Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14]
Reactant: N#CC(Br)c1ccccn1
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(Sc1nc2ccccc2[nH]1)c1ccccn1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
A mixture of 2-mercaptobenzimidazole (0.30 g, 3.0 mmole), bromo(2-pyridyl)acetonitrile (0.59 g, 3.0 mmole) and potassium carbonate (0.37 g 3.0 mmole) in 50 ml of dry N,N-dimethylformamide was heated at 60° C. for 6 h. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with water and then saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated to give a solid. The crude product was further purified by column chromatography on silica gel (100% ethyl acetate) to give 66 mg (10%) of the title compound as a solid; mp 166-167° C.; 1H NMR (DMSO-d6) δ 9.3 (m, 1H), 8.65 (m, 2H), 8.32 (m, 1H), 7.78 (br s, 4H), 4.81 (br s, 2H) ppm; IR ν 2206, 1512, 1465, 1432, 1357, 1179, 740 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:14]=O)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=[N:26][NH:25][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(c1ccc(F)cc1)C(C=O)c1ccc(SC)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1ccc(C2C=NNC(=O)C2c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 5.3 %

Procedure:
The aldehyde-ester, hydrate, and hydroxy lactone from Example 16 (0.10 g, 3 mmol), were dissolved in 100 mL of ethanol. This solution was treated with hydrazine monohydrate (0.15 mL, 30 mmol) and the resulting solution was stirred at reflux in a Soxhelet apparatus containing molcular sieves. After 18 hours, the reaction mixture was cooled and the volatile materials removed under reduced pressure. The residue was partitioned between ethyl acetate and aqueous HCl. The aqueous layer was washed twice with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (4:1 hexanes/ethyl acetate) to obtain the title compound (yield: 50 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 3.75 (d, J=12 Hz, 1H), 3.87 (d, J=12 Hz, 1H), 6.93-7.08 (m, 6H), 7.16 (d, J=9 Hz, 2H), 8.71 (s(br), 1H). MS (DCI/NH3) m/z 315 (M+H)+ and m/z 332 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:14]2[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]3[CH:10]=[C:9]([CH3:28])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]=3[CH:13]=2)[CH2:23][CH2:24]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2cc3c(cc(C)n3Cc3ccccc3)n3c(C)nnc23)CC1
Reaction time: 0.25 h

Procedure:
To 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (10. mg, 0.027 mmol, from Example 206) in DCM (1.0 mL) was added acetyl chloride (2.3 μL, 0.032 mmol, Aldrich), followed by the addition of triethylamine (7.4 μL, 0.053 mmol). After 15 minutes, volatiles were removed in vacuo. The mixture was diluted with water and MeOH, and the product was isolated via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (7.6 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:17]([O:19][C:20](=[O:25])[CH:21](Cl)[CH2:22][CH3:23])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:19][C:20](=[O:25])[CH:21]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:2]=2[Cl:1])=[CH:10][CH:9]=1)[CH2:22][CH3:23])[CH3:18]
Reactant: CCOC(=O)C(Cl)CC
Reactant: Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1
Yield: 45.9 %

Procedure:
A solution of 25.3 g of 4-(2,4-dichlorobenzyl)-phenol and 15 g of α-chlorobutyric acid ethyl ester in 100 ml of dimethyl formamide were stirred for 2 hours at 100° C with 16 g of potassium carbonate. After cooling, the reaction mixture was poured into 1 liter of water. An oil precipitated which was separated and dried over sodium sulfate. By vacuum distillation, 16.8 g of 2-[p-(2,4-dichlorobenzyl)-phenoxi]-butyric acid ethyl ester were obtained. b.p. 180° - 183° C/0.8 mm Hg/nD21 : 1.5912 ##STR7## The following compounds were prepared according to the methods described in the above Examples.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](Cl)=[O:11].[NH:14]1[CH:18]=[CH:17]N=N1.C(=O)([O-])[O-].[K+].[K+]>C1S(=O)(=O)CCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:17]=[CH:18][N:14]=1
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccccc1-c1ncco1
Temperature: 140 °C
Yield: 18.8 %

Procedure:
A mixture of 2-Chlorocarbonyl-benzoic acid methyl ester (1.3 gram, 6.56 mmol), 1H-triazole (0.42 ml, 7.22 mmol) and potassium carbonate (2.78 g, 20 mmol) in 12 ml of tetramethylene sulfone was heated at 140° C for half an hour. The mixture was cooled, diluted with ethyl acetate, washed with water 5 times, and dried. After concentration the crude was purified by flash column (50% ethyl acetate in hexane) to afford 250 mg of 2-Oxazol-2-yl-benzoic acid methyl ester as a light yellow liquid. MS: (M+H)/z=204.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C1C[O:29]CC1.C(#N)C>CCOC(C)=O>[OH:29][C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]1[C:4](=[O:3])[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)=[C:6]([CH3:14])[C:7](=[O:13])[C:8]=1[CH3:12]
Reactant: Cc1c(O)c(C)c(-c2ccc(C(F)(F)F)cc2)c2c1CCC(C)(C)O2
Reactant: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1=C(CCC(C)(C)O)C(=O)C(c2ccc(C(F)(F)F)cc2)=C(C)C1=O

Procedure:
The purified residue containing 2,2,5,7-tetramethyl-8-(4-(trifluoromethyl)phenyl) chroman-6-ol from the above reaction (60 mg) was dissolved in THF/acetonitrile (1:1, 2 ml) and cooled in an ice-water bath. To the resulting solution was added dropwise an aqueous solution of ceric ammonium nitrate (170 mg, 310 μmol in 1 mL) until a reddish color persisted. When the titration endpoint was reached, the mixture was diluted in 5 mL EtOAc, washed once with brine (2 mL). The remaining organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (5→25% EtOAc/hexanes) producing 80 mg of 2-(3-hydroxy-3-methylbutyl)-3,5-dimethyl-6-(4-(trifluoromethyl)phenyl)cyclohexa-2,5-diene-1,4-dione, a yellow oil. 1H NMR (CDCl3, 400 MHz) 7.67 (d, 2H), 7.26 (d, 2H), 2.60 (m, 2H), 2.11 (s, 3H), 1.92 (s, 3H), 1.54 (m, 2H), 1.25 (s, 6H) ppm.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH3:29].CC(C)(C)CNC[C@@H]1OC2C=C(S(C)(=O)=O)C=CC=2OC1>C(#N)C>[CH3:27][N:28]([CH3:29])[CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=2)[O:14]1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Agent: CC(C)(C)CNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Solvent: CC#N
Product: CN(C)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-methylmethanamine (2.0 M in MeOH, 0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 269 (M+, 2), 131 (4), 77 (4), 63 (2), 59 (4), 58 (bp).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[N:19]=2)[CH:15]=[CH:14][S:13]3)[CH:7]=[CH:8][CH:9]=1)#[N:3].C(N(CC)CC)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>ClCCl>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[N:16]5[C:12]([S:13][CH:14]=[CH:15]5)=[N:11][C:10]=4[C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([C:2]#[N:3])[CH:5]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26]2)(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
The 4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (˜5.79 mmol) in dichloromethane (DCM) (50 mL) was cooled to 0° C. and treated with triethylamine (4.0 mL, 28.9 mmol), then 4-chlorophenylsulfonyl chloride (1.34 g, 6.37 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, diluted with dichloromethane (100 mL), washed with water (50 mL×3), dried over sodium sulfate and concentrated in vacuo to provide 3.22 g (97%) of the title compound as a yellow solid. M.p.=144-146° C.; 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.65 (br. s, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.94 (dd, J=0.8 and 7.6 Hz, 1H), 7.82-7.85 (m, 1H), 7.77-7.75 (m, 2H), 7.67-7.64 (m, 3H), 7.44 (d, J=4.4 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 6.37 (d, J=4.8 Hz, 1H), 3.91 (bs, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.48-2.45 (m, 1H), 2.32 (t, J=10 Hz, 1H), 1.89-1.82 (m, 2H), 1.60-1.56 (m, 1H), 1.41-1.36 (m, 1H). LCMS: 576 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.NC(C1SC=C(C(OCC)=O)N=1)CC(C)C.[C:29]([NH:39][C@H:40]([C:45](O)=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:32]([O:31][C:29]([NH:39][C@@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:45]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:46])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1csc(CN)n1
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)c1csc(C(N)CC(C)C)n1
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the of Example 13, except substituting 1-tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2yl)methane for (1S)-1-tert-butoxycarbonyl)amino-1-(4carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared 0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
A mixture of 4-iodoaniline (20.00 g, 90.0 mmol, 1.0 equiv) triethylamine (38.4 ml, 274 mmol, 3.0 equiv) and CH2Cl2 (200 ml) was cooled to 0° C. Acetic anhydride (26.0 ml, 270 mmol, 3.0 equiv) was added drop wise. The reaction mixture was stirred at 0° C. for 10 min, and at rt for 2 h. The volatile materials were removed under vacuum, and the solid residue was dissolved in 30 ml of hot CH2Cl2. The solution was left to stand in a freezer for 72 h. The separated solid was filtered out and dried under vacuum to give N-(4-iodophenyl)acetamide (20.35 g, 86.6%). 1H NMR (CDCl3) δ 7.58–7.28 (d, 2H), 7.25–7.23 (d, 2H), 2.15 (s, 3H).
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[C:52](=[O:63])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CC(O)C>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([Br:32])=[CH:34][N:35]=3)=[CH:60][CH:61]=2)[C:52](=[O:63])[CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)C(=O)C1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)C(=O)C1
Yield: 51.6 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.283 g, 1.00 mmol), 4-(4-amino-phenyl)-3-oxo-piperazine-1-carboxylic acid ter-t-butyl ester (0.300 g, 1.00 mmol) and N-ethyldiisopropyl-amine (0.20 mL, 1.02 mmol) in 2-propanol (1 mL). Purification of the crude material by silica gel column chromatography eluting with DCM followed by 98:2 DCM:MeOH affords 4-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester as a white solid (0.252 g, 51%).
Reaction SMILES: [C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:8]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N1CCC(NC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1

Procedure:
A solution of ethyl 4-[(diphenylmethyl)amino]-1-piperidinecarboxylate (42 g) and sodium hydroxide (50 g) in methanol (300 mL) was refluxed for 24 hours. This reaction mixture was diluted with water and extracted with chloroform. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to give N-(diphenylmethyl)-4-piperidinamine. This product was converted to the dihydrochloride using 4N-HCl solution in ethanol and the precipitate was collected by filtration and dried to provide 31 g of the title compound. Yield 73%.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[NH:19]([C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH2:26][NH:27][C:28](=[O:30])[CH3:29])[C:20]([NH2:22])=[NH:21]>CC#N>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:22]=[C:20]([NH:19][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[CH2:26][NH:27][C:28](=[O:30])[CH3:29])[N:21]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: CC(=O)NCc1cccc(NC(=N)N)c1
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: CC(=O)NCc1cccc(Nc2nccc(-c3sc(C)nc3C)n2)c1

Procedure:
By treatment of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(3-guanidino-benzyl)-acetamide nitrate. Yellow solid. Mp 206-207° C. Anal. RP-HPLC: tR=13.6 min (0-60% MeCN, purity>95%). 1H-NMR (DMSO-D6) δ: 1.99 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.68 (s, 3H, CH3), 4.38 (s, 2H, CH2), 6.94 (d, 1H, J=7.5 Hz, Ph-H), 7.01 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.26 (d, 1H, J=8.0 Hz, Ph-H), 7.56 (d, 1H, J=7.5 Hz, Ph-H), 7.70 (s, 1H, Ph-H), 8.40 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 345.42 [M+H]+ (C18H19N5OS requires 353.44).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([OH:19])=O)=[CH:14][C:13]=3[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][NH:34][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:20][C:13]=3[CH:14]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (156 mg, 0.50 mmol) and 4-(2-aminoethoxyl)benzoic acid methyl ester hydrochloride (129 mg, 0.56 mmol) in DMF (4.5 ml) in a 20 ml vial was added diisopropylethylamine (0.88 ml, 5.1 mmol). A solution of 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (740 μL, 0.82 M, 0.61 mmol) in DMF was added to give a bright yellow solution. The vial was purged with nitrogen and stirred at room temperature for 18 h. The solution was removed and the residue was dissolved in EtOAc (25 ml) and washed with H2O, 1.0M aqueous K2CO3, and brine. The organic layer was dried over anhydrous MgSO4 and solvent was removed on a rotary evaporator. Purification of the residue by column chromatography on a silica gel column using 93:5:2 CH2Cl2:MeOH:TEA eluent provided 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester as a beige solid (174 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:33]>C1COCC1>[Br:33][CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8]
Reactant: N#Cc1ccc(CO)cc1C#N
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)cc1C#N
Reaction time: 21 h

Procedure:
4-Hydroxymethyl-phthalonitrile from step 2 (1.3 g, 8.2 mmol) was dissolved in THF (41 ml) and treated with Ph3P (3.2 g, 12.3 mmol) followed by CBr4 (4 g, 12.3 mmol). The reaction mixture was stirred at room temp. for 21 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][Si:13]([C:16]1([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17]1)([CH3:15])[CH3:14].Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[CH3:22][Si:21]([C:16]1([Si:13]([CH3:12])([CH3:14])[CH3:15])[C:20]([P:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=[CH:17]1)([CH3:24])[CH3:23]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1P(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
76.6 ml of a 2.5 molar solution of butyllithium in hexane (0.19 moles) were added over 10 min at 0° C. to a solution of compound 1 (40.2 g, 0.19 moles) in 500 ml of ether. When the addition was complete. the bath was removed and the solution was stirred for 1 h at room temperature. After cooling to 0° C., 42.2 g (0.19 moles) of chlorodiphenylphosphine were added over 10 min, after which the bath was removed and the suspension was heated to room temperature. After stirring for 1 hour at room temperature, the ether was removed under vacuum and the product was dissolved in hexane again. After the salts had been filtered off, the hexane was removed under vacuum to leave 69.1 g (yield: 91%) of compound 16 in the form of an oil. 1H NMR (400 MHz, CDCl3): δ=7.45 (m, 4H); 7.35 (m, 6H); 6.8 (m, 1H); 6.65 (m, 1H); 6.6 (m, 1H); 0 (s, 18H); 31P NMR (161.9 MHz, CDCl3): δ=−19.5 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][O:11][CH2:16][CH2:17][CH3:18])=[CH:7][C:6]=2[CH:12]=1
Reactant: CCCBr
Reactant: OCc1cc2cc(Br)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCOCc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (57 ml) was dissolved 5-bromo-2-(hydroxymethyl)-1-benzofuran (5.7 g), and to the solution was added at 0° C. 60% sodium hydride (1.4 g). The mixture was stirred at room temperature for 1 hour, and to the mixture was added at 0° C. 1-bromopropane (3.1 ml). The mixture was stirred at 65° C. for 16 hours and cooled to room temperature. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 5-bromo-2-(propoxymethyl)-1-benzofuran (5.0 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:15](C(OC(C)(C)C)=O)[NH:16][C:17](=[O:44])[C:18](=[O:43])[CH:19]([NH:27][C:28]([C@H:30]1[CH2:34][CH2:33][C:32](=[O:35])[N:31]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:36]([N:31]1[C:32](=[O:35])[CH2:33][CH2:34][C@@H:30]1[C:28]([NH:27][CH:19]([C:18](=[O:43])[C:17]([NH:16][NH:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:44])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NNCc1ccccc1)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (TFA) (0.2 mL, 2.60 mmol) was added to a solution of tert-butyl 1-benzyl-2-(3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-oxo-4-phenylbutanoyl)hydrazinecarboxylate (110 mg, 0.184 mmol) in DCM (2 mL). After stirring for 4 h the solvent was removed in vacuo and the residue obtained was triturated with diethyl ether providing the title compound (48 mg, 43%).