Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N.O>[CH2:19]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (34.9 g, 0.213 mol) in MeCN (350 mL), K2CO3 (58.7 g, 0.425 mol) and benzylbromide (36.4 g, 0.213 mol) is added. The mixture is stirred at 60° C. for 2 h before it is cooled to rt, diluted with water and extracted twice with EA. The org. extracts are washed with water and concentrated to give crude 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde as an orange oil (45 g). 1H NMR (CDCl3): δ1.29 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.77 (q, J=7.8 Hz, 2H), 4.90 (s, 2H), 7.31-7.52 (m, 5H), 7.62 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (256 mg, 0.85 mmol), 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (1272 mg, 3.80 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (485 mg, 1.03 mmol) in Chloroform (8.5 mL). DIEA (750 μL, 4.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=583 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C.CCCCCC.C(OCC)(=O)C>C(#N)C>[Cl-:12].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([O:13][CH2:21][CH2:22][NH3+:23])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: [Cl-]
Product: [NH3+]CCOc1ccc2cc(Br)ccc2c1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 138.5 %

Procedure:
To a solution of 6-bromo-1-chloronaphthalen-2-ol (100 mg, 0.39 mmol) and K2CO3 (108 mg, 0.78 mmol) in 4 mL of acetonitrile was added tert-butyl (2-bromoethyl)carbamate (175 mg, 0.78 mmol). The resulting mixture was heated at 60° C. for 2 h. After TLC control (n-hexane/ethyl acetate 90:10) showed the disappearance of 6-bromo-1-chloronaphthalen-2-ol, solvent was evaporated in vacuo and the crude was taken up in 10 mL of 4M HCl in dioxane and stirred for 1 h. The solvent was removed under vacuum and the residue was diluted with n-hexane (10 mL) and triturated at room temperature overnight. The solid was filtered and dried under vacuum at 50° C. to afford 2-[(6-bromo-1-chloronaphthalen-2-yl)oxy]ethanaminium chloride as white solid (91 mg, 69% yield). HPLC-MS (ESI+): m/z 337.83 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.CCN(C(C)C)C(C)C.[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH:25]2[CH2:28][NH:27][CH2:26]2)=[C:22]([F:31])[CH:21]=1>C(O)(C)C>[Cl:8][C:6]1[N:7]=[C:2]([N:27]2[CH2:28][CH:25]([O:24][C:23]3[CH:29]=[CH:30][C:20]([Cl:19])=[CH:21][C:22]=3[F:31])[CH2:26]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(Cl)nc(N2CC(Oc3ccc(Cl)cc3F)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.800 g, 4.87 mmol) in isopropanol (15 mL) was added DIPEA (1.3 mL) and 3-(4-chloro-2-fluorophenoxy)azetidine (0.600 g, 2.92 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-6-methyl-1,3,5-triazine (1.0 g) as a solid. Observed mass (M+1): 329. The crude material was taken to next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[CH:44]=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cncc(-c2cc(C)c(Br)c(C)c2)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cncc(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-bromo-3,5-dimethyl-phenyl)-5-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1cnc(-c2ccccc2)s1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cnc(-c2ccccc2)s1
Yield: 51 %

Procedure:
This compound was synthesized from 2-methyl-2-(2-phenylthiazol-5-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 51%). 1H NMR (400 MHz, MeOD) δ 8.55 (t, J=1.6 Hz, 1H), 8.29-8.26 (dt, J=7.9 Hz, 1.3 Hz, 1H), 8.03-8.01 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.91-7.88 (m, 2H), 7.70-7.66 (m, 2H), 7.47-7.45 (m, 3H), 3.64 (s, 2H), 1.53 (s, 6H). MS (ESI) m/z: Calculated for C23H19F3N4O2S: 472.12. found: 473.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:57][C:58]([NH2:62])([CH2:60][CH3:61])[CH3:59]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:62][C:58]([CH2:60][CH3:61])([CH3:59])[CH3:57])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CCC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Reaction time: 16 h
Yield: 20.8 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.19 mmol), HATU (91.20 mmol, 0.24 mmol) and DIPEA (49 mg, 0.38 mmol) in 6 mL of DMF, 2-methylbutan-2-amine (21.60 mg, 0.24 mmol) was added in one portion at room temperature. Then the reaction mixture was stirred for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 15% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-tert-pentyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 20.7%) as a white solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.07 (s, 1H), 8.47-8.37 (m, 2H), 7.81 (s, 1H), 7.70 (dd, 1H, J=9.6, 2.1 Hz), 7.17 (t, 1H, J=2.1 Hz), 4.15 (s, 3H), 1.89 (q, 2H, J=7.6 Hz), 1.46 (s, 6H), 0.87 (t, 3H, J=7.5 Hz).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:18][Mg]Cl.COC1C=C(C=CC=1OC)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>[Pd]>[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Cc1ccc(C[Mg]Cl)cc1C
Agent: [Pd]
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(OC)c(OC)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(C)c(C)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 3,4-dimethyl-benzylmagnesium chloride (0.25 M in THF, 28.0 mL, 7.0 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3,4-dimethylbenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane to afford the title compound. 0.050 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.02-2.19 (m, 1H) 2.19-2.35 (m, 6H) 2.44-2.62 (m, 1H) 2.62-2.87 (m, 4H) 3.19-3.38 (m, 1H) 3.82 (s, 3H) 6.46 (d, J=1.56 Hz, 1H) 6.95 (d, J=7.52 Hz, 1H) 7.00 (s, 1H) 7.07 (d, J=7.42 Hz, 1H) 8.93 (br. s, 1H).
Reaction SMILES: [CH2:1]([Cl:3])Cl.Br[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([NH:19][C:20](=[O:23])[CH2:21]Br)[CH:10]=1)=[O:7].[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][CH2:5][C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([NH:19][C:20](=[O:23])[CH2:21][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:1]([Cl:3])[CH:14]=3)[CH:10]=2)=[O:7])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CBr)Nc1cc(NC(=O)CBr)cc(C(F)(F)F)c1
Reactant: Nc1cccc(Cl)c1
Reactant: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CNc1cccc(Cl)c1)Nc1cc(NC(=O)CNc2cccc(Cl)c2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a CH2Cl2 solution of 2-Bromo-N-[3-(2-bromo-acetylamino)-5-trifluoromethyl-phenyl]-acetamide (150 mg, 0.30 mmol) at room temperature was added 3-chloroaniline (100 μL), the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with NaHCO3 solution followed byl N HCl (2×) and brine. The organic layer was dried over MgSO4, filtered and stripped and the crude product was purified by flash chromatography on silica gel eluted with hexane/ethyl acetate (2:1) to give 132 mg of the title compound in 92% yield. 1H NMR (400 MHz, CDCl3): δ 3.87(s, 4H), 6.49(dd, J=2, 8.4 Hz, 2H), 6.63(s, 2H), 6.79(d, J=2, 8.4 Hz, 2H), 7.10(t, J=8.0 Hz, 2H), 7.46(s, 2H), 8.20(s, 1H), 8.77(s, 2H). MS SEI m/z relative intensity:M+H, 511.2(100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C)C=O>[C:7]1([C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Piperazine (1.00 g, 11.6 mmol) (Wako Pure Chemical Industries, Ltd.) was dissolved in N,N-dimethylformamide (25 mL) (Wako Pure Chemical Industries, Ltd.), and triphenylchloromethane (0.65 g, 2.33 mmol) (Wako Pure Chemical Industries, Ltd.) was added little by little, and the mixture was stirred at room temperature overnight. Water was poured into the reaction solution, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=9:1 as an eluent). The residue was dissolved in ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.), and the mixture was shaken, followed by separation of the organic layer. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and then the solvent was distilled off under reduced pressure, to thereby obtain the title compound (0.76 g, 99% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-].Cl>O1CCCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C)nc(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C#N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-cyano-6-methylisonicotinate (0.490 g, 2.78 mmol, Eq: 1.00) was dissolved in Tetrahydrofuran (25 ml) and Methanol (3.03 ml). At 0° C., 1M LiOH in H2O (3.48 ml, 3.48 mmol, Eq: 1.25) was added and the RM was stirred at 0° C. for 30 minutes. Control with TLC: the reaction was finished. The reaction mixture was acidified with 1M HCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO4; filtered; concentrated in vacuo. Pink solid. MS (EIC): 160.8 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 200 mg, 0.569 mmol), KF (371 mg, 6.26 mmol) and piperazine (490 mg, 5.69 mmol) were suspended in NMP (2.85 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afford the title compound as a yellow foam (tR 2.78 min (conditions 1), MH+=395).
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH3:35])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].O1CCOCC1>Cl.C(Cl)Cl>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([CH3:35])[N:26]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](N)C3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A solution of tert-butyl [(1R,3S)- 3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin- 1 -ylcarbonyl)cyclopentyl]carbamate (200 mg, 1.65 mmol) dissolved in 4 M of HCl in 1,4-dioxane (10 mL, 40 mmol) was stirred at room temperature for 1 h. The reaction was diluted with methylene chloride, washed with saturated NaHCO3 solution, dried with sodium sulfate, filtered, and concentrated in vacuo to provide the desired product (0.15 g, 94%). LCMS calculated for C20H30F3N4O:(M+H) 399.2; found 399.2.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1>>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[C:3]=1[C:4]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1)=[O:6]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C)c(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c(C)c1
Yield: 12.9 %

Procedure:
2,4,6-Trimethylbenzoic acid (25 mg, 0.15 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (6 mg, yield 13%) was obtained as slightly brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: ClC1C=C(C=CC=1[N+]([O-])=O)C[P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].Cl[CH2:21][C:22]1[CH:23]=[C:24]([O:32][CH3:33])[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([F:28])[CH:27]=1>>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([O:32][CH3:33])[C:25]=1[N+:29]([O-:31])=[O:30])[CH2:21][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: COc1cc(CCl)cc(F)c1[N+](=O)[O-]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Product: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Compound 104C (Diethyl (3-chloro-4-nitrobenzyl)phosphonate) with 5-(chloromethyl)-1-fluoro-3-methoxy-2-nitrobenzene (Compound 146C). 1H NMR (CDCl3, 400 MHz): δ=1.31 (t, J=7.07 Hz, 6H), 3.11-3.18 (m, 2H), 3.94 (s, 3H), 4.07-4.13 (m, 4H), 6.77 (dt, J=9.79, 1.93 Hz, 1H), 6.82 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)=[O:4].[CH3:14][CH:15](C)[CH2:16]N(C=CC)CC(C)C.CC(N(C)C)=O.[OH:32][CH2:33][C:34]([CH3:38])([CH2:36][OH:37])[CH3:35]>O>[CH3:35][C:34]1([CH3:38])[CH2:36][O:37][CH:14]([CH:15]([CH3:16])[CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][CH:6]=2)=[O:4])[O:32][CH2:33]1
Reactant: CC(C)(CO)CO
Reactant: CC=CN(CC(C)C)CC(C)C
Reactant: CCOc1ccc(C(=O)CBr)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOc1ccc(C(=O)CC(C)C2OCC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
2-Bromo-1-(4-ethoxyphenyl)ethan-1-one (4.0 g) and N,N-bis(2-methylpropyl)-1-propenylamine (4.0 g) were added to 16 ml of dimethylacetamide under an atmosphere of nitrogen and the mixture was stirred between 50° C. and 55° C. for 2 hours. To the reaction mixture were added successively 1.6 g of paratoluenesulfonic acid and 2.1 g of neopentyl glycol and the mixture was stirred between 50° C. and 60° C. for 3 hours. After addition of 8 ml of water to the reaction mixture and cooling the reaction mixture to the room temperature, crystals precipitated. These crystals were isolated by filtration to give 3.7 g (yield 74%) of the title compound as white crystals. The 1H-NMR spectrum of the product is substantially identical with that of the product of Example 1.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:36])[NH:27][CH2:28][C@H:29]1[CH2:33][CH2:32][C@H:31]([O:34][NH2:35])[CH2:30]1)([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:21]([O:25][C:26](=[O:36])[NH:27][CH2:28][C@H:29]1[CH2:33][CH2:32][C@H:31]([O:34][NH:35][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:20])[CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol, US2005/20572 A1, 2005) in DCM (20 was added tert-butyl[trans-3-(aminooxy)cyclopentyl]methylcarbamate 116 (0.32 g, 1.39 mmol), 1-hydroxybenzotriazole (0.18 g, 1.33 mmol), and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.26 g, 1.36 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 6 hours, then concentrated in vacuo to provide a residue which was subjected to chromatography to give 117 (0.45 g, contains some byproduct) as a white foam.