:1 mixture of ethyl acetate:methanol:acetic acid yielded 140 mg (yield: 18%) of the target product as a brown oily liquid. LC-MS-ES negative mode: 390.3 (100%, [M−H]—), 290.9 (10%, (M-C6H10N]−), 264.9 (5%, [M-C7H12NO]−); positive mode: 392.5 (40%, [M+H]+), 264.95 (100%, [M-C7H10NO]+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]([CH:15]1[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14].I[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[NH4+].[Cl-]>C1COCC1>[CH3:11][O:12][C:13]([C:15]1([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14]
Reactant: COC(=O)C1CC(=O)N(c2c(C)cccc2C)C1
Reactant: IC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C2CCCC2)CC(=O)N(c2c(C)cccc2C)C1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 19 %

Procedure:
LHMDS (1 M solution in THF, 2.4 mL, 2.4 mmol) was added slowly to a cooled (−50° C.) solution of 1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (494 mg, 2 mmol) in THF (5 mL). Stirred at −50° C. for 5 min then warmed to 0° C. and stirred further for 5 min. After cooling back to −50° C., iodocyclopentane (462.5 μL, 4 mmol) was added and the resulting reaction mixture was warmed to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (10 mL) was added, and the aqueous solution was extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2, 20→50% EtOAc/hexanes) to give 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (120 mg, 19% yield). LC-MS: Rt (retention time): 2.54 min, MS: (ES) m/z 316.4 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: C#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2cccc(Cl)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 98.6 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.19 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.22 g of potassium carbonate, and 0.13 g of 3-chlorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-(3-chlorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (15)), m.p.: 71.6° C.
Reaction SMILES: [OH:1][CH:2]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)[C:3]#[N:4].[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1>ClCCl.CN(C)C1C=CN=CC=1.O>[Si:35]([O:1][CH:2]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[C:3]#[N:4])([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC(O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 2-hydroxy-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (290 mg, 0.68 mmol, 1.00 equiv) in dichloromethane (10 mL). TBSCl (153 mg, 1.02 mmol, 1.51 equiv), imidazole (92 mg, 1.35 mmol, 2.00 equiv) and 4-dimethylaminopyridine (17 mg, 0.14 mmol, 0.21 equiv) were added successively at 0° C. under nitrogen. The resulting mixture was stirred overnight at room temperature. After completion, the resulting solution was diluted with water, extracted with 3×30 mL of dichloromethane, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with ethyl acetate/petroleum ether (1:1) to afford the desired 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]propanenitrile (350 mg, 95%) as a yellow oil. MS (ES): m/z 543 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:30][S:31]([C:34]1[O:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[CH:36][CH:35]=1)(=[O:33])=[O:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.[Cl-].[NH4+]>[CH3:30][S:31]([C:34]1[O:38][C:37]([C:39]2([NH:42][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:19])[CH2:41][CH2:40]2)=[CH:36][CH:35]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)c1ccc(C2(N)CC2)o1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)o1
Reaction time: 18 h

Procedure:
To a stirred mixture of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (0.310 g, 1.21 mmol), N,N-diisopropylethylamine (0.630 mL, 3.62 mmol) and 1-(5-methanesulfonyl-furan-2-yl)-cyclopropylamine-hydrochloride salt (364 mg, 1.53 mmol) in DMF (30 mL) is added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.650 g, 1.25 mmol). After 18 hours, the mixture is diluted with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (4×30 mL). The combined organic layers are washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=4)=[O:23])=[CH:25][CH:26]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)nc1OC
Reactant: NCCc1cc[nH]c(=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(-c3ccc(C(=O)NCCc4cc[nH]c(=O)c4)cc3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
A mixture of 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (76 mg, 0.195 mmol), 4-(2-aminoethyl)pyridin-2(1H)-one (64 mg, 0.215 mmol), 1-methyl-1H-imidazole (96 mg, 1.17 mmol) and EDCI (223 mg, 1.17 mmol) in dichloromethane (10 mL) and DMF (0.5 mL) was stirred at room temperature for 16 h then dichloromethane (20 mL) was added. The mixture was washed with water (2×2 mL) and brine (2×2 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, MeOH:dichloromethane=1:10) to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (44 mg, 44%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 11.35 (s, 1H), 9.94 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.02-7.93 (m, 4 h), 7.66 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=6.6 Hz), 7.10 (d, 1H, J=8.1 Hz), 6.16 (s, 1H), 6.08 (d, 1H, J=6.3 Hz), 4.00 (s, 3H), 3.76 (s, 3H), 3.50-3.40 (m, 2H), 2.69-2.67 (m, 2H). LC-MS: [M+H]+, 512, tR=1.412 min, HPLC: 98.19% at 214 nm, 97.49% at 254 nm, tR=7.244 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.Cl.[F:14][C:15]([F:26])([F:25])[C:16]1[N:20]2[CH2:21][CH2:22][NH:23][CH2:24][C:19]2=[N:18][N:17]=1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([N:23]1[CH2:22][CH2:21][N:20]3[C:16]([C:15]([F:26])([F:14])[F:25])=[N:17][N:18]=[C:19]3[CH2:24]1)=[N:3][N:4]=[CH:5]2
Reactant: Clc1ccc2c(Cl)nncc2c1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc2n1CCN(c1nncc3cc(Cl)ccc13)C2

Procedure:
The title compound was prepared according to the method described in Example 19, using 1,6-dichlorophthalazine (400 mg, 2010 μmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (Balsells, et. al. Org. Lett., 7:1039-1042 (2005), 689 mg, 3015 μmol) and N,N-diisopropylethylamine (702 μl, 4019 μmol) in NMP (5 mL). MS (ESI, pos. ion) m/z: 355 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)C(C)C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>C(#N)C>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1

Procedure:
4-Methylimidazole (45.1 g, 0.55 M) and N,N-diisopropylethylamine (161 g, 1.25 M) were dissolved in acetonitrile (800 ml), and 3,4-difluoronitrobenzene (79.5 g, 0.5 M) added. The mixture was stirred and heated to reflux under nitrogen for 24 hours. Solvent was evaporated, the residue dissolved in ethyl acetate (800 ml), washed with water (400 ml), brine (200 ml), and dried (magnesium sulfate). The residue was dissolved in toluene (250 ml), treated with charcoal, filtered, and diluted with hot cyclohexane (75 ml) to crystallise 3-fluoro-4-(4-methylimidazol-1-yl)nitrobenzene (64.7 g). NMR (DMSO-d6) δ: 2.18 (s, 3H); 7.29 (s, 1H); 7.92 (t, 1H); 8.07 (s, 1H); 8.18 (dd, 1H); 8.38 (dd, 1H). MS (ESP): 222 (MH+) for C10H8FN3O2
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.[CH3:12][C:13](OC(C)=O)=[O:14].N1C=CC=CC=1>ClCCl>[C:13]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][CH:9]=1)(=[O:14])[CH3:12]
Reactant: CCCCc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10 g of 4-n-butylphenol, 10 ml of Ac2O and 8 ml of pyridine is stirred at reflux in 10 ml of dichloromethane. After 2 hours, the medium is cooled to room temperature, diluted with dichloromethane, washed with water, washed with 1M HCl solution, washed with saturated CuSO4 solution, washed with water and dried over MgSO4. After evaporation, 10.8 g of the expected compound are recovered in the form of an oil.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH2:14][N:15]=[C:16]=[O:17].[OH-].[Na+]>ClCCl.O>[O:17]1[CH2:13][CH2:14][N:15]=[C:16]1[NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C=NCCCl
Reactant: NC1CCCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2NC1=NCCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 5,6,7,8-tetrahydroquinolin-8-amine (Intermediate 17) (3.0 mmol) in dichloromethane (10 mL) was added chloroethylisocyanate (3.3 mmol). The solution was stirred at room temperature for 1.5 hour. The solvent was removed under vacuum gave a crude material, which was refluxed in H2O (60 mL) for 1 hour. After cooling to room temperature, the reaction was basified with NaOH (pH 14), extracted in Ethyl acetate (3×50 mL). The pooled organic layers were washed with brine and dried over magnesium sulphate to give 747. (4,5-Dihydro-oxazol-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 747 as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.O1CCOCCOCCOCCOCCOCC1>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:33]=[CH:32][C:24]([O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Oc1ccc(CCl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(COc2ccc(-n3nc(C)n(C(F)F)c3=O)c(F)c2)cc1
Yield: 93.3 %

Procedure:
By the method of Example 1, Step I, 0.50 g (0.0019 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step E) and 0.87 g (0.0038 mole) of methyl 2-(4-chloromethylphenoxy)propionate were reacted in the presence of 0.2 g of 1,4,7,10,13,16-hexaoxacyclooctadecane in 25 mL of N,N-dimethylformamide, yielding 0.80 g of methyl 2-[4-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]phenoxy]propionate as a colorless oil that solidified upon standing, m.p. 83-85° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:19](Cl)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:6][CH:7]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: NC(=O)c1cccc(O)c1
Reactant: CCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1cccc(C(N)=O)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-hydroxybenzenecarboxamide (200 mg, 1.46 mmol, 1 equiv.) in DMF (3 ml) was added K2CO3 (302 mg, 2.19 mmol, 1.5 equiv.) and NaI (43.5 mg, 0.29 mmol, 0.2 equiv). The suspension was stirred for 5 min before n-nonyl chloride (0.32 ml, 1.61 mmol, 1.1 equiv) was introduced. The resulting mixture was warmed to 60° C. where it was maintained for 16 h. After this time, the reaction was cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated, washed with additional water (×2), dried (MgSO4), filtered and concentrated in vacuo to reveal a colourless solid. In the case of 3-n-nonyloxybenzamide this colourless solid was stirred for 5 min with MeOH (˜0.5 ml) [NB: 3-n-nonyloxybenzamide partially soluble in MeOH] and then filtered to reveal the desired compound as a colourless solid (116 mg, 30%). HPLC-MS (method 3): m/z 264 [M+H]+, Rt=1.80 min. 1H NMR (d6-DMSO) δ=7.95 (s, 1H), 7.44-7.31 (m, 4H), 7.06 (ddd, J=8 Hz, J=2 Hz, J=1 Hz, 1H), 3.99 (t, J=6.5 Hz, 2H), 1.72 (quintet, J=6.5 Hz, 2H), 1.42 (m, 2H), 1.34-1.26 (m, 10H), 0.86 (t, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][C:13](=[O:14])[N:5]([C:6]=23)[CH2:4][C:3]1=[O:15].[H-].[Na+].Br[CH2:19][C:20]#[N:21]>CN(C=O)C>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[N:12]([CH2:19][C:20]#[N:21])[C:13](=[O:14])[N:5]([C:6]=23)[CH2:4][C:3]1=[O:15]
Reactant: N#CCBr
Reactant: CN1C(=O)Cn2c(=O)[nH]c3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)Cn2c(=O)n(CC#N)c3cccc1c32
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-methyl-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione (296 mg, 1.46 mmol, described in Intermediate 28) in DMF (5 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 78 mg, 1.96 mmol) and the resulting mixture was stirred for 5 min. Bromoacetonitrile (0.122 mL, 1.75 mmol) in was added dropwise and the reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h, then quenched with H2O (20 mL). The mixture was extracted with EtOAc (2×30 mL) and the combined organic extracts were washed with brine (10 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, followed by trituration with CH2Cl2 to give the title compound. MS: m/z=243 (M+1).