Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[CH3:16][NH2:17].C[O-].[Na+]>>[NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:3]=1[C:4]([NH:17][CH3:16])=[O:6]
Reactant: CCOC(=O)c1cc(C#N)cc(C)c1N
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 96.9 %

Procedure:
The above-described method (Example 3) was repeated to stir ethyl 2-amino-5-cyano-3-methylbenzoate (0.50 g, 2.40 mmol) with methylamine (3.73 g, 48 mmol, 40% in methanol) and sodium methoxide (22 mg, 30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and 2-amino-5-cyano-N,3-dimethylbenzamide (0.44 g, 95.9% of theory, 99.0 area % LC) was obtained as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=Cc1cc(O)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(OCC(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a magnetically stirred solution of 3-chloro-5-hydroxybenzaldehyde (2.0 g, 12.8 mmol; see Example 1(ii) above) and potassium carbonate (2.3 g, 16.6 mmol) in DMF (35 mL) under nitrogen was added 2,2,2-trifluoroethyl p-toluenesulfonate (4.2 g, 16.6 mmol) at room temperature. The mixture was heated to 110° C. for 7 h and then stirred overnight at room temperature. The reaction was cooled to 0° C., poured into ice-cold 2 N HCl (100 mL) and extracted with EtOAc (2×75 mL). The combined organic extracts were washed with 0.5 N HCl (2×50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The brown oil was chromatographed on silica gel eluting with Hex:EtOAc (6:1) to afford the sub-title compound (1.9 g, 61%) as a yellow oil.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:18]=[C:19]=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[CH2:11]([N:18]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][N:10]=[C:19]1[S:20][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccc1
Reactant: S=C=NCc1ccccc1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(CSc2nnc(-c3ccccc3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using benzoic acid hydrazide, benzyl isothiocyanate and 4-methoxybenzyl bromide as the starting materials. (M+H)+−388.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[NH:42][C:41](=[O:43])[O:40][N:39]=4)=[CH:36][CH:37]=3)=[O:23])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(-c5noc(=O)[nH]5)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
To a mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (40 mg, 0.1 mmol) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (22 mg, 0.1 mmol) in 3 mL of DCM was added EDCI (58 mg, 0.3 mmol) followed by N-methylimidazole (25 mg, 0.3 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)benzamide (15 mg, 26%) as white solid. 1H NMR (300 MHz, DMSO): δ 10.82 (s, 1H), 10.22 (s, 1H), 9.43 (s, 1H), 8.98 (s, 1H), 8.64 (d, 1H, J=8.1 Hz), 8.12-8.02 (m, 3H), 7.87-7.54 (m, 5H), 7.01 (d, 1H, J=9.0 Hz), 3.82 (s, 3H), 3.76 (s, 3H). LC-MS: 568 [M+H]+, tR=1.54 min. HPLC: 97.16% at 214 nm, 96.94% at 254 nm, tR=2.86 min.
Reaction SMILES: [CH2:1]=[C:2]1[C:6](=[CH2:7])[S:5][C:4]([NH2:8])=[N:3]1.[C:9]([O:13][C:14](=[O:17])[CH2:15][Br:16])([CH3:12])([CH3:11])[CH3:10]>>[BrH:16].[C:9]([O:13][C:14](=[O:17])[CH2:15][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]1=[NH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=c1nc(N)sc1=C
Reactant: CC(C)(C)OC(=O)CBr
Product: Br
Product: Cc1sc(=N)n(CC(=O)OC(C)(C)C)c1C
Temperature: 85 °C

Procedure:
A mixture of 4,5-dimethlyl-thiazol-2-ylamine (1.0 g, 7.8 mmol) and bromo-acetic acid tert-butyl ester (1.4 mL, 9.4 mmol) was heated at 85° C. for 14 hours and then cooled to ambient temperature. Recrystallization of the residue from ethyl acetate provided 2.9 g of a 4:1 mixture of the title compound to starting 4,5-dimethyl-thiazol-2-ylamine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:19])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:20]Br>C(O)(=O)C>[Br-:20].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:19])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[NH+:13]=3)[Br:20])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)OCO3)[nH+]1
Product: [Br-]
Temperature: 25 °C
Yield: 184.6 %

Procedure:
To a stirred solution of 1-benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethanone (2 g, 7.83 mmol) in acetic acid (15 mL) was slowly added a solution of bromine (0.40 mL, 7.83 mmol, 1 equiv) in acetic acid (5 mL). The resulting reaction mixture was stirred at ambient temperature for I hour and then concentrated in vacuo. The residue was stirred in diethyl ether (20 mL) and methylene chloride (10 mL) over night. A light beige solid was filtered off, providing 2-(2-Benzo[1,3]dioxol-5-yl-1-bromo-2-oxo-ethyl)-6-methyl-pyridinium bromide (3.0 g, 92%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1>C(#N)C.O>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:29]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (25 mg, 0.085 mmol, EXAMPLE 1 Step 3), indole-2-carboxylic acid (15 mg, 0.093 mmol), triethylamine (0.060 mL, 0.43 mmol), and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (48 mg, 0.13 mmol) in acetonitrile (1 mL) was stirred at room temperature for 4 h. The mixture was poured into water, and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual solid was washed with methanol to give 22 mg (71%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[N:12]=1)([CH3:4])([CH3:3])C.ClC(O[C:24]1[CH:29]=CC=C[CH:25]=1)=O.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([O:5][C:6](=[O:19])[NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[N:12]=2)[CH:3]=[CH:29][CH:24]=[CH:25][CH:4]=1
Reactant: COCCOCc1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COCCOCc1csc(NC(=O)Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-butyl 4-((2-methoxyethoxy)methyl)thiazol-2-ylcarbamate (Intermediate III, 3.4 g, 0.018 mol) was dissolved in pyridine (50 mL) and a catalytic amount of DMAP was added (0.2 g, ˜10 mol %). To this mixture a solution of phenyl chloroformate (2.27 mL, 1 eq.) in THF (50 mL) was added drop wise and the resulting reaction mixture was stirred for 3 hours at ambient temperature. Then, H2O was added and the diluted mixture was extracted with EtOAc. Dried the organic layer over Na2SO4, filtered and concentrated in vacuo. Purification over SiO2 eluting with 1:1 EtOAc/heptane gave 2.4 gram of the product as a yellow fluffy solid. 1H-NMR (300 MHz, DMSO-d6) δ 11.70 (s, br, 1H), 7.42 (d, 1H), 7.37 (m, 1H), 7.08 (m, 3H), 4.59 (s, 2H), 4.38 (d, 2H), 3.30 (s, 2H), 3.23 (t, 2H), 1.75 (q, 2H), 0.97 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:15]4[N:43]=[C:18]([C:19]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[C:20]5[NH:36][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[Zn:50].Cl[S:52]([OH:55])(=[O:54])=[O:53]>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:44]4[CH:49]=[CH:48][C:47]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:46][CH:45]=4)=[C:15]4[N:43]=[C:18]([C:19]([C:37]5[CH:38]=[CH:39][C:40]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:41][CH:42]=5)=[C:20]5[NH:36][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[Zn+2:50].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:44]4[CH:49]=[CH:48][C:47]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:46][CH:45]=4)=[C:15]4[N:43]=[C:18]([C:19]([C:37]5[CH:38]=[CH:39][C:40]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:41][CH:42]=5)=[C:20]5[NH:36][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[Zn+2:50].[Zn+2:50]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccc(-c2c3nc(c(-c4ccccc4)c4ccc([nH]4)c(-c4ccccc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: [Zn]
Solvent: ClC(Cl)Cl
Product: O=S(=O)([O-])c1ccc(-c2c3nc(c(-c4ccc(S(=O)(=O)[O-])cc4)c4ccc([nH]4)c(-c4ccc(S(=O)(=O)[O-])cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Product: [Zn+2]
Reaction time: 12 h

Procedure:
To a mixture of 1 g of zinc 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin and chloroform, there was added 60 μl of chlorosulfonic acid dissolved in 10 ml of chloroform at 0° C. After 12 h, the solution was poured on ice, and the organic phase was separated. Evaporation of the solvent yielded the product.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (117.0 mg, 1.39 mmol) in 6.8 mL water was added 2-aminoethanethiol hydrochloride (85.0 mg, 0.75 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25e (148.0 mg, 0.78 mmol) in 6.8 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 169.2 mg (91% from 24e) of clean 26e as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=[CH:10][N:9]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CO>[N:26](=[C:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=[CH:10][N:9]=1)[CH3:2])[OH:27]
Reactant: NO
Reactant: COC(=O)Cc1c(Oc2cccc(C(C)=O)c2)ncnc1N(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(Oc2cccc(C(C)=NO)c2)ncnc1N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The methyl 4-(3-acetylphenoxy)-6-dimethylamino-pyrimidin-5-yl-acetate obtained is dissolved in 500 ml methanol, and hydroxylamine hydrochloride (76 g, 1.1 mol) and sodium acetate (107 g, 1.3 mol) are added at 0° C. After stirring for 2 hours at room temperature the product is crystallized by adding water. Filtering and drying gives methyl 4-[3-(1-hydroximinoethyl)-phenoxy]-6-dimethylamino-pyrimidin-5-yl-acetate in form of yellowish crystals (292 g) having a m.p. of 113°-115° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH3:12])(=[O:3])[NH2:2].C1C(=O)N([Br:26])C(=O)C1>CC(O)=O.O>[Br:26][C:7]1[S:6][C:5]([NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:13])=[C:4]([C:1](=[O:3])[NH2:2])[CH:8]=1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sccc1C(N)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(C)(C)C(=O)Nc1sc(Br)cc1C(N)=O
Temperature: 25 °C

Procedure:
Intermediate 10 (46.5 g, 172 mmol) is dissolved in AcOH (700 mL). To the resulting suspension, NBS (32.2 g, 181 mmol) is added. The mixture is stirred at room temperature, after which it is evaporated to give a slurry. This slurry is taken up in water to give a suspension that is filtered. Resulting precipitate is dried in the vacuum oven and used as such.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10](I)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>C1COCC1.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[N:15][CH:16]=1
Reactant: Cc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1ccc(C2CN(C(=O)OC(C)(C)C)C2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-Boc-3-iodoazetidine (126-1) (500 mg, 1.77 mmol) in THF (5 mL) was added a solution of Reike Zinc (1.4 mL, 0.1 g/mL in THF, 2.2 mmol); a slight exotherm was noted upon addition of the zinc. After stirring for 1 h at room temperature, a solution of 2-bromo-5-methylpyridine (304 mg, 1.77 mmol) in THF (2 mL) was added, followed by bis(tri-tert-butylphosphine)palladium(0) (90 mg, 0.17 mmol) and the reaction was heated at 75° C. for 2 h. After stirring for 16 h at room temperature, the reaction was filtered through Celite, rinsing with EtOAc. The filtrate was washed with aqueous NaHCO3 (sat.) and brine, and the organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/hexane) to provide 126-2 as a colorless oil. MS: m/z=249.4 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCCCCC.O.P(Cl)(C(C)(C)C)C(C)(C)C>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 24 mg (0.044 mmol) of (t-Bu)2PCl)2PdCl2,, 1.0 (8.8 mmol) of chlorobenzene, 1.3 g (10.66 mmol) of Ph—B(OH)2, 3.7 g (26.77 mmol) of K2CO3 in 5 mL of THF. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 220 mL of hexane and 150 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (100 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 0.78 g (57% yield) of biphenyl.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[NH2:40][OH:41]>ClCCl.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([C:17](=[N:40][OH:41])[NH2:16])=[CH:19][CH:20]=2)=[O:15])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C(O)c1cnn(Cc2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: NC(=NO)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1

Procedure:
20.8 g of 1-benzylpyrazole-4-carboxylic acid was reacted with 1 equivalent of 4-(aminomethyl)benzonitrile, in the presence of 1.1 equivalents of oxalyl chloride, 3 equivalents of triethylamine in dichloromethane at room temperature for 3 h. The product was then reacted with hydroxylamine hydrochloride (3 equivalents) in ethanol at 80° C. for 3 h. The target compound (17.5 g) was obtained as a off-white powder following solvent removal by evaporation. Purity assessed by HPLC was 98.7%, and mass was verified by LC/MS/MS (predicted m+1=350.2, obtained m+1=350.2). 1H-NMR (DMSO): δ 4.39-4.40 (2H), 5.34 (2H), 5.76 (2H), 7.25-7.30 (4H), 7.34-7.36 (3H), 7.59-7.62 (2H), 7.91 (1H), 8.27 (1H), 8.63 (1H), 9.57 (1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:32]=[N:33][CH:34]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1cncc(Cl)c1
Product: C[C@@H](c1ccc(-c2cncc(Cl)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-chloropyridine-3-boronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.64 min, m/z=469.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=O.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH:25]1([NH:28][C:3](=[O:5])[CH:2]([Cl:1])[CH2:6][C:7]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]3)[C:10]([Cl:23])=[CH:9][C:8]=2[Cl:24])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2cc(CC(Cl)C(=O)NC3CC3)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A stirred solution of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (Compound 2), 0.071 g (0.0013 mole) of cyclopropylamine, 0.17 g (0.0013 mole) of 1-hydroxybenzotriazole hydrate, and 0.18 g (0.0014 mole) of N,N-diisopropylethylamine in approximately 15 mL of tetrahydrofuran was cooled to 0° C. To this cold mixture was added 0.26 g (0.0013 mole) of 1,3-dicyclohexylcarbodiimide. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was filtered. The filtrate was diluted with carbon tetrachloride and was washed in succession with a IN hydrochloric acid solution, an aqueous 10% sodium hydroxide solution, water, and an aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give 0.43 g of N-cyclopropyl2 -chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionamide as a solid, m.p. 139°-143° C., Compound 17 of Table 1.
Reaction SMILES: FC1C=CC=CC=1C#N.OCCN1CCNCC1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]#[N:35])[CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C.[C:45]12([C:55](Cl)=[O:56])[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:53][CH:47]([CH2:48]3)[CH2:46]1)[CH2:52]2>CN(C)C=O.C(Cl)Cl>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][O:19][C:55]([C:45]23[CH2:54][CH:49]4[CH2:48][CH:47]([CH2:53][CH:51]([CH2:50]4)[CH2:52]2)[CH2:46]3)=[O:56])[CH2:23][CH2:24]1)#[N:35]
Reactant: N#Cc1ccccc1N1CCN(CCO)CC1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: N#Cc1ccccc1F
Agent: OCCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(CCOC(=O)C23CC4CC(CC(C4)C2)C3)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
2-Fluorobenzonitrile (6.0 g, 50 mmoles) and 1-(2-hydroxyethyl)-piperazine (6.5 g, 50 mmoles) were combined in 500 mL of dimethylformamide and heated at 80° C. under N2 for 24 hours. After cooling, the solvent was removed in vacuum and the crude 1-(2-hydroxyethyl)-4-(2-cyanophenyl)piperazine thus produced was used without purification. 2.3 Grams (10 mmole) of the crude 1-(2-hydroxyethyl)-4-(2-cyanophenyl)piperazine was dissolved in 100 mL of CH2Cl2 and 1.3 g (10 mmole) of diisopropyl ethylamine was added, followed by addition of 2.0 g (10 mmole) of 1-adamantanecarbonyl chloride. The mixture was stirred at room temperature for 3 hours, washed with saturated NaHCO3 solution, saturated brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel with CHCl3 and the product thus obtained was crystallized from isopropanol with the addition of 4N isopropanolic HCl to give 1.1 g of title compound as the monohydrochloride salt, mp. 230°-231° C.