Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=2)[O:13][N:12]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:52]1[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][N:52]2[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]2)[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=2)[O:13][N:12]=1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(F)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(CN2CC(C(=O)OC)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {6-ethyl-5-[5-(3-fluoro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.13 g, 0.38 mmol) that was obtained in Example 30 (30a), carbon tetrabromide (0.25 g, 0.75 mmol), triphenylphosphine (0.20 g, 0.75 mmol), methyl 3-azetidinecarboxylate hydrochloride (78 mg, 0.51 mmol), and N,N-diisopropylethylamine (0.15 ml, 0.86 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7 to 7:3) as the eluent to afford the title compound (0.11 g) in a yield of 69% as a pale yellow oily product.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])OCC([O-])=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[N:18]=[C:14]([C:2]([F:1])([F:8])[F:9])[CH:13]=[C:12]2[OH:11]
Reactant: COc1ccc(N)cc1
Reactant: O=C([O-])COC(F)(F)F
Product: COc1ccc2nc(C(F)(F)F)cc(O)c2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 117.5 %

Procedure:
A solution of trifluoro-3-oxa-butyrate (14.95 g, 81 mmol) and PPA (72 ml) was heated at 100° C. and then treated with p-anisidine (10 g, 81 mmol) portion wise. The reaction mixture was further heated to 150° C. and stirred for 2 h at 150° C. After cooling to RT, the reaction mixture was poured into a beaker containing ice water. After stirring for 20 min, the mixture was filtered, and the resulting solid was washed with water (˜3 L). The resulting pinkish-purple solid was dried under vacuum to provide 6-methoxy-2-(trifluoromethyl)quinolin -4-ol (11.58 g, 47.6 mmol, 58.6% yield), which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1CCc2ccccc2NC1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1CCc2ccccc2NC1=O

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (General Procedure 6-B), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.15 in 12% methanol/dichloromethane) and purification was by flash chromatography using 12% methanol/dichloromethane as the eluant.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([C:14]([NH2:16])=[O:15])[O:11][C:10]2=[O:17])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:7]2[CH:6]=[CH:5][C:4]([N:9]3[CH2:13][C@H:12]([C:14]([NH2:16])=[O:15])[O:11][C:10]3=[O:17])=[CH:3][C:2]=2[F:1])[CH:21]=1
Reactant: NC(=O)[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C[Sn](C)(C)c1cccnc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)[C@H]1CN(c2ccc(-c3cccnc3)c(F)c2)C(=O)O1
Temperature: 50 °C

Procedure:
A mixture of (5R)-(−)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxamide (Step 3, 422 mg, 1.21 mmol), 3-(trimethylstannyl)pyridine (Step 4, 350 mg, 1.45 mmol), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.0242 mmol), triphenylarsine (59 mg, 0.194 mmol) and copper(I) iodide (9 mg, 0.0484 mmol) in N-methyl-2-pyrrolidinone (4.8 mL) under nitrogen was degassed, heated up to 50° C. and stirred at this temperature for 2 days, during which additional tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.0242 mmol), triphenylarsine (59 mg, 0.194 mmol) and copper(I) iodide (9 mg, 0.0484 mmol) are added. The resulting mixture was diluted with water (15 mL) and extracted with methylene chloride (3×20 mL), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was diluted with ethyl acetate (25 mL) and extracted with aqueous hydrochloric acid (1M, 25 mL), and the aqueous phase was neutralized with sodium hydroxide (s), saturated with sodium chloride and extracted with methylene chloride (3×25 mL) containing a small amount of methanol. This combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the title compound, mp 240-242° C. (dec.); MS (ESI+) for C15H12FN3O3 m/z 302 (M+H)+; [α]25D=−25 (c 0.94, DMSO).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:13]([OH:15])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:22][O:23][C:24](=[O:42])[CH2:25][C:26]1[C:27]([CH3:41])=[N:28][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][C:34]=2[F:40])[C:30]=1[CH3:31].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:22][O:23][C:24](=[O:42])[CH2:25][C:26]1[C:27]([CH3:41])=[N:28][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:13]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([CH:5]=3)=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)=[O:15])=[CH:35][C:34]=2[F:40])[C:30]=1[CH3:31]
Reactant: CCn1c(C(=O)O)cc2cc(F)ccc21
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2F)c1C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(=O)Nc2ccc(Cn3nc(C)c(CC(=O)OC)c3C)c(F)c2)cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To a solution of 1-ethyl-5-fluoro-1H-indole-2-carboxylic acid (140 mg, 0.68 mmol) in 6 mL dichloromethane is added oxalyl chloride (0.094 mL, 0.68 mmol) and a drop dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a solution of [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (177 mg, 0.61 mmol) and diisopropylethylamine (0.23 mL, 1.35 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (8.255 mg, 0.069 mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated in vacuo. The residue is purified by MPLC (dichloromethane/methanol 95:5) to yield 160 mg of (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=481; Retention time HPLC: 0.93 min (method D)). b) To a solution of (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (160 mg, 0.33 mmol) in dioxane (2 mL) is added an aqueous solution of NaOH (1 M, 0.66 mL) and the mixture is stirred at 60° C. for 1 hour. The solvent is evaporated in vacuo, and the residue is suspended in water and treated with acetic acid (2 M). The precipitate is freeze dried, dissolved in methanol and a little dimethylformamide, and the product is precipitated with a little water, filtered and dried to yield 137 mg of the title compound (ESI mass spectrum: [M+H]+=467; Retention time HPLC: 0.89 min (method D)).
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23]C(O)=O)([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].[C:27]([OH:33])(=[O:32])[CH2:28][C:29]([OH:31])=O>O1CCCC1>[CH3:1][C:2]([C@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23][C:29](=[O:31])[CH2:28][C:27]([O:33][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:32])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6])[CH3:3]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 153.4 %

Procedure:
To a solution of [(2R,3S)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-acetic acid (56.4 mg) in tetrahydrofuran (1.13 ml) was added N,N'-carbonyldiimidazole (27.5 mg) at ambient temperature. After stirring for 6 hours at ambient temperature, the magnesium salt of the mono-p-nitrobenzyl ester of malonic acid (84.8 mg) was added and the resulting mixture was stirred overnight at ambient temperature. The solvent was distilled off and the residue was dissolved in ethyl acetate (30 ml) and filtered with a diatomaceous earth. The filtrate was washed with 1N hydrochloric acid, water, phosphate buffer solution (pH 6.8), and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (78.8 mg) was chromatographed on silica gel (1.6 g) eluting with a mixture of methylene chloride and ethyl acetate (10:1 to 2:1) to give 4-nitrobenzyl 4-[(2R,3S)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (64.2 mg) as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([CH3:23])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:30](I)([CH3:32])[CH3:31]>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)=[C:12]([CH3:23])[N:11]([CH:30]([CH3:32])[CH3:31])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: CCc1ccc(Cc2c(OCc3ccccc3)n[nH]c2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2c(OCc3ccccc3)nn(C(C)C)c2C)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 79 %

Procedure:
To a suspension of the thus obtained 3-benzyloxy-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole (200 mg, 0.65 mmol) and cesium carbonate (1.06 g, 3.25 mmol) in N,N-dimethylformamide (4 mL), isopropyl iodide (350 mg, 2.06 mmol) was added dropwise at room temperature. After stirring at room temperature for 13 hours, additional cesium carbonate (1.06 g, 3.25 mmol) and isopropyl iodide (350 mg, 2.06 mmol) were added. After stirring at room temperature for an additional 3 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-benzyloxy-4-(4-ethylbenzyl)-1-isopropyl-5-methyl-1H-pyrazole (179 mg, 79%) as a light-brown oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)O1.Br[C:24]1[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=1.O>C1(C)C(CCO)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([C:24]2[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CCOC(=O)Cc1ccc(Br)s1
Agent: [Pd]
Agent: Cc1ccccc1CCO
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2ccc(O)cc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
After tris(dibenzylideneacetone)dipalladium (0) (110 mg, 0.12 mmol), tri-o-tolylphosphine (61 mg, 0.2 mmol) and 2N aqueous sodium carbonate solution (4 ml) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.8 g, 3.65 mmol) and ethyl (5-bromo-2-thienyl)acetate (1.00 g, 4.01 mmol) which was synthesized according to the method described in literature (Jackson, P. M. et al., J. Chem. Soc. Perkin Trans. 1, 1990, vol. 11, pp. 2909-2918) in a mixture of toluene-ethanol (5:1, 24 ml), the mixture was stirred at 80° C. for 3 hours. After water was poured into the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=3/1) to give ethyl [5-(4-hydroxyphenyl)-2-thienyl]acetate (0.73 g, yield: 77%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[S:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:21]O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:21])=[S:12])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(=S)c1ccc(-c2ccccc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=S)c1ccc(-c2ccccc2)cc1
Reaction time: 10 h

Procedure:
A mixture of 4-phenylthiobenzoic acid (26.29 g), conc. sulfuric acid (5 ml) and methanol (400 ml) is refluxed with stirring for 10 hours. After the reaction is completed, the reaction mixture is concentrated under reduced pressure, and to the residue is added ethyl acetate (400 ml). The mixture is washed with saturated aqueous sodium chloride solution (200 ml×3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 4-phenylthiobenzoate (27.44 g).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6]C[CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2C3CCC2CC([OH:54])C3)CC1>>[OH:54][C@@H:3]1[CH2:4][CH2:6][CH2:7][N:1]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:2]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: NC1CCN(CCN2C3CCC2CC(O)C3)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC[C@@H](O)C2)CC1)c1cc2c(OCC3CCC3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (preparation see Example 22) and amine 24.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH3:23][N:24]([CH3:28])[C:25]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)[CH2:11][CH2:12]1)=[O:26]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Yield: 94.7 %

Procedure:
A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.30 g, 1.0 mmol), dimethylcarbamic chloride (0.09 ml, 1.0 mmol) and triethylamine (0.16 ml, 2.0 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. 5-(4-dimethylcarbamylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (0.35 g, 95%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.88 (s, 6H), 3.31 (dd, J=1.5, 6.4 Hz, 4H), 3.42 (dd, J=1.5, 6.4 Hz, 4H), 6.34 (dd, J=2.6, 9.6 Hz, 1H), 6.41 (d, J=2.6 Hz, 1H), 7.26-7.47 (m, 5H), 8.17 (d, J=9.6 Hz, 1H), 9.88 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 38.9, 46.6, 47.0, 60.9, 96.5, 106.2, 125.0, 126.0, 129.4, 130.2, 139.4, 145.9, 156.0, 164.8.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH:18]([CH3:20])[CH3:19])=[N:16][N:17]=2)[N:14]=1)C(OCC)=O)#[N:2].Cl>>[CH:18]([C:15]1[N:13]2[N:14]=[C:9]([CH2:3][C:1]#[N:2])[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C#N)c1ccc2nnc(C(C)C)n2n1
Agent: Cl
Product: CC(C)c1nnc2ccc(CC#N)nn12
Temperature: 105 °C
Yield: 57.8 %

Procedure:
Ethyl 2-cyano-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)acetate (1.16 g, 4.24 mmol) was suspended in 5N HCl (15 mL, 75 mmol) then heated at about 105° C. for about 20 min. The mixture was cooled to ambient temperature then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (25 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (25 mL), the combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The oil was purified by flash chromatography on silica gel using DCM/MeOH (95:5) as an eluent to give the title compound (0.493 g, 58%): LC/MS (Table 1, Method g) Rt=1.41 min; MS m/z: 202.1 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[N:24](C(C)(C)C)[C:23](=[O:32])[CH2:22]2)=[C:17]([F:33])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:26])(=[O:27])[NH:24][C:23](=[O:32])[CH2:22]2)=[C:17]([F:33])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1
Yield: 61 %

Procedure:
Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxo-isothiazolidin-5-yl)-3-fluorophenyl]propanoate (1.10 g, 2.26 mmol) in trifluoroacetic acid (10.0 mL) was heated for 2 minutes at 130° C. in the microwave. The solution was concentrated in vacuo and purified by preparative LCMS to afford product as a white solid (614 mg, 61%). 1H NMR (400 MHz, CD3OD): δ 7.53 (m, 1H), 7.18–7.14 (m, 2H), 5.33–5.30 (m, 1H), 4.39 (m, 1H), 3.82 (s, 3H), 3.43–3.12 (m, 4H). LCMS found for C13H16FN2O5S (M+H)+: m/z=331.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O-:20][C:21]#[N:22].[Na+]>C(O)(=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:21]([NH2:22])=[O:20])[N:16]=3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: N#C[O-]
Reactant: Fc1ccc(Sc2ccc(-c3cc[nH]n3)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)n1ccc(-c2ccc(Sc3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A solution of 3-[4-(4-fluorophenylthio)phenyl]-1H-pyrazole (85 mg, 0.31 mmol) in 1.5 mL glacial acetic acid was treated with a solution of sodium cyanate (31 mg, 0.47 mmol) in 0.5 mL of water. The resulting white suspension was stirred at room temperature overnight. The suspension was then diluted with 10 mL of EtOAc, resulting in a yellow solution which was washed with water and sat. NaHCO3 solution, dried over Na2SO4 and evaporated. The residue was trituated with 3 mL of 25% EtOAc/hexane. The white solid that formed was collected by filtration and dried to give 65 mg (66%) of the title compound, mp 150-155° C. (TLC Rf=0.22 (25% EtOAc/hexane)). 1H NMR (300 MHz, CDCl3): δ8.27 (d, J=2.1 Hz, 1H, pyrazole H), 7.77 (d, J=7.5 Hz, 2H, PhH), 7.48-7.06 (m, 6H, PhH), 6.71 (d, J=2.1 Hz, 1H, pyrazole H), 5.31 (br s, 2H, NH2).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1(=O)[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]([NH:4][C:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)NC1=CC(=O)CCC1

Procedure:
Equimolar amounts of isopropylamine and cyclohexane-1,3-dione were dissolved in benzene and heated with addition of p-toluenesulfonic acid to boiling with a water trap. After the trapping of water was complete, the mixture was thoroughly washed with water, the solvent was stripped off, and the residue was recrystallized.
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[K+].[Na+].[Cl-]>C1COCC1>[C:12]1([S:11][CH:10]([S:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][C:8]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Sc1ccccc1
Reactant: C(=CC(=Nc1ccccc1)Sc1ccccc1)Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(N=C(CC(Sc2ccccc2)Sc2ccccc2)Sc2ccccc2)cc1
Reaction time: 10 h
Yield: 75.9 %

Procedure:
To a solution of 2.0 g of phenyl N-phenyl-3-(phenylthio)-2-propenimidothioate in THF (45 mL) was added 1.61 g of thiophenol and 88.9 g of potassium tert-butoxide at room temperature and stirred for 10 hours. To the reaction mixture was added 50 ml of a saturated NaCl solution and extracted with 100 ml of ethyl acetate. The organic layer was dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1 to hexane:ethyl acetate=10:1) to obtain 2.0 g of phenyl 3,3-bis(phenylthio)-N-phenylpropanimidothioate as a yellow oil.