Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[CH3:11][Si](C=[N+]=[N-])(C)C>ClCCl.C(OCC)C>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH3:11])=[O:5]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Reaction was carried out in two separate batches, employing 5 g of 3,3,3-trifluoro-2,2-dimethylpropionic acid in each batch. To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (5 g, 32 mmol) in anhydrous dichloromethane (20 mL) at 0° C. (under an argon atmosphere), was added dropwise a solution of (trimethylsilyl)diazomethane (18 mL of a 2M solution in diethyl ether, 35 mmol) (gas evolution observed). The resulting yellow solution was allowed to warm to rt and stirred for a further 48 h. An additional 5 mL of 2M (trimethylsilyl)diazomethane solution (10 mmol) was added, and stirring continued for a further 5 h whereupon a further 6 mL of 2 M (trimethylsilyl)diazomethane solution (12 mmol) was added. After stirring for a further 15 h, the reaction mixture was concentrated in vacuo (keeping bath temperature below 30° C.). The resulting oil was redissolved in diethyl ether (200 mL), washed with saturated sodium hydrogencarbonate solution (100 mL), separated, and dried over MgSO4. Filtration followed by concentration in vacuo (keeping bath temperature below 30° C.) gave crude product. Crude product from both batches were combined to afford crude methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (7.69 g) as a yellow oil which was taken on without further purification. 1H NMR (300 MHz, CDCl3) δ 3.86 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:10][O:9][CH2:8][CH2:7]1.[CH2:11]([C:17]1[S:18]C=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C=O)C>[Cl-].[NH4+]>[CH2:11]([C:17]1[S:18][C:6]([CH:10]=[O:9])=[CH:7][CH:8]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCc1cccs1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(C=O)s1
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere at 0° C., 24 ml of n-butyllithium (1.6M in hexane) were added by dripping to a THF solution containing 2-hexylthiophene (5 g). The solution was then stirred for another 15 minutes and, after adding DMF (5 ml), set to room temperature. The resulting solution was then poured into a IN ammonium chloride solution and extracted with methylene chloride. An organic layer was washed with water and dried with anhydrous magnesium sulfate. A crude product was collected by removing the solvent and then purified by a column chromatograph (carrier: silicon dioxide; eluate: hexane/methylene chloride-4/1 (volume ratio)) to obtain 4.6 g of a product.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F-].[Cs+].[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH3:37])=[CH:24]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>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=1.O>[CH3:37][C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[CH2:31][CH2:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)=[CH:29][CH:28]=2
Reactant: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2[nH]1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2[nH]1
Temperature: 65 °C
Yield: 44.9 %

Procedure:
A reaction flask was charged with Cs2CO3 (1.14 g, 3.5 mmol), CsF (0.38 g, 2.5 mmol), 4-cyanophenylboronic acid (425 mg, 2.5 mmol), and H2O (10 mL) followed by a toluene solution (10 mL) of 5-bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-indole (307 mg, 1.0 mmol). The resulting mixture was purged with nitrogen. To the reaction mixture was then added 2-dicyclohexylphosphino(biphenyl) (35 mg, 0.1 mmol) and Pd2(dba)3 (46 mg, 0.05 mmol). The resulting reaction mixture was then heated to 65° C. overnight under nitrogen after which HPLC indicated that all the 5-bromo-2-[2-(-(R)-methyl-pyrrolidin-1-yl-ethyl]-1H-indole was consumed. The reaction mixture was cooled to room temperature and IPAc (20 mL) was added. The organic layer was separated and concentrated. The residue was purified by column chromatography eluting with heptane/acetone/CH2Cl2/Et3N (600 mL/40 mL/5 mL/2 mL). The fractions containing product were combined and concentrated under reduced pressure to provide the title compound as a semi-solid (148 mg). 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.65–7.74 (m, 5H), 7.40 (d, J=8.5 Hz, 1H), 7.33 (dd, J=1.8, 8.5 Hz, 1H), 6.27 (s, 1H), 3.37–3.42 (m, 1H), 3.21–3.25 (m, 1H), 3.01–3.16 (m, 2H), 2.54–2.62 (m, 2H), 2.33 (q, J=8.78Hz, 1H), 2.04–2.08 (m, 1H), 1.80–1.93 (m, 2H), 1.56–1.63 (m, 1H), 1.21 (d, J=6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 146.99, 139.96, 135.61, 132.05, 130.30, 128.74, 127.32, 120.02, 119.13, 118.36, 111.13, 109.16, 99.49, 61.25, 53.68, 53.57, 32.92, 26.21, 22.14, 18.98. [M+H]+ at m/z 330.
Reaction SMILES: [N:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:26][CH:27]3[CH2:29][O:28]3)[C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][C:20]([Br:25])=[CH:19][CH:18]=3.[Li+].[Br-]>C1COCC1>[N:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:29][CH:27]([OH:28])[CH2:26][N:16]2[C:17]3[CH:18]=[CH:19][C:20]([Br:25])=[CH:21][C:22]=3[C:23]3[C:15]2=[CH:14][CH:13]=[C:12]([Br:11])[CH:24]=3)=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23 %

Procedure:
4-Azidoaniline (0.038 g, 0.283 mmol) was added to a solution of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (0.100 g, 0.262 mmol) in THF (0.10 mL). LiBr (0.001 g, 0.013 mmol) was added and the reaction was stirred at room temperature for 3 days. The reaction was purified directly by chromatography (SiO2, 0-25% EtOAc/Hexane) to afford the desired product (31 mg, 23%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[N:21]=[C:20]2[C:22]([Cl:28])=[CH:23][C:24]([Cl:27])=[C:25]([Cl:26])[C:19]2=[N:18]1)[C:14]#[N:15]>C1COCC1>[C:14]([C:13]([NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:29])[CH2:16][N:17]1[N:21]=[C:20]2[C:22]([Cl:28])=[CH:23][C:24]([Cl:27])=[C:25]([Cl:26])[C:19]2=[N:18]1)#[N:15]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C#N)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-cyanobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (4.2 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=433, RT=0.64 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([OH:15])=O)[N:10]([CH3:16])[C:9]2=[O:17])=[N:6][CH:7]=1.C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[CH2:57][NH2:58]>ClCCl.C(OCC)C>[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[CH2:57][NH:58][C:13]([CH:11]1[CH2:12][N:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=2)[C:9](=[O:17])[N:10]1[CH3:16])=[O:15]
Reactant: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
1-(5-Fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (211 mg, 0.878 mmol) was suspended in dichloromethane (5 ml) under argon and treated with N-ethylmorpholine (0.667 ml, 5.27 mmol), 1-hydroxybenzotriazole hydrate (161 mg, 1.054 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.054 mmol) and stirred at room temperature for ˜5 minutes. The mixture was then treated with 1-(2,4-dichlorophenyl)methanamine (0.117 ml, 0.878 mmol) and left to stir overnight at room temperature. The mixture was diluted with dichloromethane (˜10 ml) and washed with saturated sodium hydrogen carbonate solution, water, 10% aqueous citric acid, water, and brine, then filtered through a hydrophobic frit and evaporated. Trituration of the resulting oil with diethyl ether gave N-[(2,4-dichlorophenyl)methyl]-1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxamide (187 mg, 53.5% yield) as a white solid which was collected by filtration and dried in vacuo. LC/MS [M+H]+=398, retention time=2.12 minutes.
Reaction SMILES: C(Cl)Cl.C[O:5][C:6]1[CH:21]=[CH:20][C:9]([CH2:10][N:11]2[NH:17][C:16](=[O:18])[CH:15]3[CH:13]([CH2:14]3)[C:12]2=[O:19])=[CH:8][CH:7]=1.B(Br)(Br)Br>O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[NH:17][C:16](=[O:18])[CH:15]3[CH:13]([CH2:14]3)[C:12]2=[O:19])=[CH:20][CH:21]=1
Reactant: COc1ccc(CN2NC(=O)C3CC3C2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1NN(Cc2ccc(O)cc2)C(=O)C2CC12
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To 5 ml of methylene chloride was added 462 mg (1.87 mmol) of (±)-3-(4-methoxybenzyl)-3,4-diazabicyclo[4.1.0]heptane-2,5-dione obtained in Reference Example 19. The mixture was cooled on a dry ice/ethanol bath, and 0.1 ml (1.1 mmol) of boron tribromide was added thereto dropwise. The temperature was elevated to room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was recrystallized from ethanol/chloroform to obtain 120 mg (29.6%) of the titled compound.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]#[C:14][CH2:15][CH:16]([OH:18])[CH3:17])=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH3:3].C([O-])(O)=[O:31].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].Cl[Pd]Cl.C(Cl)Cl>[CH2:2]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](=[O:31])[CH2:14][CH2:15][CH:16]([OH:18])[CH3:17])=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH3:3]
Reactant: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C#CCC(C)O)ccc21
Reactant: O=C([O-])O
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: ClCCl
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(=O)CCC(C)O)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the bi-layer system of 3 N HCl (5 mL) and CH2Cl2 is added 5-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl)-pent-4-yn-2-ol (107 mg, 0.27 mmol), PdCl2 (5 mg, 0.028 mmol), and n-Bu4NCl (17 mg, 0.056 mmol). The resulting mixture is stirred at room temperature for 72 hr, and then poured into saturated NaHCO3 solution. The aqueous layer is extracted with CH2Cl2 and the combined organic layers are dried over Na2SO4. Solvent is removed and purification by preparative TLC provides the product as white solid. 1H NMR (CDCl3) δ 8.44 (d, 1H), 7.80 (dd, 1H), 7.85 (d, 1H), 7.40 (d, 1H), 7.36 (d, 1H), 7.18 (d, 1H), 7.14 (d, 1H), 6.36 (s, 2H), 4.27 (q, 2H), 3.86 (m, 1H), 3.19 (t, 2H), 1.93 (m, 2H), 1.25 (d, 3H), 1.09 (t, 3H). LCMS 410.2 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19]([OH:21])=O.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:41][NH:42][C@H:43]1[C:52]2[C:47](=[CH:48][C:49]([CH2:53][N:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][N:42]([C@H:43]1[C:52]2[C:47](=[CH:48][C:49]([CH2:53][N:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1)[C:19](=[O:21])[CH2:18][C@@H:3]1[C:2](=[O:1])[NH:7][CH:6]=[CH:5][N:4]1[S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)O)cc1
Reactant: CN[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)N(C)[C@@H]2CCCc3cc(CN4CCCCC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 10 ml of dry DCM, 0.5 mmol of (R)-2-(3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetic acid and 0.5 mmol of PyClU were combined. Next, 0.6 mmol of (R)—N-methyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (prepared in Example 11) and 1.5 mmol of DIEA were added and the mix was stirred at room temperature under nitrogen for 1 h. The reaction was then quenched with 20 ml of saturated sodium bicarbonate, then extracted with EtOAc (2×30 ml), washed with brine (1×20 ml), dried with sodium sulfate, and concentrated. Purification by chomatography over silica gel using 0 to 15% MeOH (2M ammonia) in ethyl acetate gave the title compound. MS 551 (ESI, pos. ion). Similarly, N-methyl-2-((R)-3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydropyrazin-2-yl)-N—((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide, N-methyl-2-((R)-3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)-N—((R)-7-(piperidin-1-ylmethyl)choman-4-yl)acetamide, N-methyl-2-((R)-3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydropyrazin-2-yl)-N—((R)-7-(piperidin-1-ylmethyl)choman-4-yl)acetamide, N—((R)-7-((tert-butylamino)methyl)choman-4-yl)-N-methyl-2-((R)-3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetamide, and N—((R)-6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-N-methyl-2-((R)-3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetamide were prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)C(=O)O
Yield: 68.9 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl) -allyloxy]-phenyl}-2-ethoxy-propionate (example 127) (522 mg, 1.0 mmol) and sodium hydroxide (1M, 10.0 ml, 10.0 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionic acid (325 mg, 67%) as a colourless wax, which contained 0.167 molar equivalents of AcOEt.
Reaction SMILES: C(O[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[C:16]3[S:20][C:19]([NH:21][CH:22]4[CH2:24][CH:23]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:18][C:17]3=[O:31])[N:13]=2)[N:8]=[CH:7][C:6]=1[C:32]#[N:33])(C)C.C(O[Na])(C)=O.O=C1C(=CC2N=C3C(=CC=2)N=CC(C#N)=C3)SC(NCC2SC=CC=2)=N1>CC(O)=O>[O:31]=[C:17]1[C:16](=[CH:15][C:12]2[N:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:32]#[N:33])=[CH:5]3)[S:20][C:19]([NH:21][CH:22]2[CH2:24][CH:23]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18]1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc2c1
Temperature: 100 °C
Yield: 21.5 %

Procedure:
To a mixture of 2-(trans)-phenylcyclopylamino-thiazol-4-one (38.0 mg, 0.16 mmol) (see Example 3), AcONa (160 mg, 1.95 mmol), and 6-formyl-[1,5]naphthyridine-3-carbonitrile (38.5 mg, 0.21 mmol) (see Example 11), in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water acetone and ether to give 6-[4-oxo-2-(2-phenyl-cyclopropylamino)-4H-thiazol-5-ylidenemethyl]-[1,5]naphthyridine-3-carbonitrile as a yellowish solid (13.7 mg, 18.3%). HR-ES (+) m/e calcd for C22H15N5OS (M+H)+ 398.1070. found 398.1071.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].O>C(#N)C>[C:24]1(=[O:33])[N:23]([CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc(OCCCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Methyl 3-hydroxybenzoate (3.0 g, 19.7 mmol) was dissolved in 50 mL of acetonitrile and K2CO3 (3.27 g, 23.7 mmol) was added. The resulting mixture was reacted with N-(4-bromobutyl)phthalimide (6.68 g, 23.7 mmol) and KI (3.93 g, 23.7 mmol) and stirred overnight at 70° C. Following the addition of water, the resulting mixture was extracted with chloroform. The organic layer was washed with brine. The organic layer was dried with sodium sulfate and then concentrated under reduced pressure, followed by recrystallization with n-hexane/ethyl acetate to give a white crystal (6.60 g, 94.8%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH2:26](O)[CH2:27][CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[O:9]=[C:6]1[C:5]2[CH:10]=[CH:11][C:2]([O:1][CH2:26][CH2:27][CH3:28])=[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[C:4]=2[O:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.522 g, 1.50 mmol), n-propanol (0.135 mL, 1.80 mmol) and triphenylphosphine (0.590 g, 2.25 mmol) in toluene (6 mL) was added with a 40% solution of diethyl azodicarboxylate in toluene (0.980 g, 2.25 mmol), and the mixture was stirred at 110° C. for 5 hours in a sealed tube. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(3-oxo-6-propoxy-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.205 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:17][CH2:18][S:19][CH3:20])[N:14]=1)=[O:8].ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:17][CH2:18][S:19]([CH3:20])=[O:33])[N:14]=1)=[O:8]
Reactant: CSCCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)CCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
1-(3,4-Dichlorobenzyl)-3-(4-((2-(methylthio)ethoxy)methyl)thiazol-2-yl)urea (Example 26) (0.98 mmol, 0.4 g) was dissolved in CHCl3 (10 mL) and cooled to 0° C. 3-Chloroperbenzoic acid (1 eq, 0.98 mmol, 0.17 g) was added and the mixture was stirred at room temperature overnight. LC-MS indicated the product was a mixture of sulfoxide and sulfone. Sodium bicarbonate (saturated, 10 mL) was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give an oil. Purification by preparative HPLC yielded 0.048 g of the title compound as a white solid. 1H NMR (300 MHz, CD3OD): δ 7.49-7.45 (m, 2H), 7.25 (m, 1H), 6.85 (s, 1H), 4.87 (s, 2H), 4.45 (s, 2H), 3.86 (m, 2H), 3.11-2.91 (m, 2H), 2.65 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][N:30]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:29]2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Clc1ccc(CC2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccc(Cl)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (8.1 mg). Calcd for C22H21ClN2O2: 380.1292, found 380.1295.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=O)[C:12]([CH3:14])=[O:13].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12](=[O:13])[CH3:14]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=NNc1ccc(Cl)cc1Cl)C(C)=O
Yield: 85.1 %

Procedure:
A mixture of 2,4-dichlorophenylhydrazine (1.0 g, 4.7 mmol), ethyl pyruvate (0.53 mL, 4.7 mmol), triethylamine (0.65 mL, 4.7 mmol) and ethanol (5 mL) was heated at reflux overnight. The solvent was evaporated and the residue taken up in chloroform. The solution was washed with water and brine and dried over magnesium sulfate and concentrated, leaving an oil (1.1 g, 98%).