Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: CN1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
In 50 mL of methanol, 6.77 g (21 mmol) of (3-nitro-5-(trifluoromethyl)phenyl)-(4-methylpiperazin-1-yl)methanone was dissolved, and 400 mg of 10% palladium carbon was added thereto and the mixture solution was stirred in an hydrogen atmosphere under normal pressures at room temperature for three hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and the residue was recrystallized from hexane and diethyl ether to obtain 6.14 g (quantitative) of a target product as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]([C:33]4[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=4)[C:36]([O:38]CC)=[O:37])[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)[N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCOCC1>[C:44]1([C:7]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]([C:33]4[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=4)[C:36]([OH:38])=[O:37])[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)[N:10]=[N:9]2)[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)c1cccc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of ethyl 3-[N-[[4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methyl]-N-pentanoylamino]benzoate (11.50 g) synthesized in Example 1a in dioxane (100 ml) was added 1N-aqueous sodium hydroxide solution (19 ml), and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated, ethyl acetate and saturated aqueous potassium bisulfate solution were added to carry out partitioning and extraction. The extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated and concentrated to give a crude product of 3-[N-[[4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methyl]-N-pentanoylamino]benzoic acid. To a solution of the obtained crude product in DMA (90 ml) were added potassium carbonate (4.86 g) and a solution of 4-chloromethyl-5-methyl-1,3-dioxolen-2-one (3.92 g) in DMA (5 ml), and the mixture was stirred at room temperature for 24 hrs. The reaction mixture was poured into ethyl acetate-water to carry out partitioning and extraction. The extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated and concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate:1-1 v/v) to give (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl3-[N-[[4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methyl]-N-pentanoylamino]benzoate (11.57 g).
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([OH:23])=O)[N:19]=1)=[O:13].[NH2:34][CH:35]1[C:69](=[O:70])[N:37]2[C:38]([C:53]([O:55][CH:56]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:54])=[C:39]([O:42][S:43]([C:46]3[CH:52]=[CH:51][C:49]([CH3:50])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[CH2:40][S:41][C@H:36]12>O1CCCC1.C(Cl)Cl.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([NH:34][CH:35]2[C:69](=[O:70])[N:37]3[C:38]([C:53]([O:55][CH:56]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)=[O:54])=[C:39]([O:42][S:43]([C:46]4[CH:52]=[CH:51][C:49]([CH3:50])=[CH:48][CH:47]=4)(=[O:44])=[O:45])[CH2:40][S:41][C@H:36]23)=[O:23])[N:19]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)cc1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c4csc(NC=O)n4)[C@H]3SC2)cc1
Yield: 71.7 %

Procedure:
Vilsmeier reagent prepared from phosphorus oxychloride (0.67 ml) and N,N-dimethylformamide (0.57 ml) was suspended in dry tetrahydrofuran (24 ml). To the suspension was added 2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (2.4 g) at 0° to 5° C. The solution was stirred at the same temperature for an hour to prepare the activated acid solution. To a solution of benzhydryl 7-amino-3-tosyloxy-3-cephem-4-carboxylate (3.0 g) and monotrimethylsilylacetamide (5.8 g) in methylene chloride (30 ml) was added the activated acid solution obtained above at -20° C. all at once. The reaction mixture was stirred at -10° C. for an hour. The resulting solution was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The separated organic layer was washed with a saturated aqueous solution of sodium bicarbonate, and with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-tosyloxy-3-cephem-4-carboxylate (syn isomer) (3.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=1)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][NH:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=3)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(-c3ccc(F)cc3)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
4′-Fluorobiphenyl-4-carbaldehyde (1.0 g, 5 mmol, 1.0 eq) and tert-butyl 3-(amino methyl)benzylcarbamate (1.18 g, 5 mmol, 1 eq) were dissolved in dry methanol under nitrogen and refluxed for 4 h. The reaction mass was cooled to 0° C. and sodium borohydride (570 mg, 15 mmol, 3 eq) was added portionwise at 0° C. over 20-30 minutes. The mixture was stirred for 1 h at 0° C. and then the reaction was quenched with 10% aq. sodium bicarbonate solution. The mixture was stirred at room temperature for 1 h. The resulting solution was completely evaporated under vacuum and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel (60-120) column chromatography using 5-10% methanol dichloromethane as the eluent to afford the desired compound (1.8 g, 85%) as a light yellow liquid. 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.37 (d, 9H), 3.66-3.69 (d, 4H), 4.09-4.11 (d, 2H), 7.07-7.09 (d, 1H), 7.18-7.29 (m, 6H), 7.36-7.42 (m, 1H), 7.56-7.59 (m, 2H), 7.65-7.67 (d, 2H), 7.68-7.70 (m, 2H). MS (ESI): 421.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([O:23][C:24]([F:27])([F:26])[F:25])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:19])([F:18])[F:17])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2)[CH3:2].[OH:28]S(O)(=O)=O>CC(C)=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([O:23][C:24]([F:25])([F:27])[F:26])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:17])([F:18])[F:19])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2)[CH3:2]
Reactant: CCOC#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 198.8 %

Procedure:
To a solution of the crude product from Step 1 (2.13 g) in a mixture of acetone (80 mL) and H2O (10 mL) was added H2SO4 (0.250 g, 2.55 mmole) and the resulting mixture was stirred at room temperature for 2.5 hrs. Brine (200 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2.10 g of the crude product as a yellow oil: ESLRMS m/z 414.0 (M+H, C16H12F6O6, Calc'd 415.0).
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[C:12]([N:18]4[CH:22]=[CH:21][N:20]=[N:19]4)=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28]([CH3:30])[C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:17][C:14]1[N:13]=[C:12]([N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)[C:11]([C:9]([N:8]2[C@H:1]3[C@H:6]([CH2:5][CH2:4][N:3]([C:24]4[N:29]=[C:28]([CH3:30])[C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=4)[CH2:2]3)[CH2:7]2)=[O:10])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)N2C[C@H]3CCNC[C@H]32)c(-n2ccnn2)n1
Reactant: Cc1nc(Cl)nc(C)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(C(=O)N2C[C@H]3CCN(c4nc(C)c(C)c(C)n4)C[C@H]32)c(-n2ccnn2)n1
Temperature: 180 °C
Yield: 53.4 %

Procedure:
To a microwave safe vial was added (1S,6R)-3,8-diazabicyclo[4.2.0]octan-8-yl(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methanone (80 mg, 0.27 mmol), 2-chloro-4,5,6-trimethylpyrimidine (84 mg, 0.54 mmol), ACN (3 mL) and DIPEA (0.093 mL, 0.54 mmol). The resulting mixture was heated to 180° C. in a microwave reactor. After 2 hours the mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC (acidic) to yield the title compound (60.3 mg, 42%) as the TFA salt. MS (ESI) mass calcd. for C22H26N8O, 418.2; m/z found, 419.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.44-8.32 (m, 1H), 7.82-7.72 (m, 2H), 7.22-7.16 (m, 1H), 4.52-4.46 (m, 1H), 4.30 (dd, J=10.0, 9.0 Hz, 1H), 4.04 (tt, J=9.6, 4.8 Hz, 1H), 3.99-3.92 (m, 1H), 3.89-3.57 (m, 2H), 3.13-2.83 (m, 2H), 2.65-2.57 (m, 3H), 2.39-2.31 (m, 6H), 2.15-2.02 (m, 4H), 1.99-1.81 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:32][CH3:33])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][N:9]=1.[OH-].[Na+:51]>C(O)C>[Na+:51].[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:32][CH3:33])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[CH:12][N:13]=1
Reactant: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCC(=O)[O-])cn1

Procedure:
3-(2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propan-1-ol (140 mg) is dissolved in methylene chloride (2 ml), and thereto is added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (188 mg) at room temperature and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in the mixed solvent of tert-butanol (4 ml) and water (1 ml) and thereto are added 2-methyl-2-butene (128 μl), sodium dihydrogenphosphate dihydrate (44 mg) and sodium chlorite (73 mg) and the mixture is stirred at room temperature for 30 minutes. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:3) to give 3-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propionic acid (60 mg). The resulting carboxylic acid is dissolved in ethanol (0.5 ml), and thereto is added 1N-aqueous sodium hydroxide solution (85 μl) and the reaction solution is concentrated under reduced pressure to give 3-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propionic acid sodium salt (60 mg). MS (m/z): 705 [M−Na]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[Na+]>CN(C=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[CH:2][CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Temperature: 95 °C
Reaction time: 8 h
Yield: 131.6 %

Procedure:
A mixture of (5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine 5.0 g, 15.3 mmol), bis(pinacolato)diboron (7.8 g, 30.6 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (559 mg, 0.8 mmol), and sodium acetate (3.8, 45.8 mmol) in DMF (20 ml) was stirred at 95° C. overnight. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-(4,4,5,5)-tetramethyl[1,3,2]dioxa-borolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 88% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.02 (s, 9H), 0.95 (, 2H), 1.45 (s, 2H), 3.65 (m, 2H), 5.75 (s, 2H), 6.70 (s, 1H), 7.75 (s, 1H), 8.40 (s, 1H), 8.60 (s, 1H). MS: m/z 375.2 (M+H+).
Reaction SMILES: [Na+].[I-].C([O-])([O-])=O.[K+].[K+].[CH2:9]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12].Cl[CH2:20][CH2:21][CH2:22][N:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:26][CH2:25][C:24]1=[O:33]>C(#N)C.CO>[CH2:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][N:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][CH2:25][C:24]2=[O:33])[CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC1CCNCC1
Reactant: O=C1CSc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CSc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 13 h

Procedure:
NaI (1.24 g, 8.27 mmol), K2CO3 (1.14 g, 8.27 mmol), and 4-butylpiperidine (0.62 g, 4.34 mmol) in acetonitrile (10 mL) were stirred at rt. 4-(3-chloropropyl)-4H-benzo[1,4]thiazin-3-one (1.0 g, 4.14 mmol) in acetonitrile (15 mL) was added via a syringe. The reaction was stirred at 60° C. for 13 hours and then at 80° C. for another 25 hours under nitrogen atmosphere and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1.63 g of crude. The crude product was subjected to CC[eluent:EtOAC:MeOH(100:1-5%)] to give the pure title compound. Yield 1.06 g 74.2% HPLC-MS [M+H]+ 347 (UV/MS(%)=100/99. 1H NMR (CDCl3): δ 0.88 (t, 3H), 1.23 (m, 9H), 1.64 (d, 2H), 1.85 (m, 4H), 2.34 (t, 2H), 2.83 (d, 2H), 3.36 (s, 1H), 4.03 (t, 2H), 6.99 (m, 1H), 7.22 (d, 2H), 7.34 (d, 1H), 13C NMR (CDCl3): δ 14.21, 23.03, 25.23, 29.15, 31.80, 32.63, 35.90, 36.44, 43.28, 54.26, 55.91, 118.18, 123.45, 124.17, 127.27, 128.56, 139.63, 165.19.
Reaction SMILES: CCN(CC)CC.[Al+3].[Cl-].[Cl-].[Cl-].[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:24]1(=[O:30])[O:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClC(Cl)C.ClCCCl>[OH:30][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([N:21]1[CH2:22][CH2:23][N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20]1)=[O:29]
Reactant: O=C1CCCCO1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: O=C(CCCCO)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5.4 mL (37.5 mmol) Et3N in 10 ml, 2-dichloroethane was added drop by drop under ice cooling to a suspension of 3.70 g (27.5 mmol) AlCl3 in 20mL dichloroethane. At room temperature a solution of 4.21 ml (27.5 mmol) 1-phenylpiperazine and 2.32 mL (25 mmol) delta-valerolactone in 15 mL 1,2-dichloroethane was added to the mixture. After one hour of stirring at room temperature the mixture was quenched with ice water and stirred for another 30 minutes. The suspension was filtered by Celite. After adding of dichloromethane, separating of the organic layer, washing it with water, drying it with Na2SO4 and evaporating of the solvent, followed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][O:18][CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][O:18][CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: COCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: COCc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 91 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methoxymethyl-4,5,6,7-tetrahydroindazol-4-one (0.1 g), aminoguanidine hydrochloride (0.046 g), concentrated hydrochloric acid (0.086 ml), water (0.086 ml) and ethanol (10 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid (1ml), and the solution was concentrated. The resulting crystals were recrystallized from ethanol-ethyl acetate to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methoxymethyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 148) (0.06 g) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[C:38]([F:41])([F:40])[F:39]>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[C:27]([C:38]([F:40])([F:41])[F:39])[CH:28]=3)[CH2:37][CH2:36]2)=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1C(F)(F)F
Reactant: COc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(NC(=O)CN2CCN(c3ccc(OC)c(C(F)(F)F)c3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(4-methoxy-2-nitro-phenyl)-acetamide (6.7 g; 19.6 mmol) is dissolved in 200 ml ethanol in the presence of 6.3 g sodium carbonate. 1-(4-Methoxy-3-trifluoromethyl-phenyl)-piperazine hydrochloride (5.8 g; 19.6 mmol) is added to the resulting suspension and the mixture is stirred overnight at room temperature. The mixture is evaporated to dryness under vacuum and the residue is taken up with water and ethylacetate. The organic phase is separated and washed twice with water. After drying over magnesium sulfate, evaporation of the solvent leaves a residue which is triturated with ethylether.
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11](N3CCCC3)=[O:12])[CH2:10][C:5]=2[NH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.P(Cl)(Cl)(Cl)=O.O>C(Cl)CCl>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:11]([CH:9]2[CH2:8][CH2:7][C:6]3[N:2]=[CH:3][NH:4][C:5]=3[CH2:10]2)=[O:12])=[CH:20]1
Reactant: Cn1ccc2ccccc21
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: Cn1cc(C(=O)C2CCc3nc[nH]c3C2)c2ccccc21
Reaction time: 7 h
Yield: 89.9 %

Procedure:
In a suspension of 7.0 g of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride and 5.4 g of N-methylindole in 70 ml of ethylene chloride was added 12.6 g of phosphorus oxychloride, and the mixture was stirred at 80° to 85° C. for 7 hours. After allowing the mixture to cool, the mixture was cooled to 0° to 5° C., and 70 ml of cold water was slowly added to the reaction mixture while maintaining the temperature of the mixture below room temperature to thereby decompose the excess of phosphorus oxychloride. The organic layer was removed, and the aqueous layer was adjusted to a pH of 9 with a 20% sodium hydroxide aqueous solution under cooling, followed by extracting from chloroform. To the chloroform layer was added 70 ml of water, and 6N hydrochloric acid was added thereto under ice-cooling while stirring to adjust to a pH of from 2.4 to 2.8. The chloroform layer was removed. The aqueous layer was washed with chloroform, and 40 ml of methanol was added thereto. The solution was made alkaline with a 20% sodium hydroxide aqueous solution while cooling. The formed crystal was collected by filtration and washed with a cold 1:1 (by volume) mixture of methanol and water to give 6.87 g (89.9%) of 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([F:21])([F:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([F:21])([F:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:26]#[C:25][C:23]([OH:27])([CH3:24])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(F)(F)COc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1nc2c(s1)C(F)(F)COc1ccc(C#CC(C)(C)O)cc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
A mixture of 9-Bromo-4,4-difluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester as a yellow solid (166.5 mg, 0.443 mmol), 2-methyl-3-butyn-2-ol (298 mg, 3.544 mmol), Pd(OAc)2 (10 mg, 0.0443 mmol), CuI (17 mg, 0.0886 mmol) and PPh3 (35 mg, 0.1329 mmol) in Et3N (20 mL) was degassed with N2, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 40%) to give 4,4-Difluoro-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester as a yellow solid (86 mg, 51%). LC-MS (ESI & APCI): 380.4 (M+1).