Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>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.C(O)C>[C:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N)c(Br)c1
Reactant: N#Cc1ccccc1B1OCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)c1ccc2nc(N)c3ccccc3c2c1
Yield: 35.4 %

Procedure:
35.7 g (190 mmol) 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 31.9 g (158 mmol) 2-bromo-4-(tertbutyl)aniline, 3.6 g (3.16 mmol) tetrakis(triphenylphosphine)palladium(0) and 59.0 g (427 mmol) K2CO3 were heated to reflux in a 2 L flask containing 400 ml toluene and 300 mL ethanol. The reaction mixture was heated for 19 hours under constant N2 purge. HPLC of the reaction mixture indicated consumption of the starting aniline. The mixture was cooled and then filtered to remove the base. The base was washed with EtOAc to remove trace organic. The combined filtrate was evaporated down to give impure oil. The oil was purified on a column of silica using 95/5/0.05 CH2Cl2/MeOH/NH4OH as eluent to obtain separation. The product fractions were evaporated of solvent and the resultant residue recrystallized from CH2Cl2/hexanes to yield 14.0 g of the target compound as white solids (35.5% yield, confirmed by GC-MS).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:38]=[CH:37][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:34]([CH3:36])[CH3:35])[N:28]=[C:29]([CH2:31][O:32][CH3:33])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH:34]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:38]=[CH:37][C:17]=43)[CH:21]=2)=[N:30][C:29]([CH2:31][O:32][CH3:33])=[N:28]1)([CH3:36])[CH3:35]
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (158 mg, 0.30 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (1.5 mL, 20.2 mmol) and the reaction mixture stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the residue azeotroped with ether. The resultant oil was triturated with diethyl ether to give 2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetate salt as a solid which was collected by filtration (103 mg, 64%). LCMS RT=3.03 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d) δ: 8.56 (1H, s), 8.33 (1H, d, J=8.33 Hz), 7.90 (1H, s), 7.00 (1H, dd, J=8.38, 1.78 Hz), 6.85 (1H, d, J=1.73 Hz), 5.81-5.80 (1H, m), 4.46 (4H, d, J=2.51 Hz), 4.33 (2H, s), 3.34 (2H, d, J=12.58 Hz), 3.27 (3H, s), 2.98-2.95 (2H, m), 2.82 (1H, t, J=11.91 Hz), 1.93 (2H, d, J=13.66 Hz), 1.75 (2H, t, J=12.95 Hz), 1.44 (6H, d, J=6.60 Hz)
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12](C(F)(F)F)[CH:13]=1)[C:5]([OH:7])=[O:6].[F:25][C:26]([F:43])([F:42])[C:27]1[CH:28]=[C:29](/[CH:37]=[CH:38]/B(O)O)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:43])([F:42])[C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][C:12]2[CH:13]=[C:8]([CH:4]([CH2:3][CH:2]([CH3:1])[CH3:24])[C:5]([OH:7])=[O:6])[CH:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:26]([F:43])([F:42])[F:25])=[CH:20][CH:19]=3)[CH:11]=2)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1
Reactant: CC(C)CC(C(=O)O)c1cc(-c2ccccc2)cc(C(F)(F)F)c1
Reactant: OB(O)/C=C/c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(C)CC(C(=O)O)c1cc(C=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Nigishi coupling of 4-methyl-2-(5-trifluoromethyl-biphenyl-3-yl)pentanoic acid (intermediate compound 1g) with trans-2-(3,5-bis-trifluoromethylphenyl)-vinyl-boronic acid under the conditions described in Example 14; 1H NMR (400 MHz, MeOD) δ ppm 0.98 (dd, J=6.60, 3.18 Hz, 6 H), 1.56 (dt, J=13.39, 6.63 Hz, 1 H), 1.75 (ddd, J=13.69, 7.21, 6.97 Hz, 1 H), 2.05 (ddd, J=13.57, 7.70, 7.58 Hz, 1 H), 3.82 (t, J=7.70 Hz, 1 H), 7.52 (d, J=16.5 Hz, 1 H), 7.44 (d, J=16.5 Hz, 1 H), 7.60 (s, 1 H), 7.67 (s, 1 H), 7.74-7.84 (m, 6 H), 8.18 (s, 2 H); Calcd for C29H23F9O2 (M+H) 575.16, Found 575.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1

Procedure:
Tetrakis(triphenylphosphine)palladium (1 g) was added to a mixture of 5 g of 2-methoxyphenylboronic acid, 6.6 g of 5-bromo-2-fluoronitrobenzene and 30 mL of 2 M sodium carbonate solution in 50 mL of toluene and 50 mL of ethanol. The mixture was refluxed for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried, and concentrated to give a dark green oil which solidified on standing to give crude 4-fluoro-2′-methoxy-3-nitrobiphenyl.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:29])[C:14]3[CH:19]=[C:18]([N:20]4[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]4)[CH:17]=[CH:16][C:15]=3[Cl:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CO.[CH3:32][Si](C=[N+]=[N-])(C)C>O1CCOCC1>[C:1]12([CH2:11][NH:12][C:13](=[O:29])[C:14]3[CH:19]=[C:18]([N:20]4[C:25](=[O:26])[N:24]([CH3:32])[C:23](=[O:27])[CH:22]=[N:21]4)[CH:17]=[CH:16][C:15]=3[Cl:28])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-adamantan-1-ylmethyl-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide (66 mg, 0.159 mmol) in dioxane (1.5 ml) was added methanol (0.32 ml) followed by a 2.0 M solution of (trimethylsilyl)diazomethane (0.32 ml). After stirring for 18 hours at ambient temperature the mixture was concentrated under reduced pressure to give 67 mg of a light yellow amorphous solid. Mass Specrum (ES+) 429.6; (ES−) 427.6. Liquid chromatography retention time=2.8 min (using the LC/MS and method outlined for the examples in Table 1).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].[CH3:27][S-:28].[Na+]>O1CCCC1>[CH3:26][N:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][S:28][CH3:27])(=[O:10])=[O:9]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Yield: 99.7 %

Procedure:
A solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (250 mg) and sodium methanethiolate (50 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained crystals were collected by filtration. The crystals were washed with water and diethyl ether, and dried to give the title compound (256 mg, yield 99%) as pale-brown crystals. melting point 213° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>CC(N(C)C)=O>[O:32]1[CH2:33][CH2:34][CH:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]3[CH:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([O:1][CH2:2][C@H:3]4[CH2:7][NH:6][C:5](=[O:8])[CH2:4]4)[N:21]=3)=[CH:23][C:24]=2[C:35]([F:38])([F:37])[F:36])[CH2:30][CH2:31]1
Reactant: FC(F)(F)c1cc(-c2cc3ncccc3c(Cl)n2)ccc1OC1CCOCC1
Reactant: O=C1C[C@@H](CO)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C1C[C@@H](COc2nc(-c3ccc(OC4CCOCC4)c(C(F)(F)F)c3)cc3ncccc23)CN1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
50.7 mg (R)-4-Hydroxymethyl-pyrrolidine-2-one (2.2) was placed in 1.5 mL of dimethylacetamide at ambient temperature under nitrogen before 20.5 mg sodium hydride (60% dispersion in oil) was added. The reaction was stirred for 10 min and then 150 mg 5-chloro-7-[4-(tetrahydro-pyran-4-yloxy)-3-trifluoromethyl-phenyl]-[1,6]naphthyridine (6.23) was introduced and the reaction was heated to 70° C. and stirred overnight. After this time the mixture was cooled to ambient temperature and partitioned between ethyl acetate, water and some saturated sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by chromatography on silica provided the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1O)([O-:3])=[O:2].S(Cl)([Cl:20])=O.CN(C)C=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[Cl:20])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Yield: 86.6 %

Procedure:
180 grams (0.75 moles) of 2,6-dinitro-4-tert-butylphenol thus prepared was placed in a mixture of 113 grams (0.95 moles) thionyl chloride, 55 grams (0.76 moles) dimethylformamide and 300 ml. of dry toluene. The mixture was stirred and heated to reflux temperature for 15 hours after which time the thionyl chloride, DMF and toluene were removed under reduced pressure until a slush remained. Hexane was then added to the reaction vessel, the mixture cooled and filtered. The product was then recrystallized from boiling hexane to give 168 grams 2,6-dinitro-4-tert-butylchlorobenzene in the form of light yellow needles melting at 114° - 116° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Cl:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][Cl:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc(Cl)nn1
Yield: 43.9 %

Procedure:
A suspension of 3-chloro-6-methylpyridazine (3 g), benzoyl peroxide (150 mg) and N-chlorosuccinimide (3.12 g) in CCl4 (30 ml) was refluxed 16 hours, cooled, filtered and evaporated. Chromatography (EtOAc/hexane) gave title compound (1.67 g). NMR δ(CDCl3) 4.87 (2H, s), 7.58 (1H, d), 7.71 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Cc1cc(Cl)ccc1CCl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)ccc1CC#N
Yield: 72.5 %

Procedure:
Step B In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methylbenzyl chloride (1.83 g, 10 mmol) was reacted with KCN (1.76 g, 27 mmol) in ethanol (13 mL) and water (10 mL) at 100° C. for 1 h to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (1.2 g, 69%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])[C:5]([N+:28]([O-])=O)=[C:6]([CH:27]=1)[O:7][C:8]1[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=1)[CH2:11][NH:12][S:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:15])=[O:14].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[NH2:28][C:5]1[C:4]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[CH:3][C:2]([F:1])=[CH:27][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=1)[CH2:11][NH:12][S:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Reaction time: 5 h
Yield: 30.1 %

Procedure:
3.08 g of tert-butyl [(3-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxy}benzyl)sulfamoyl]carbamate (4.55 mmol, 1 eq.) were dissolved in 88 mL THF and heated to 50° C. upon which a solution of 13.5 g sodium dithionite (77.4 mmol, 17 eq.) in 70 mL water was added and stirring was continued at that temperature for 5 h. The layers were separated and the THF layer was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried, filtered and concentrated in vacuo. The residue was further purified by flash column chromatography (hexan to hexan/ethyl acetate 1:1 gradient) to yield 886 mg (30% yield) of the target compound (as a 2-3:1 regioisomeric mixture).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[O:16][C:15]2[C:10](=[N:11][C:12]([Cl:17])=[CH:13][CH:14]=2)[CH:9]=1.C=O.[C:20]([O-])([O-])=O.[K+].[K+]>C(O)=O>[ClH:17].[Cl:17][C:12]1[N:11]=[C:10]2[CH:9]=[C:8]([C@@H:4]3[CH2:5][CH2:6][CH2:7][N:3]3[CH3:20])[O:16][C:15]2=[CH:14][CH:13]=1
Reactant: Clc1ccc2oc([C@@H]3CCCN3)cc2n1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O=CO
Product: CN1CCC[C@H]1c1cc2nc(Cl)ccc2o1

Procedure:
A 660 mg (1.04 mmol) sample of 2-(2-(S)-pyrrolidinyl)-5-chlorofuro[3,2-b]pyridine dihydrochloride, from Example 11e above, was dissolved in 5 mL of 88% formic acid and 10 mL of 37% aqueous formaldehyde and heated at reflux for 1 hour. The reaction mixture was cooled, poured into saturated K2CO3, and the mixture was extracted with CH2Cl2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :MeOH. The residue was converted to the salt by treatment with HCl/ether to give 540 mg of title compound: 1H NMR (D2O, 300 MHz) δ 2.28-2.38 (m, 2H), 2.49-2.72 (m, 2H), 2.92 (br s, 3H), 3.41 (m, 1H), 3.80 (m, 1H), 4.84 (m, 1H), 7.50 (d, 1H, J=8.8 Hz), 8.0 (d, 1H, J=8.8 Hz), 8.56 (d, 1H); MS m/z: 237 (M+H)+ ; Anal. Calcd for C12H13N2OCl.1.0 HCl. C, 52.07; H, 5.13; N, 10.12. Found: C, 51.85; H, 5.46; N, 9.78.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[CH:25])=[O:16]>O1CCCC1.C(N(CC)CC)C>[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[O:11][N:10]=[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH:25]=1)=[O:16]
Reactant: C#Cc1ccccc1NC(=O)C(Cl)Cl
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1-c1cc(-c2c(Cl)cccc2Cl)no1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (1.25 g, 5.6 mmol) and 2,2-dichloro-N-(2-ethynylphenyl)acetamide (1.93 g, 8.5 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL) and triethylamine (1.0 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 4 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(2-ethynylphenyl)acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give 2,2-dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl]acetamide as a light brown solid, 1.24 g.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10](C(O)=O)[S:9][N:8]=2)[CH:2]=1.CCCCCC>ClC1C=CC=CC=1Cl>[C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][S:9][N:8]=2)[CH:2]=1
Reactant: Cc1cccc(-c2nsc(C(=O)O)c2C(=O)O)c1
Solvent: Clc1ccccc1Cl
Solvent: CCCCCC
Product: Cc1cccc(-c2nscc2C(=O)O)c1
Yield: 85.1 %

Procedure:
3-(m-Tolyl)-4,5-isothiazoledicarboxylic acid (7.98 g, 0.0303 mol) was heated in 25 ml of o-dichlorobenzene at vigorous reflux for 15 minutes and cooled. Hexane was added and the resultant precipitate was filtered off to yield 5.52 g (0.0258 mol, 83.1%) of a light pink solid, m.p. 144.5°-146°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13].C([BH3-])#N.[Na+]>CO>[CH2:9]([NH:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: N#Cc1[nH]cnc1N
Reactant: CCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc[nH]c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
4-amino-1H-imidazole-5-carbonitrile (10.0 g, 0.0925 mol) and pentanal (11 mL, 0.10 mol) were mixed in methanol (100 mL). After stirring at room temperature for 2 hours, Sodium cyanoborohydride (7.0 g, 0.11 mol) was added to the mixture. The mixture was continued to stir overnight. The reaction mixture was concentrated, diluted with EtOAc (IL) and washed with sat. NaHCO3 (30 ml) and then brine (50 ml) solutions respectively. The organic layers were dried over Na2SO4, concentrated and purified with combi-flash silica gel chromatography (20%-80% EtOAc in hexane) to yield the desired product (11.5 g, 70%). LCMS calculated for C9H15N4(M+H): 179; found: 179.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[C:11]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:12]=[C:13]([N:32]([CH3:33])[CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:14]=2)[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: Oc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CNC1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(N(C)c2nc(Nc3ccc(O)c(Cl)c3)nc(NC3CCCCCC3)n2)CC1
Yield: 14.3 %

Procedure:
To E7 (1.00 g, 2.7 mmol) dissolved in THF (25 mL) was added a solution of N-methyl-4-(methylamino)-piperidine (0.45 mL, 3.1 mmol) in THF (5 mL) followed by addition of 2.5 N NaOH (1.1 mL, 2.7 mmol) and 2.5 mL of water. The reaction mixture was stirred and heated at reflux overnight. The reaction mixture was extracted three times using dichloromethane, the combined organic layers were washed with a brine and dried over sodium sulfate. The sample was concentrated and the resulting solid was dried overnight under vacuum. Column chromatography (silica gel, 100% methanol) yielded an off-white solid (138) (177 mg, 14%); mp 68° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 v:v:v [KH2PO4(0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 4.7 min, 99.6% purity; MS (TOF ES+) m/z 460 (M+H, 55.3), 251 (100), 224 (51.1).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1.Cl>C1COCC1.O.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:20]1[C:21]([C:22]([F:23])([F:24])[F:25])=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=3)[N:16]=2)[CH:18]=[N:19]1
Reactant: FC(F)(F)c1c(-c2nc(-c3ccc(C4OCCO4)cc3)no2)cnn1-c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Yield: 84.2 %

Procedure:
A solution of 3-(4-(1,3-dioxolan-2-yl)phenyl)-5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazole (25 g, 58.2 mmol) and con. HCl (500 mL) in THF/water (500 mL/500 mL) was stirred at RT for 3 hours. Upon completion of the reaction, as monitored by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried and concentrated under reduced pressure to afford 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (19 g, 49 mmol). The compound had an HPLC retention time=1.90 min.—CHROMOLITH® SpeedROD 4.6×30 mm. flow=5 mL/min (2 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=386.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19](#[N:21])[CH3:20].Cl>C1(C)C=CC=CC=1>[CH2:3]([O:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13](=[O:15])[CH2:20][C:19]#[N:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)(C)COCc1ccccc1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(COCc1ccccc1)C(=O)CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
To a suspension of sodium hydride (1.62 g of a 60% w/w dispersion in mineral oil, 40.5 mmol) in toluene (20 mL) at reflux was added a solution of methyl 3-(benzyloxy)-2,2-dimethylpropanoate [Eur. J. Org. Chem., 2007 (6) 934-942] (6.00 g, 27.0 mmol) and acetonitrile (2.12 ml, 40.5 mmol) in toluene, dropwise over 1 hr. The reaction mixture was heated for a further 5 hr at reflux then cooled to RT. The mixture was acidified to pH 4 with aqueous hydrochloric acid (1M) and extracted with EtOAc. The organic extract was washed with water and with brine then dried (MgSO4) and evaporated in vacuo to afford 5-(benzyloxy)-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (7.50 g, 96%): m/z 232 (M+H)+ (ES+), which was used without purification in the next step.