Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH2:38][NH2:39])[CH:35]=[CH:36][CH:37]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=2)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCc2cccc(C(F)(F)F)c2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 1-[3-(trifluoromethyl)phenyl]methanamine (45.58 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (27 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 75 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 3.56 (s, 2H), 4.61 (s, 2H), 7.16 (t, J=75.3 Hz, 1H), 7.18-7.25 (m, 1H), 7.36-7.51 (m, 2H), 7.57-7.65 (m, 3H), 7.71-7.77 (m, 2H), 7.83 (d, J=15.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.82-8.88 (m, 1H); APCI-MS (m/z) 580.29 (MH)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].Cl.[CH3:16][NH:17][O:18][CH3:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]([N:17]([CH3:16])[O:18][CH3:19])[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCNc1ncnc(NCCC)n1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(N(C)OC)n1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (10.00 g, 43.53 mmol), N,O-dimethylhydroxylamine hydrochloride (8.49 g, 87.06 mmol) and NaOH (3.13 g, 78.35 mmol) in 1,4-dioxane (120 mL) and water (30 mL) was heated at 60° C. for 6 h, after which the volatiles were removed under reduced pressure. Saturated NaHCO3 solution (500 mL) was added to the residue and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water (300 mL), then with a brine solution (300 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resultant residue was filtered through silica gel using eluent CH2Cl2/EtOH (9/1 v/v) to yield N-(4,6-bis-n-propylamino[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) (9.96 g, 90% yield).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]1[C:28](=[O:29])[N:7]2[C:8]([C:25]([O-:27])=[O:26])=[C:9]([CH2:12][N+:13]3[N:14]([CH3:24])[C:15]([NH:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:39][C:40]1[S:44][N:43]=[C:42](/[C:45](=[N:49]/[O:50][CH3:51])/[C:46](Cl)=[O:47])[N:41]=1.C(OCC)(=O)C>O1CCCC1>[NH2:39][C:40]1[S:44][N:43]=[C:42]([C:45](=[N:49][O:50][CH3:51])[C:46]([NH:4][C@@H:5]2[C:28](=[O:29])[N:7]3[C:8]([C:25]([O-:27])=[O:26])=[C:9]([CH2:12][N+:13]4[N:14]([CH3:24])[C:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:47])[N:41]=1
Reactant: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: COC(=O)CNc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1C
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NCC(=O)O)n3C)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a solution of 7β-amino-3-[2-methyl-3-methoxycarbonylmethylamino-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride (0.7 g) and N-(trimethylsilyl)acetamide (1.87 g) in tetrahydrofuran (14 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride (0.37 g) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (140 ml) and the resultant powder was collected by filtration. The powder was dissolved in ice-water and adjusted to pH 13 with 1N aqueous sodium hydroxide. After stirring for 20 minutes under ice-cooling, the solution was adjusted to pH 2 with 3N hydrochloric acid and subjected to column chromatography on "Diaion HP-20" using 5% aqueous isopropyl alcohol as an eluent. Fractions containing the object compound were combined, evaporated in vacuo to remove isopropyl alcohol and lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-carboxymethylamino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (0.24 g).
Reaction SMILES: [C:1]1([C:7]2[S:15][C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:16])[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:24])C(=O)C1.O>CN(C=O)C>[Br:24][C:13]1[C:14]2[S:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]=2[C:10](=[O:16])[NH:11][CH:12]=1
Reactant: O=c1[nH]ccc2sc(-c3ccccc3)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cc(Br)c2sc(-c3ccccc3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To compound 2 (3.92 g, 17.24 mmol) in DMF (133 mL) was added NBS (3.37 g, 19.0 mmol). The solution was heated to 60° C. After 1 h, the solution volume was reduced to approximately one half the volume, and the solution was poured into H2O (700 mL). The precipitate was filtered, washed with water, and dried to yield 5.08 g of 3. 1H NMR (400 MHz, d6-DMSO) δ: 11.84 (s, 1H), 8.05 (s, 1H), 7.82 (d, J=7 Hz, 2H), 7.61 (s, 1H), 7.48 (t, J=7 Hz 2H), 7.4 (t, J=7 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:19]3[CH2:21][CH2:20]3)[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH2:34][C:35](O)=[O:36])[CH:27]=[CH:28][C:29]=1[C:30]([F:33])([F:32])[F:31].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:19]3[CH2:20][CH2:21]3)[C:14]=2[NH:18][C:35](=[O:36])[CH2:34][C:26]2[CH:27]=[CH:28][C:29]([C:30]([F:31])([F:32])[F:33])=[C:24]([F:23])[CH:25]=2)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C3CC3)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C3CC3)ccc2c1=O
Temperature: 40 °C

Procedure:
A reaction vial was charged with (R)-2-(5-amino-6-cyclopropyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (23.0 mg, 0.0000766 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (26 mg, 0.00011 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (73 mg, 0.00019 mol), N,N-diisopropylethylamine (33 μL, 0.00019 mol) and methylene chloride (2 mL, 0.03 mol) and the reaction was stirred at 40° C. over night. the solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as light yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.C1COCC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:3]3[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=4)[N:17]=3)[CH:5]=[CH:6][C:7]=2[C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:38][CH:37]=1
Reactant: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc3c2Cl)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc3c2-c2ccc(Cl)cc2)cc1
Temperature: 70 °C
Yield: 27.1 %

Procedure:
To a stirring solution of 8-chloro-7-p-tolyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (28 mg, 0.067 mmol) in a 1:1 mixture of THF and methanol (4 mL) at room temperature under argon was added 4-chlorophenylboronic acid (12.5 g, 0.080 mmol), PXPd (11 g, 0.02 mmol), and K2CO3 (18.5 mg, 0.13 mmol). The resulting suspension was heated at 70° C. under argon for 10 min. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, water (25 mL) and EtOAc (25 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC (without TFA) to obtain 9 mg of the title compound as a white lyophilate. HPLC/MS: retention time=4.16 min, [M+H]+=495. 1H NMR (CDCl3): δ 8.79 (s, 1H), 7.95 (d, J=6.7 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H) 7.69 (d, J=6.7 Hz, 1H), 7.29-7.18 (m, 4H), 7.12 (d, J=6.2 Hz, 2H), 7.00 (d, J=6.2 Hz, 2H), 6.70 (d, J=6.5 Hz, 1H), 5.27 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH2:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)[CH3:35]>CN(C=O)C>[CH2:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][CH2:2]/[C:3](/[CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:4]/[C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:38][CH2:37]1)[CH3:35]
Reactant: CCN1CCC(N)CC1
Reactant: COC(=O)c1ccc(C=C(CBr)COc2cccc3ccccc23)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCC(NC/C(=C/c2ccc(C(=O)OC)cc2)COc2cccc3ccccc23)CC1
Yield: 46 %

Procedure:
Methyl 4-[2-bromomethyl-3-(naphthalen-1-yloxy)-propenyl]-benzoate (412 mg, 1 mmol) was dissolved in N,N′-dimethylformamide (2.5 ml) in a 100 ml flask at 0° C., and to the resulting solution, triethylamine (0.17 ml, 1.2 mmol, 1.2 eq.) and 1-ethylpiperidin-4-ylamine (128 ml, 1.0 mmol, 1.0 eq.) were added while stirring. The resulting mixture was heated from 0° C. to room temperature, and then reacted for 4 hours. After the completion of reaction, the mixture was concentrated under reduced pressure, and the residue thus obtained was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 211 mg of the title compound as pale yellow oil (yield 46%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=1.C(O)(=O)C>O>[N:1]1([CH2:7][C:8]2[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: C1CCNC1
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(CN2CCCC2)[nH]c(=O)[nH]1
Reaction time: 24 h
Yield: 28.8 %

Procedure:
To a solution of 1.78 g of pyrrolidine in water (20 ml), 1.33 g of 6-chloromethyluracil were added. The resulting mixture was stirred at roomtemperature for 24 hours and neutralized with acetic acid. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was washed with methanol and then filtered, whereby 466 mg of thetitle compound were obtained (yield: 29%).
Reaction SMILES: CS([Br:5])(=O)=O.[CH3:6][O:7][C:8](=[O:35])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33]O)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8](=[O:35])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][Br:5])[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: CS(=O)(=O)Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CO)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylsulfonyl bromide (0.96 mL) is added to a solution of {(S)-6-[(R)-4-hydroxymethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (2.00 g) and triethylamine (1.98 mL) in dichloromethane (20 mL) chilled in an ice bath. The cooling bath is removed, and the solution is stirred at room temperature overnight. More dichloromethane is added, and the resulting solution is washed with aqueous NaHCO3 solution and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 4): tR=1.24 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:12]([O:11][C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([C:15](=[O:17])[CH3:16])[CH2:19][CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([CH3:14])[CH3:13]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CC1

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12](#[N:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC1C=CC=CC=1Cl>>[C:13]1([C:12]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:19]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)c1nsc(=O)o1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nsc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 3 %

Procedure:
A mixture of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate (U.S. Publication No. 2005/0096362) (1.5 g, 8.56 mmol) and benzonitrile (4.37 ml, 42.8 mmol) in 1,2-dichlorobenzene (15.42 ml, 137 mmol) was heated to 160° C. for 4 days. The reaction was then cooled down to RT and the solvent was evaporated by heated the reaction at 75° C. at maximum vacuum. The residue was purified on silica gel chromatography (100% CH2Cl2 to 3% EtOAc in CH2Cl2) to provide the title material (0.064 g, 3%). LC (Method B): 2.021 min. HRMS (ESI) calcd for C11H11N2O2S [M+H]+ m/z 235.0541, found 235. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.01-8.09 (m, 1H), 7.49-7.59 (m, 2H), 4.56 (q, J=7.17 Hz, 1H), 1.50 (t, J=7.24 Hz, 1H).
Reaction SMILES: [C:1]([NH:13][NH2:14])(=O)[C:2]1[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:4](NN)=[O:5].P(Br)(Br)(Br)(Br)[Br:16].O>C(Br)(Br)(Br)Br>[Br:16][C:1]1[C:2]2[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4](=[O:5])[NH:14][N:13]=1
Reactant: NNC(=O)c1ccccc1C(=O)NN
Reactant: BrP(Br)(Br)(Br)Br
Agent: BrC(Br)(Br)Br
Solvent: O
Product: O=c1[nH]nc(Br)c2ccccc12

Procedure:
A mixture of phthalhydrazide (3.2 g) and phosphorus pentabromide (19.0 g) was heated with stirring in carbon tetrabromide (50 g) at 125° for 16 hours. The cooled mixture was poured into water (50 cm3) and the product collected by filtration. The solid product was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with diethyl ether:dichloromethane, 1:3 by volume. Combination and evaporation of appropriate fractions afforded the title compound, m.p. 268°-271° (1.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14](Br)=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=2[Cl:25])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 58.8 %

Procedure:
In a sealed tube, a mixture of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (4.48 g, 14.8 mmol, prepared according to Example 1, Step 1.3), 2,4-dichloro-benzeneboronic acid (4.24 g, 22.2 mmol), Pd(PPh3)4 (855 mg, 0.74 mmol) and Na2CO3 (2.0 M solution in water, 26 mL, 52.0 mmol) in DME (50 mL) was heated at 150° C. for 17 min in a microwave oven. The reaction mixture was cooled to RT, diluted in AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→100% TBME) to yield the title compound (3.2 g, 8.7 mmol, 59%) as a white solid. MS: 368 [M−1]+; HPLC: AtRet=1.69.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[NH:11])OCC)=[CH:5][CH:4]=1.[CH:14]([NH:16][NH2:17])=O.C(N(CC)CC)C>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[NH:11][CH:14]=[N:16][N:17]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=N)c1ccc(Br)cc1
Reactant: NNC=O
Agent: Cl
Solvent: CCN(CC)CC
Product: Brc1ccc(-c2nnc[nH]2)cc1
Temperature: 85 °C
Yield: 48.3 %

Procedure:
Ethyl 4-bromobenzimidate hydrochloride (35.6 g, 135 mmol), formic hydrazide (16.16 g, 269 mmol) and triethylamine (75 mL, 538 mmol) were combined in a screw capped flask and heated to 85° C. for 16 h. The solution was condensed under reduced pressure to afford a solid, which was partitioned between water and ethyl acetate (3×), dried over magnesium sulfate and solvent removed under reduced pressure. The resulting solid was sonicated with 20% ethyl acetate in hexanes, filtered and dried to afford the title compound (14.6 g, 65.2 mmol, 48% yield). MS (ESI) m/z 224.1 [M]+, 226.1 [M+2]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCCC1=O>[Cl:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][NH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:2]([N:29]2[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]2)=[N:3][N:4]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: OC1CCNCC1
Agent: CN1CCCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Yield: 85.6 %

Procedure:
1H-NMR(400 MHz, CDCl3) δ: 3.87(3H, s), 4.78(2H, d, J=5.0 Hz), 5.75(1H, t, J=5.0 Hz), 6.87(1H, d, J=8.5 Hz), 7.31(1H, dd, J=8.5, 2.0 Hz), 7.43(1H, d, J=2.0 Hz), 8.05(1H, dd, J=8.5, 1.5 Hz), 8.24(1H, dd, J=1.5, 1.0 Hz), 8.29(1H, dd, J=8.5, 0.5 Hz). 10.0 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine was dissolved in 50 ml of N-methyl-2-piperidone. After adding 43.32 g of 4-hydroxypiperidine and 10 ml of diisopropylethylamine, the resulting mixture was heated at 170° C. for 8 hours. Then ethyl acetate wag added thereto and the resulting mixture was successively washed for three times with water and once with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1) to give 10.1 g of 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazine as yellow crystals. M.p.: 172.0-173.5° C., Mass 424(MH+),
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O-:12].[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: C[O-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(Br)ccc1C#N
Yield: 79.6 %

Procedure:
In a 1 L round-bottomed flask, 53.94 g (270 mmol) of 4-bromo-2-fluorobenzonitrile was dissolved in 500 mL of THF. Sodium methoxide (21.99 g, 407 mmol) was added and the mixture was heated to reflux until TLC (SiO2: CH2Cl2) showed complete consumption of starting material. The mixture was poured into 1N HCl and the THF was evaporated in vacuo. The remaining mixture was extracted with diethyl ether. The extract was dried (MgSO4) and filtered over a plug of silica gel. The plug was eluted with CH2Cl2 and the filtrate was evaporated in vacuo to afford 45.56 g (80%) of the product as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.42 (d, 1H), 7.17 (dd, 1H), 7.14 (d, 1H), 3.95 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)=[O:4].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH2:20]([NH:27][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)[OH:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCCCCCOc1ccc(C(=O)CBr)cc1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(C(O)CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a cooled (0° C.) suspension of 2-Bromo-1-(4-octyloxy-phenyl)-ethanone (36.1 g; 110.3 mmol) in EtOH (500 mL) and CHCl3 (100 mL) was added benzylamine (48.2 mL; 441.2 mmol). After 30 minutes the ice-bath was removed and the mixture stirred for another 2 hours at RT. Subsequently the reaction mixture was cooled again to 0° C. and NaBH4 (6.26 g; 165.5 mmol) was added in small portions. The resulting mixture was stirred at 0° C. for 1 hour and thereafter another 4 hours at RT. The reaction mixture was quenched with 1M aqueous HCl (750 mL) at 0° C. and stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 2 N aqueous NaOH. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, EtOAc) to give 2-benzylamino-1-(4-octyloxy-phenyl)ethanol (22.58 g)