Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1>>[F:22][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][NH:1][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[C:15]1[S:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: O=C(O)C1CC1
Product: O=C1CSC(c2ccc(N3C[C@H](CNC(=O)C4CC4)OC3=O)cc2F)=NN1

Procedure:
Prepared from 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.30 g, 0.925 mmol and cyclopropanecarboxylic acid (0.0812 ml, 1.02 mmol) according to the method of Example 15 (0.30 g, 84%); 1HNMR (300 MHz, DMSO-d6) δ 0.59-0.68 (m, 4H), 1.53-1.62 (m, 1H), 3.44 (t, J=5.2 Hz, 2H), 3.58 (s, 2H), 3.72 (dd, J=6.3, 9.1 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.72-4.78 (m, 1H), 7.41 (dd, J=2.2, 8.5 Hz, 1H), 7.53 (dd, J=2.2, 14 Hz, 1H), 7.68 (t, J=8.8 Hz, 1H), 8.46 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 239-40; MS (m/z): [M+H]+=393.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[OH-].[K+].[CH2:37]([OH:39])[CH3:38]>>[CH2:37]([O:39][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:18][CH2:19][CH2:20]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1)[CH3:38]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 0 °C
Yield: 42 %

Procedure:
A mixture of tert-butyl {1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.2 (0.050 g, 0.11 mmol) and potassium hydroxide (powder, 0.050 g, 0.89 mmol, 8.5 equiv) in ethanol (0.8 mL) was irradiated in a microwave apparatus at 120° C. for 120 min. The resulting mixture was added to ice water (10 mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (4×10 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; SNAP 10 g cartridge: 100% DCM 4.0 min., gradient to 95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min., gradient to 90% DCM/10% MeOH 1 min., 90% DCM/10% MeOH 3.5 min., gradient to 80% DCM/20% MeOH 6 min., 80% DCM/20% MeOH 4.7 min.) to give 1-[4-(6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.017 g, 42%):
Reaction SMILES: [C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:4]([CH3:8])[C:5](Cl)=[O:6])#[N:2].[CH:21]([NH:24][CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22].C(C(C1C=CC=CC=1)(C1C=CC=CC=1)C(CC)C(N(C)C)=O)#N>O>[C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:4]([CH3:8])[C:5]([N:24]([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[O:6])#[N:2]
Reactant: CC(C(=O)Cl)C(C#N)(c1ccccc1)c1ccccc1
Reactant: CC(C)NC(C)C
Agent: CCC(C(=O)N(C)C)C(C#N)(c1ccccc1)c1ccccc1
Solvent: O
Product: CC(C)N(C(=O)C(C)C(C#N)(c1ccccc1)c1ccccc1)C(C)C
Reaction time: 8 h

Procedure:
0.1 Mol of 3-cyano-3,3-diphenyl-2-methylpropionyl chloride were added dropwise while cooling and stirring to 50 g (0.5 mol) of diisopropylamine. The mixture was left standing at room temperature overnight and heated at 40°-50° C. for 30 minutes. The mixture was poured into water and isolated as described above for the preparation of 3-cyano-3,3-diphenyl-2-ethyl-N,N-dimethyl-propanamide. The amide was crystallized from a mixture of toluen and ether. Yield: 25 g (50%), melting at 195°-205° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].Cl[C:13]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[C:16]([Cl:35])[C:17]([O:33][CH3:34])=[CH:18][CH:19]=2)[N:14]=1.CCOC(C)=O>CN(C=O)C>[Cl:35][C:16]1[C:17]([O:33][CH3:34])=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[C:13]([N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]1)[CH:22]=[C:21]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred solution of compound 233a (821 mg, 1.1 eq.) in anhydrous DMF (20 mL) at 0° C. was added NaH (241 mg, 1.1 eq.) portionwise. After the reaction mixture was stirred for 1 hr at room temperature, compound 221d (2 g, 1 eq.) was added and the mixture was stirred at 90° C. for 16 hrs. After the reaction mixture was cooled to room temperature, EtOAc was added. The organic phase was washed with HCl (2.5 N), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (petroleum ether/DCM, 50/50) to give compound 234a as a white solid in 51% yield. MS (ESI, EI−) m/z=461.9 (MH−).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-:22])=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
Commercially available 6-nitroquinoline (1.0 g, 5.6 mmol) was dissolved in CHCl3 (30 mL) and mCPBA (1.76 g, 7.8 mmol) was added portionwise and the reactions stirred at rt for 48 h. The mixture was then washed with saturated aqueous NaHCO3, 1 N aqueous NaOH, and 5% aqueous NaHSO3, dried (Na2SO4), filtered and concentrated under reduced pressure to give compound 45A (1.0 g, 93%) as a light yellow solid. LC/MS m/z 191 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17]O)=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCO)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCS(C)(=O)=O)nc21
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-4, 46.4 mg, 0.15 mmol, 1.0 equiv) was added to anhydrous DCM (1.5 mL) and cooled to −10° C. Triethylamine (90 μL, 0.64 mmol, 4.2 equiv) and methanesulfonyl chloride (26 μL, 0.33 mmol, 2.2 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 32-4. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give 32-5 as a clear, yellow oil. The crude product was carried forward without further purification.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][Si@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[CH2:19]([C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1)[CH2:20][CH3:21].Cl[SiH]1CCC(CC[C@H]2CC[C@H](CCCCC)CC2)CC1.FC1C=C([Mg]Br)C=CC=1F>>[CH2:19]([C:22]1[CH:27]=[CH:26][C:25]([C@H:2]2[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][C@H:10]3[CH2:15][CH2:14][Si@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]3)[CH2:4][CH2:3]2)=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: CCC[Si@H]1CC[C@H](CCC2CCC(Br)CC2)CC1
Reactant: CCCc1ccc([Mg]Br)cc1
Agent: CCCCC[C@H]1CC[C@H](CCC2CC[SiH](Cl)CC2)CC1
Agent: Fc1ccc([Mg]Br)cc1F
Product: CCCc1ccc([C@H]2CC[C@H](CC[C@H]3CC[Si@H](CCC)CC3)CC2)cc1

Procedure:
The preparation was conducted in the same manner as in Example 33, except that 2.6 g (7.9 mmol) of 1-bromo-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexane and p-n-propylphenylmagnesium bromide were used instead of 2.5 g (7.9 mmol) of 1-chloro-4-(2-(trans-4-n-pentylcyclohexyl) ethyl)-1-silacyclohexane and 3,4-difluorophenylmagnesium bromide.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl.[OH-].[Na+]>O>[O:13]1[CH2:12][CH:11]1[CH2:9][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc(OCC2CO2)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To an ice-cooled solution of 55 g. (0.5 mole) of hydroquinone and 46 g. (0.5 mole) of epichlorohydrin in 900 ml. of water was added an ice-cooled solution of 20 g. (0.5 mole) of sodium hydroxide in 900 ml. of water. The mixture was allowed to stand at 0° C. for 3 days. After washing with ether, the solution was added to 72 g. of sodium hydroxide in 4 l. of water and stored at 10° C. for 3 hours. The solution was saturated with ammonium carbonate and extracted with chloroform. After drying (Na2SO4) and concentrating the chloroform, the residual oil was predominantly 4-(2,3-epoxy-1-propoxy)-phenol (23%) which was used in later step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:49])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1)[CH3:36]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:35]([O:37][C:38](=[O:49])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)=[CH:44][CH:43]=1)[CH3:36]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)CCCc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CCCc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, 4-(4-bromo-phenyl)-butyric acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride were reacted to provide 4-(4′-{4-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-butyric acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(=O)OC(C)(C)C)[C:15]2[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][C:3]1=[O:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C@@H:16]1[C:15]2[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][C:3](=[O:29])[C@H:2]([CH3:1])[CH2:19][CH2:18][CH2:17]1
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCC[C@H](N)c2cc(ccn2)-c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 45G (950 mg, 2.402 mmol) in DCM (20.300 ml) was added TFA (5.55 ml, 72.1 mmol) dropwise over 10 min. The dark brownish solution was stirred at rt for 1 hour. The reaction mixture was concentrated to give example 45H compound as a dark brownish gum. Used in next step without purification. MS (ESI) m/z: 296.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[N:12]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:13]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])=[O:18])[N:15]=1)=[O:10])=[O:4].[I-].[Na+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.CS(C)=O>COCCOC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([NH:16][C:14]2[N:15]=[C:11]([C:9]([O:8][CH2:7][CH2:6][O:5][C:3](=[O:4])[CH2:2][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:10])[N:12]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH:13]=2)=[O:18])=[C:21]([CH3:27])[CH:22]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCOC(=O)CBr)n1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCOC(=O)CN2CCOCC2)n1

Procedure:
61.8 mg (0.1 mmol) of 2-[(2-bromoacetyl)oxy]ethyl 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylate (Example 24A) are dissolved in 0.4 ml of 1,2-dimethoxyethane under argon, and 15 mg (0.1 mmol) of sodium iodide and 43.6 mg (0.5 mmol) of morpholine are added. The reaction mixture is heated under reflux for 2 h and then mixed with 0.3 ml of DMSO, filtered and purified by preparative HPLC (Method 9).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1>C(Cl)CCl>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:23]2[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[F:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Cc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(C)cc2F)CC1

Procedure:
By following the manipulative procedure described above in Example 4(a), 25 g of 1-acetylisonipecotoyl chloride are added to stirred suspension of 25 g of aluminum chloride and 14 g of m-fluorotoluene in 220 ml of ethylene dichloride to produce the oil, 1-acetyl-4-(2-fluoro-4-methylbenzoyl)piperidine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16].[CH3:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][CH:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]2.[I-].[Na+].NC1C2C(=CC=CC=2)CCC1>CN(C)C=O.C(N(CC)CC)C>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][CH:27]([N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]1(=[O:17])=[O:16])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]2
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: CCCNC1CCc2cccc(OC)c2C1
Agent: NC1CCCc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN(CCCCN1C(=O)c2ccccc2S1(=O)=O)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.6 %

Procedure:
1.9 g (6.0 mmol) of 2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide were added dropwise to the solution of the 1.3 g (6.0 mmol) of 8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene and 1.3 g (12 mmol) of triethylamine in 15 ml of dimethylformamide. After stirring for 15 hours at room temperature, a spatula tip of sodium iodide was added, and the mixture was heated to 60° C. After 4 hours at this temperature, 0.4 g of the above aminotetralin and 0.3 g of triethylamine were added. Chromatography on silica gel (toluene/ethyl acetate gradients) of the crude product, obtained after removal of the solvent in vacuo, yielded 0.70 g (25%) of the title compound as a yellowish oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:33])[C@@H:29]([NH2:32])[CH2:30][CH3:31])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20](=[O:22])[NH:32][C@H:29]([C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:33])[CH2:30][CH3:31])[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](C(=O)O)c1ccc(O)cc1)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccc(O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of (R)-N-benzyloxycarbonyl-α-carboxy-4-hydroxybenzylamine (Method 17; 2.00 g, 6.64 mmol), (2S)-2-amino butanoic acid t-butyl ester (1.30 g, 6.64 mmol) and N-methylmorpholine (2.0 g, 19.8 mmol) in DCM (30 ml) was stirred at RT for 5 min, after which TBTU (2.60 g, 8.10 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel DCM:Acetone—60:40). The product was crystallized from toluene (20 ml) giving 1.85 g of the desired product as a white solid. NMR (400 MHz): 0.80 (3H, t), 1.45 (9H, s), 1.50–1.80 (2H, m), 4.10–4.20 (1H, m), 5.05 (1H, d(AB)), 5.15 (1H, d(AB)), 6.75 (2H, d), 7.20–7.40 (7H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: CN1CCNCC1
Reactant: Clc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: CN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 8-chloro-1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-chloro-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1F>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Product: CN1CCN(c2cc(C(F)(F)F)ccc2Br)CC1
Temperature: 180 °C

Procedure:
A microwave vial was charged with 1-methylpiperazine (1.371 mL, 12.35 mmol) and 4-bromo-3-fluorobenzotrifluoride (1.000 mL, 4.12 mmol), and was heated under microwave irradiation at 180° C. for 90 minutes. The reaction was concentrated under a vacuum, and the solids were then filtered and washed with DCM (solids contained only minor amounts of product). The filtrate was then concentrated under a vacuum to yield 1-(2-bromo-5-(trifluoromethyl)phenyl)-4-methylpiperazine, mixed with starting bromide. Material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.[F:20][C:21]([F:29])([F:28])[C:22]([F:27])([F:26])[C:23](O)=[O:24]>ClCCl.CN(C1C=CN=CC=1)C>[F:26][C:22]([F:27])([C:21]([F:29])([F:28])[F:20])[C:23]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:24]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
In 15 ml of anhydrous dichloromethane, 300 mg (3.19 mmol) of 2-aminopyridine was dissolved. To this solution, 919 mg (4.78 mmol) of EDC-HCl, 583 mg (4.78 mmol) of DMAP, and 397 μl (628 mg, 3.83 mmol) of pentafluoropropionic acid were added in this order, followed by stirring at room temperature overnight. After completion of the reaction, the reaction liquid was diluted with dichloromethane, washed once with water, and twice with 1% hydrochloric acid, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thus, 85 mg of 2,2,3,3,3-pentafluoro-N-(pyridin-2(1H)-ylidene)propanamide was obtained (Percentage Yield: 11%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[Cl:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([C@H:25]1[CH2:29][N:28]([C:30]([C:32]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33]2)=[O:31])[C@H:27]([C:42](O)=[O:43])[CH2:26]1)(=[O:24])=[O:23]>>[Cl:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([C@H:25]1[CH2:29][N:28]([C:30]([C:32]2([C:35]3[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=3)[CH2:34][CH2:33]2)=[O:31])[C@H:27]([C:42]([NH:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C:3](=[O:10])[C:4]([NH:6][CH:7]2[CH2:8][CH2:9]2)=[O:5])=[O:43])[CH2:26]1)(=[O:24])=[O:23]
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide and (2S,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid in step 1. MS (m/e)=652.14 [M+H+].
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[C:22]2[N:21]=1.B(F)(F)F.O>C(#N)C>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:9]1[S:14][CH2:15][C:6]([CH2:5][S:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]3[N:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[C:22]3[N:21]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: Cc1cc(S)nc2c(C(=O)O)cnn12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: O
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)nc2c(C(=O)O)cnn12
Reaction time: 1.5 h

Procedure:
A suspension of 4.00 g of (7R)-7-aminocephalosporanic acid and 3.34 g of 5-mercapto-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid in 20 ml of acetonitrile was treated with 25 ml of a 20 percent solution of boron trifluoride in acetonitrile and the mixture was stirred at 20° for 1.5 hours. 150 ml of cold water were added and the mixture was stirred at 0° for 1.5 hours. The precipitate was filtered off under suction and dried. There was obtained (6R,7R)-7-amino-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyri-midine-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid as an almost colorless powder.