Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([OH:11])=[CH:5][C:4]=1[O:12][CH3:13])=[O:2].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH:1]([C:3]1[C:4]([O:12][CH3:13])=[CH:5][C:6]([O:11][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:7][C:8]=1[O:9][CH3:10])=[O:2]
Reactant: CCOC(=O)CCCCBr
Reactant: COc1cc(O)cc(OC)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1cc(OC)c(C=O)c(OC)c1
Temperature: 0 °C

Procedure:
To a suspension of 4-formyl-3,5-dimethoxyphenol (22.6 g, 124 mmol) and potassium tert-butoxide (15.3 g, 136 mmol) in dimethylformamide (125 mL) was added ethyl 5-bromovalerate (28.5 g, 136 mmol) in dimethylformamide (125 mL) over a period of 20 min. The mixture was heated at 11 0° C. for 6 h and concentrated in vacuo. To the obtained product was added ethyl acetate (400 mL) and the mixture was filtered. The filtrate was washed with water (100 mL), 1 N sodium hydroxide (2×50 mL), and brine (3×100 mL), dried (magnesium sulfate), and concentrated in vacuo to 37 g of ethyl 5-(4-formyl-3,5-dimethoxyphenoxy)valerate.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=[C:2]1[C:11](=[N:15][O:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH:19]1[C:36](=[O:37])[N:21]2[C:22]([C:33]([OH:35])=[O:34])=[C:23]([CH2:26][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12>>[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=[C:2]1[C:11](=[N:15][O:16][CH3:17])[C:12]([NH:18][CH:19]1[C:36](=[O:37])[N:21]2[C:22]([C:33]([OH:35])=[O:34])=[C:23]([CH2:26][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12)=[O:14]
Reactant: CON=C(C(=O)O)C1=CSc2ccccc2S1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1=CSc2ccccc2S1

Procedure:
2-(1,4-Benzodithiin-2-yl)-2-methoxyiminoacetic acid (syn isomer, 0.75 g.) was allowed to react with 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1 g.) in a similar manner to that of Example 1 to give the captioned compound (0.7 g.), yellow powder, mp. 142° to 147° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH:15]([CH:17]=O)=[O:16].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[CH:17][CH:15]=[O:16]
Reactant: O=CC=O
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=CC=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (5 g) in acetic acid was added dropwise to a mixture of 40% aqueous glyoxal (50 ml) and water (400 ml). The mixture was stirred at room temperature for 2 hours and solid collected by filtration. A sample was recrystallised from ethanol to give 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)acetaldehyde, m.p. 131°-133°. This crude product (2.85 g) in ethanol (30 ml) was added to a solution of hydroxylamine hydrochloride (0.7 g) in water (10 ml), which had been neutralized with sodium acetate (0.82 g). The mixture was stirred at room temperature and then extracted with ethyl acetate. The extract was washed with brine, dried and evaporated to 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)acetaldehyde oxime. This was then treated with copper sulphate, in a similar manner to Example 1, to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole 1-oxide, m.p. 153°-154°, which in turn was treated with trimethyloxonium tetrafluoroborate and sodium methanethiolate, in a similar manner to Example 3, to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthio-2H-1,2,3-triazole, m p. 100°-101°. (Compound 11)
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1>C(O)(=O)C>[CH2:8]([O:7][C:1]([C:2]1[C:16]2[C:15](=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)[NH:18][C:3]=1[CH3:5])=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(NN)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC)cc12
Temperature: 110 °C
Reaction time: 16 h

Procedure:
Ethyl acetoacetate (5.5 ml, 43.15 mmol) was added into a solution of (4-methoxy-phenyl)-hydrazine (5.0 g, 28.63 mmol) in glacial acetic acid (500 ml) at room temperature. The mixture was heated at 110° C. for 2 hours, and kept at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and 1 N sodium hydroxide solution. The organic extract was dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 2% methanol in dichloromethane to give 5-Methoxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester as a dark solid, (3.18 g, 47%). 1H NMR (CDCl3) δ:1.44 (t, 3H, J=7.1 Hz), 2.70 (s, 3H), 3.87 (s, 1H), 4.39 (q, 2H, J=7.1 Hz), 6.82(dd, 1H, J=8.8 Hz, 2.5 Hz), 7.17 (d, 1H, J=8.8 Hz), 7.63 d, 1H, J=2.5 Hz), 8.38 (bs, 1H). M−H: 232.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3=[CH:24][C:25]([CH2:26][OH:27])=[C:21]4[N:22]3[C:17](=[CH:18][CH:19]=[CH:20]4)[C:16]=2[CH2:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:40])[C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br>>[CH3:30][N:31]([CH3:40])[C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:27][CH2:26][C:25]1[CH:24]=[C:23]2[N:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=13)[C:16]([CH2:28][CH3:29])=[C:15]2[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(CO)c3cccc1n32
Reactant: CN(C)C(=O)CCCCCBr
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(COCCCCCC(=O)N(C)C)c3cccc1n32
Yield: 31 %

Procedure:
2-(4-Benzyloxyphenyl)-1-ethyl-4-hydroxymethylpyrrolo[2,1,5-cd]indolizine was alkylated, using 6-bromohexanoic acid dimethylamide as the alkylating agent, by the general synthetic principle outlined in Example 5, to afford 6-[2-(4-benzyloxyphenyl)-1-ethylpyrrolo[2,1,5-cd]indolizin-4-ylmethoxy]hexanoic acid dimethylamide as a yellow oil in 31% yield. 1H-NMR (CDCl3, 300 MHz) δ: 1.37-1.50 (m, 5H); 160-1.71 (m, 4H); 2.28 (t, 2H); 2.91 (s, 3H); 2.93 (s, 3H); 3.24 (q, 2H); 3.56 (t, 2H); 5.01 (s, 2H); 5.17 (s, 2H); 7.15 (d, 2H); 7.32-7.54 (m, 6H); 7.63 (t, 1H); 7.73 (d, 2H); 7.90 (d, 1H); 7.99 (d, 1H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].C(OC(=O)C)C>CS(C)=O>[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17]
Reactant: Nc1ccccc1Br
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Nc2c(Nc3ccccc3Br)c(=O)c2=O)c(O)c1
Temperature: 25 °C
Yield: 3.3 %

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanoanilino)-3-cyclobutene-1,2-dione (0.7 g, 2.71 mmol) and 2-bromoaniline (0.47 g, 2.73 mmol) were heated in 6 ml DMSO for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added and precipitates formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. After Gilson HPLC, 34 mg (3%) of purified product was obtained. LC/MS (H+) 386
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>CO.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]2[C:14]([O:16][CH3:19])=[O:15])=[CH:6][CH:7]=1
Reactant: C=C1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
A 100 mL round bottom flask was equipped with a magnetic stir bar and charged with a solution of 1.188 g (5.02 mmol) of the product from Step A (the combined product of two experiments) dissolved in 20 mL of methanol was stirred and cooled to 0° C. with an external ice-water bath. A solution of diazomethane in diethyl ether was added slowly until the reaction mixture developed the persistent yellow color and TLC analysis (25% ethyl acetate-hexanes) indicated that esterification was complete. Excess diazomethane was quenched by dropwise addition of acetic acid, and volatiles were removed in vacuo. The residual clear oil was used directly in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)=[CH2:2].C(O)(=[O:13])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:1]2[CH2:2][O:13]2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: C=Cc1cccc(OC)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 3-vinylanisole (5.0 g, 37.0 mmol) and acetic acid (2.1 mL, 37.0 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (7.30 g, 41.0 mmol) in three portions. The reaction was allowed to warm to R.T. and then 2M NaOH (50 ml) was added. The reaction was left to stir at RT overnight. The reaction mixture was then partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 5.60 g (100%) of the title compound as a slightly tinted oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[N+:12]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][C:2](=[O:11])[CH2:1]2)=[CH:6][CH:7]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCc2ccccc2C1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
At 0° C., 100 g of 2-tetralone are dissolved in 460 ml of pure sulphuric acid and 84.6 g of potassium nitrate in powder form are added in small portions. The mixture is then poured onto ice and extracted using dichloromethane. Following evaporation of the solvent, the residue is purified by chromatography on silica gel using as eluant a 90/10 cyclohexane/tetrahydrofuran mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:18][Si](C)(C)C)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH3:18])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnn(C[Si](C)(C)C)c1-c1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nnn(C)c1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
To a stirred solution of 5-(4-bromo-phenyl)-1-trimethylsilanylmethyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (6.5 g, 17.01 mmol) in THF (100 mL), was added water (0.61 ml, 34.03 mmol) and cooled to 0° C. Then TBAF (1M) solution in THF (20.41 mL, 20.41 mmol) was added to it and the mixture was stirred at 0° C. for 10 min. Volatiles were distilled off and crude mass was purified by normal silica gel column chromatography using EtOAc-hexane as eluting solvent to get 5-(4-bromo-phenyl)-1-methyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (4.7 g, 89.02%) as a white solid. LC-MS: 310 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.0 Hz, 3H), 3.91 (s, 3H), 4.18 (q, J=7.0 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H). The regio-chemistry was confirmed by NOE study.
Reaction SMILES: [F:1][C:2]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH:16]2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]3[O:41][CH2:40][C:39](=[O:42])[N:38]([CH2:43][CH2:44]OS(C4C=CC(C)=CC=4)(=O)=O)[C:37]=3[CH:56]=2)=[CH:11][CH:10]=1.[N-:62]=[N+:63]=[N-:64].[Na+]>CN(C)C=O>[N:62]([CH2:44][CH2:43][N:38]1[C:37]2[CH:56]=[C:33]([CH2:32][O:31][CH:16]3[CH:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]5[CH:57]=[C:58]([F:61])[CH:59]=[CH:60][C:2]=5[F:1])=[CH:10][CH:11]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH2:17]3)[CH:34]=[CH:35][C:36]=2[O:41][CH2:40][C:39]1=[O:42])=[N+:63]=[N-:64]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCN2C(=O)COc3ccc(COC4CN(C(=O)OCc5ccccc5)CCC4c4ccc(OCCCOc5cc(F)ccc5F)cc4)cc32)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
A solution of 0.880 g of benzyl 4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}-3-{3-oxo-4-[2-(toluene-4-sulphonyloxy)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy}piperidine-1-carboxylate and 0.532 g of sodium azide in 10 ml of N,N-dimethylformamide is stirred at 65° C. over 90 minutes. The reaction mixture is poured onto water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.11 (1:2 EtOAc-heptane). Rt=5.82
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:9][CH:8]1[CH2:10][C:11]1[N:19]2[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]2)=[C:13]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]([CH:29]=2)=[N:27][N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=3)[CH:12]=1)(=O)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([N:26]1[CH:25]=[C:24]2[C:28]([CH:29]=[C:21]([C:13]3[CH:12]=[C:11]([CH2:10][CH:8]4[CH2:9][CH:7]4[CH2:6][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[N:19]4[C:14]=3[C:15]([NH2:20])=[N:16][CH:17]=[N:18]4)[CH:22]=[CH:23]2)=[N:27]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)OCC1CC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnn2c(CC3CC3CN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 80 °C
Yield: 5.8 %

Procedure:
To a solution of (2-{[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}cyclopropyl)methyl methanesulfonate (0.2 g, 0.4 mmol) in DMF (2 mL) was added pyrrolidine (84 mg, 1.2 mmol) and DIEA (102 mg, 0.8 mmol), and the mixture was heated to 80° C. for 3 hours. The mixture was concentrated in vacuo and the residue was dissolved in methanol and purified by preparative HPLC to provide 11 mg (6%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 720 (s, 1 H), 5.70 (s, 2 H), 2.9-2.8 (m, 2 H), 2.4-2.2 (m, 6 H), 1.7 (m, 4 H), 1.1-0.9 (m, 2 H), 0.5-0.4 (m, 2 H); ES-MS m/z 478.2 [M+H]P, HPLC RT (min) 2.29.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][CH:15]=[N:16][C:10]=2[CH:9]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]2=[O:40])=[N:31][CH:32]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][N:16]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]4=[O:40])=[N:31][CH:32]=3)[C:10]=2[CH:9]1[C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1ccc(Cl)cn1-c1ccc(CBr)cn1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ncn(Cc3ccc(-n4cc(Cl)ccc4=O)nc3)c2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(4-Cyano-phenyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (0.16 g, 0.50 mmol) and 5'-bromomethyl-5-chloro-[1,2']bipyridinyl-2-one (Example 10, Step 2)(0.15 g, 0.50 mmol) were dissolved in DMF (6 mL). NaH (0.02 g, 0.60 mmol) was added and stirred at RT under Ar for 1.5 h. The reaction was concentrated in vacuo and partitioned between EtOAc and satd NaHCO3 soln, washed with H2O, brine, dried (MgSO4), filtered and concentrated to give the title compound as a mixture of racemic regloisomers.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH2:15]([OH:17])[CH3:16]>C(OCC)(=O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:5](=[N:1][C:2]#[N:3])[O:17][CH2:15][CH3:16])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CCO
Solvent: CCOC(C)=O
Product: CCOC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diethyl (N-cyanoimido)carbonate (1.59 g.) in ethanol (15 ml.) at room temperature was added a solution of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole (2.58 g.) in ethanol (25 ml.) over 15 minutes with sufficient cooling to maintain the temperature at about 20° C. The solution was stirred at room temperature for a further 30 minutes and then more diethyl (N-cyanoimido)carbonate (0.318 g.) in ethanol (3 ml.) was added. The solution was stirred at room temperature for 15 minutes and then evaporated to dryness under reduced pressure to give a pale yellow paste. This residue was dissolved in ethyl acetate (20 ml.) and the solution was washed with water (20 ml., 2×10 ml.) then dried (magnesium sulphate) and evaporated under reduced pressure to give 2-guanidino-4-[2-(3-cyano-2-ethylisoureido)ethylthiomethyl]thiazole containing a small amount of ethyl acetate. The n.m.r. spectrum in CDCl3 using tetramethylsilane as internal standard had the following resonances (δ): 6.5 (5H, very broad); 6.4 (1H, singlet); 4-4.5 (obscured by ethyl acetate); 3.6 (2H, singlet); 3.4 (2H, multiplet); 2.7 (2H, multiplet); 2.0 (ethyl acetate); 1.2-1.5 (obscured by ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])[N:6]=[C:5]([N:23]([CH3:25])[CH3:24])[CH:4]=1.[Br:26]N1C(=O)CCC1=O>C(#N)C>[Br:26][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N:23]([CH3:25])[CH3:24])=[N:6][C:7]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOCCCCCCCCCCc1cc(OC)cc(N(C)C)n1
Solvent: CC#N
Product: COCOCCCCCCCCCCc1nc(N(C)C)cc(OC)c1Br
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 213 mg (0.60 mmol) of 4-methoxy-6-(10-(methoxymethoxy)decyl)-N,N-dimethylpyridin-2-amine in 5 mL of acetonitrile were added 107 mg (0.60 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 23° C. protected from light for 3 h. The reaction mixture was poured into 50 mL of satd. aq. sodium bicarbonate and extracted two 50-mL portions of ethyl acetate. The combined organic layer was washed with one 50-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (3×10 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as a yellowish oil: yield 114 mg (44%); silica gel TLC Rf 0.45 (4:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.29 (br m, 12H), 1.56 (quint, 2H, J=7.2 Hz), 1.68 (quint, 2H, J=7.2 Hz), 2.55 (dd, 2H, J=7.6, 7.6 Hz), 3.03 (s, 6H), 3.33 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.85 (s, 3H), 4.59 (s, 2H) and 5.76 (s, 1H); 13C NMR (CDCl3) δ 26.17, 28.08, 29.40, 29.47, 29.51, 29.57, 29.65, 29.72, 37.31, 38.05, 38.05, 55.02, 55.65, 67.87, 86.47, 96.35, 97.29, 158.80, 159.11 and 162.60; mass spectrum (APCI), m/z (M+H)+431.1913 (C20H36N2O3Br requires 431.1909).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[F:12][C:13]([F:35])([F:34])[C:14]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]2=[O:31])=[CH:22][CH:21]=1)([OH:19])[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:23]3[CH:32]=[CH:33][C:20]([C:14]([OH:19])([C:13]([F:12])([F:34])[F:35])[C:15]([F:18])([F:16])[F:17])=[CH:21][CH:22]=3)[C:26](=[O:31])[CH2:27]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: O=C1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C(=O)C2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a stirring solution of 4-amino-3-fluorobenzoic acid (1.965 mmol, 305 mg), 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-2-one (1.965 mmol, 700 mg) and triethylamine (5.89 mmol, 596 mg) in dichloromethane (10 mL) was added 1-propanephosphonic acid cyclic anhydride (2.95 mmol, 1876 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (30 mL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with 50% ethyl acetate/50% dichloromethane—100% ethyl acetate gradient) to afford the title compound (550 mg). MS (ESI) m/z 492.3 [M−H]−
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][C:8]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=O)(=O)C.O.[NH2:29][NH2:30]>C(O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:8]=3[CH2:7][C:6]([CH2:5][OH:4])=[N:30][N:29]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: COc1cc(CC(=O)COC(C)=O)c(C(=O)c2cccc(Cl)c2)cc1OC
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)=NN=C(CO)C2
Reaction time: 8 h
Yield: 77.8 %

Procedure:
6.7 g (17.3 mmoles) of 2-(3-acetoxyacetonyl)-3'-chloro-4,5-dimethoxybenzophenone [(IV), R=CH3 ] are suspended in 70 ml of 99.5% ethanol, then 5.2 l (104 mmoles) of 100% hydrazine hydrate are added under stirring. The reaction mixture is stirred at room temperature for 72 hours, treated with activated carbon, filtered and 82 ml of distilled water are added to the filtrate. Then 4 ml of glacial acetic acid are dropped to the pale yellow solution under cooling with ice-cold water. Upon scratching crystals get separated. The suspension is kept overnight at 1° to 5° C., filtered, washed five times with 5 ml of ice-cold 50% ethanol solution each and the product is dried at a temperature between 80° and 100° C. Thus 4.64 g of crude product are obtained.