Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCOc2ccc(O)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1CCOc2ccc(OCc3ccccc3)cc21

Procedure:
A mixture of 6-hydroxy-4-chromanone (18.6 g, 113 mmol), benzyl bromide (20 g, 116 mmol), and K2CO3 (21 g, 152 mmol) in acetone (110 ml) was refluxed for 20 hrs. The mixture was cooled, diluted with EtOAc, and filtered through celite. The filtrate was concentrated to an oil, which was triturated with 10% Et2O in hexane (150 ml) to gives, after filtration and washing, 28 g (87%) of the title compound.
Reaction SMILES: FC1C=CC(C2C3C(=CC(C#N)=CC=3)CO2)=CC=1.Cl[CH2:20][CH2:21][CH2:22][C:23]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:31]2[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1.[I-:41].[Na+]>CC(C)=O>[I:41][CH2:20][CH2:21][CH2:22][C:23]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:31]2[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1
Reactant: [I-]
Reactant: N#Cc1ccc2c(c1)COC2(CCCCl)c1ccc(F)cc1
Agent: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc2c(c1)COC2(CCCI)c1ccc(F)cc1
Yield: 181 %

Procedure:
1-3-Iodopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (14a). A solution/suspension of 1-(3-chloropropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (20 g, 35 mmol, 80% pure) and sodium iodide (285 g, 1.9 mol) in dry acetone (200 ml) was heated at reflux for 24 h. The mixture was evaporated, and partitioned between ether and water. The ether layer was separated, and was washed successively with water and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to give 1-(3-iodopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (25.8 g, 99%, 80% pure) as a thick oil. 1H NMR (CDCl3) δ 1.6-1.9 (m, 2H), 2.21 (ddd, 1H), 2.31 (ddd, 1H), 3.16 (td, 2H), 5.12 (dt, 1H), 5.21 (dt, 1H), 7.02 (t, 2H), 7.41 (d, 2H), 7.43 (d, 1H), 7.51 (s, 1H), 7.62 (dq, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C(=O)(O)[O-].[Na+].O>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:24])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCCO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCCCl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of 5-(7-bromo-3-nitroquinolin-4-ylamino)pentan-1-ol (0.92 g, 2.6 mmol) in dichloromethane (13 mL) was cooled to 0° C.; thionyl chloride was added dropwise. The reaction was stirred for five minutes at 0° C. then allowed to warm to ambient temperature and stirred overnight. Saturated aqueous sodium bicarbonate (25 mL) was slowly added followed by water (25 mL). The aqueous layer was separated and extracted with dichloromethane (3×50 mL), and the combined organic fractions were dried over magnesium sulfate and concentrated under reduced pressure to provide 0.91 g of (7-bromo-3-nitroquinolin-4-yl)-(5-chloropentyl)amine as a yellow semisolid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH2:20][C:21]1([C:24]#[N:25])[CH2:23][CH2:22]1)(=O)=O.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:20][C:21]3([C:24]#[N:25])[CH2:23][CH2:22]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OCC1(C#N)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CC3(C#N)CC3)c2)OC1(C)C
Temperature: 110 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), (1-cyanocyclopropyl)methyl methanesulfonate (0.14 g, 0.77 mmol), and sodium hydride (31 mg, 0.77 mmol) in N,N-dimethylformamide (1 mL) was stirred at 110° C. for 2 h. After cooling, it was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield 0.15 g of the crude product which was used in the next step reaction without further purification.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl.Cl.[NH2:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1.Cl[C:20]1[CH:25]=[C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[C:35](=[O:37])[N:34]([CH3:38])[CH2:33][CH2:32]3)[C:23]([F:39])=[CH:22][N:21]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:39][C:23]1[C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[C:35](=[O:37])[N:34]([CH3:38])[CH2:33][CH2:32]3)=[CH:25][C:20]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=2)=[N:21][CH:22]=1
Reactant: CN1CCc2cccc(Nc3cc(Cl)ncc3F)c2C1=O
Reactant: Nc1cnn(CC(=O)O)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1CCc2cccc(Nc3cc(Nc4cnn(CC(=O)O)c4)ncc3F)c2C1=O
Temperature: 150 °C
Yield: 108.3 %

Procedure:
Reaction performed in 2 batches: sodium tert-butoxide (778 mg, 8.09 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (481 mg, 2.25 mmol) in 1,4-dioxane (15 mL) at 22° C. under an atmosphere of nitrogen. The mixture was stirred and sonicated for 5 minutes and then 8-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (275 mg, 0.90 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (84 mg, 0.15 mmol) were added and the resulting suspension purged with nitrogen. Tris(dibenzylideneacetone)dipalladium (66 mg, 0.072 mmol) was added and the mixture was purged with nitrogen. The mixture was heated at 150° C. for 60 minutes in a microwave reactor and then allowed to cool to room temperature. The two batches were combined and the mixture was evaporated. The residue was partitioned between CH2Cl2 (150 mL) and a 0.1N solution of NaOH (150 mL). The aqueous layer was separated, washed with CH2Cl2 (100 mL) and then adjusted to pH4 with 2N HCl solution. The aqueous mixture was washed with CH2Cl2 (100 mL), filtered and then evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL). The mixture was filtered and the residue washed with a 1:1 mixture of CH2Cl2/MeOH. The combined filtrates were evaporated to give 2-[4-[[5-fluoro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (400 mg, 54% yield); Mass spectrum: m/z (ESI+) (M+H)+ =411.37.
Reaction SMILES: O[Li].O.[CH2:4]([O:6][C:7](=[N:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([O:19]CC1C=CC=CC=1)=[O:18])[CH3:8])[CH3:5].C1COCC1.CO.O>O>[CH2:4]([O:6][C:7](=[N:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([OH:19])=[O:18])[CH3:8])[CH3:5]
Reactant: CCOC(C)=NOc1ccccc1C(=O)OCc1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)=NOc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 80.3 %

Procedure:
LiOH.H2O (431 mg, 10.3 mmol) was added to a solution of ethyl-N-(2-benzyloxycarbonylphenoxy)acetimidate 18 (802 mg, 2.56 mmol) in a 9/3/3 mL mixture of THF/MeOH/H2O and the reaction was stirred at room temperature. After 6 h the reaction was diluted with H2O (100 mL), washed with CH2Cl2 (4×30 mL), acidified to pH˜5.0-5.5 with 0.5 N HCl, and extracted with EtOAc (4×30 mL). The combined organics were washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford 20 as a white solid (459 mg, 80%). 1H-NMR (500 MHz, d6-Acetone) δ 1.34 (t, J=6.9 Hz, 3H), 2.18 (s, 3H), 4.20 (q, J=6.9 Hz, 2H), 7.02 (ddd, J=0.9, 7.3, 7.8 Hz, 1H), 7.51 (ddd, J=1.8, 7.3, 8.7 Hz, 1H), 7.60 (dd, J=0.9, 8.7 Hz, 1H) 7.86 (dd, J=1.8, 7.8 Hz, 1H); 13C-NMR (125 MHz, d6-Acetone) δ 14.6, 14.7, 63.8, 115.2, 118.5, 121.3, 132.4, 134.5, 160.2, 166.8, 167.4; ESI-MS 224 m/z [MH]+, C11H14NO4 requires 224.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:20][CH:21]3[C:26](=O)[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=5)[N:33]=[CH:32][C:31]4=[O:41])[CH2:22]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-]>ClCCl.CO>[NH2:46][CH:26]1[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][N:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=3)[N:33]=[CH:32][C:31]2=[O:41])[CH2:22][CH:21]1[CH2:20][N:12]([CH2:11][C:8]1[N:7]=[CH:6][C:5]2[O:4][CH2:3][CH2:2][O:1][C:10]=2[CH:9]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)CC1CN(CCn2c(=O)cnc3ccc(F)cc32)CCC1=O
Reactant: [NH4+]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)CC1CN(CCn2c(=O)cnc3ccc(F)cc32)CCC1N
Reaction time: 7 h
Yield: 47.2 %

Procedure:
A mixture of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)({1-[2-(7-fluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-4-oxo-3-piperidinyl}methyl)carbamate (0.23 g, 0.41 mmol) and ammonium acetate (0.31 g, 4.1 mmol) in 1:1 dichloromethane/methanol (10 mL) was stirred for 4 h before addition of sodium triacetoxyborohydride (0.53 g, 2.5 mmol). Stirring was continued over two nights, with further additions of borohydride (as above) after the first overnight period, and again after another 7 h. Basification with sodium bicarbonate, extraction with 10% methanol/dichloromethane, evaporation of the organic fractions and chromatography on silica, eluting with 0-20% (2M ammonia/methanol)/dichloromethane, gave the product (0.11 g, 47%).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([NH:29][C:30](=O)[CH:31]=[CH2:32])[CH:4]=1.O.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[CH:31]([C:30]1[NH:29][C:5]2[C:6]([CH:9]=1)=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)=[CH2:32]
Reactant: C=CC(=O)Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc2ccc(F)cc2[nH]1
Yield: 50 %

Procedure:
A 71.5 g (0.14 mol) sample of [[4-fluoro-2[(1-oxo-2-propenyl)amino]phenyl]-methyl]triphenylphosphonium bromide was suspended in 1.6 L of toluene and heated under reflux briefly with azeotropic removal of water. A 180 mL (0.18 mol) solution of 1M potassium t-butoxide in THF was added dropwise under Ar. The mixture was heated under reflux for one hour, cooled, washed with dilute HCl and filtered. The organic phase was washed with brine, dried (MgSO4) and concentrated. The residue was crystallized from methyl t-butyl ether (MTBE)/hexane. The precipitated triphenylphosphine oxide was collected and washed with MTBE. The combined filtrates were concentrated and flash chromatographed twice using EtOAc:hexane 1:10 as eluant. There was obtained 11.3 g (50%) of 2-ethenyl-6-fluoro-1H-indole: Cl-MS m/z=162 (M+H). 1H NMR (CDCl3) δ 8.1 (br s, 1H); 7.5 (m, 1H); 7.0 (d, 1H); 6.85 (m, 1H); 6.7 (m, 1H); 6.5 (s, 1H); 5.5 (d, 1H); 5.25 (d, 1H). ##STR19##
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]([F:25])([F:24])[C:9]([NH:11][C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14](=O)[CH2:13]1)=[O:10].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:7][C:8]([F:25])([F:24])[C:9]([NH:11][C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14](=[CH2:1])[CH2:13]1)=[O:10]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Step AF (2): To a solution of methyltriphenylphosphonium bromide (1.6 g) in THF (5 mL) was added potassium t-butoxide (700 mg), and the mixture was stirred at rt for 30 min to form a deep yellow solution. A solution of (S)-2,2,2-trifluoro-N-(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide (500 mg) in THF (2 mL) was added, and the reaction was continued for 40 min. Water was added, the aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by Biotage chromatography eluting with 1-10% EtOAc/hexanes to give (S)-2,2,2-trifluoro-N-(6-methoxy-3-methylene-2,3-dihydro-1H-inden-1-yl)-acetamide as a white solid (460 mg). 1H NMR (400 MHz, CDCl3) δ 7.45 (1H, d), 6.91 (1H, dd), 6.83 (1H, d), 6.45 (1H, br. S), 5.38 (1H, dt), 5.38 (1H, t), 4.99 (1H, t), 3.81 (3H, s), 3.45 (1H, m), and 2.62 (1H, m).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:5]2[CH:4]=1.CN(C=O)C.[NH2:22][C:23]1[CH:24]=[C:25]([C:30]2[N:34]=[C:33]([CH:35]3[CH2:38][N:37]([C:39]([O:41][CH3:42])=[O:40])[CH2:36]3)[O:32][N:31]=2)[CH:26]=[CH:27][C:28]=1[CH3:29]>ClCCl.N1C=CC=CC=1>[CH3:29][C:28]1[CH:27]=[CH:26][C:25]([C:30]2[N:34]=[C:33]([CH:35]3[CH2:36][N:37]([C:39]([O:41][CH3:42])=[O:40])[CH2:38]3)[O:32][N:31]=2)=[CH:24][C:23]=1[NH:22][C:12]([C:9]1[N:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:4][C:5]2=[N:11][CH:10]=1)=[O:14]
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: O=C(O)c1cnc2cc(C(F)(F)F)ccn12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(C(F)(F)F)ccn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (24) (89 mg, 0.387 mmol) in anhydrous dichloromethane (3 mL) at 0° C. under Argon oxalyl chloride (34 uL, 0.407 mmol) was added dropwise. Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at 0° C. for 1.5 hours. The solvent was concentrated and the crude solid was added to a stirring solution of methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (19 mg, 0.0645 mmol) in anhydrous pyridine (1.5 mL) at 0° C. The reaction was stirred at room temperature under Argon for 20 minutes. The crude product was filtered and purified by preparative HPLC to give methyl 3-(3-(4-methyl-3-(7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F57). 1H NMR (400 MHz, d6-DMSO) δ 10.25 (s, 1H), 9.64-9.61 (m, 1H), 9.75 (s, 1H), 8.33-8.30 (m, 1H), 8.10 (dd, J=1.6 Hz, 1H), 7.86 (dd, J=1.6, 8.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.46 (dd, J=2.0, 7.6 Hz, 1H), 4.40-4.33 (m, 2H), 4.31-4.25 (m, 1H), 4.22-4.18 (m, 2H), 3.59 (s, 3H), 2.38 (s, 3H). MS m/z 501.43 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:13](N)=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C-:25]#[N:26].[K+]>O.Cl>[Br:1][C:2]1[C:13]([C:25]#[N:26])=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1
Reactant: [C-]#N
Reactant: Nc1cc2c(cc1Br)nc1n2CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: N#Cc1cc2c(cc1Br)nc1n2CCC1
Reaction time: 0.25 h

Procedure:
9.2 g of 6-bromo-7-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole are dissolved in a mixture of 30 cm3 of water and 9 cm3 of hydrochloric acid. Diazotation is carried out with a solution of 2.5 g of sodium nitrite in 15 cm3 of water. The diazonium salt is neutralized with sodium carbonate and while stirring poured into a solution of 6.89 g of cuprous cyanide and 12.3 g of potassium cyanide in 100 cm3 of water. Stirring is continued for 30 min at room temperature and a further 15 min on a water-bath at 50° to 60°C. After cooling, the precipitate is sucked off. The base is purified by sublimation (200°C/2mm Hg) and recrystallized from a mixture of benzene and n-hexane. Melting point: 224°C. Yield: 4.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1.Cl>CCOCC>[ClH:1].[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:13][CH2:12]1
Reactant: Clc1ccc2nccn2n1
Reactant: NCCCN1CCOCC1
Agent: Cl
Solvent: CCOCC
Product: c1cn2nc(NCCCN3CCOCC3)ccc2n1
Yield: 32 %

Procedure:
Prepared from 6-chloroimidazo[1,2-b]pyridazine (4) and 3-morpholinopropylamine according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (125 mg, 32%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.73 (s, 1H), 7.63 (d, J=9.8 Hz, 1H), 7.45 (d, J=1.2 Hz, 1H), 6.74 (d, J=9.8 Hz, 1H), 3.89-3.88 (m, 4H), 3.45 (t, J=6.6 Hz, 2H), 3.20-3.13 (m, 6H), 2.14-2.08 (m, 2H); 13C NMR (125 MHz, CD3OD) δ 155.7, 137.0, 129.6, 125.2, 118.0, 115.8, 65.6, 56.9, 53.5, 39.7, 24.6; HPLC tR=6.5 min (Luna), >99%; ES-MS: (M+H)=262 m/z.
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=1)(=[O:4])[CH3:3].Br[CH:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:27]([CH:29]1[CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[C:27]([CH:29]2[CH2:30][CH2:31]2)=[O:28])[CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)SC1CCNC/C1=C\c1ccn(C(=O)OC(C)(C)C)n1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}piperidine hydrochloride (1.15 g) and 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (0.88 g) in N,N-dimethylformamide (20 ml) was added potassium carbonate (0.24 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:1) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (0.48 g, yield: 27%) as a colourless amorphous solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[CH:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[CH:26](N(C(C)C)CC)(C)[CH3:27].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)CCCC)=C>C(#N)C.CN1CCCC1=O.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:8]([CH:26]=[CH2:27])[CH2:9][C@H:5]12)[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: C=CC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 128 mg (0.368 mmol) of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl) -2-oxo-1-carbapenam-3-carboxylate in acetonitrile (3 ml), followed by 0.065 ml (0.37 mmol) of diisopropylethylamine at -45° C., followed by 0.062 ml (0.37 mmol) of trifluoromethanesulfonic anhydride, and the mixture was stirred for 2 hours at the same temperature. To the reaction mixture was added ethyl acetate (3 ml), and the organic layer was washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed. The residual triflate was used the next reaction without purification. To 181 mg of this crude product was added 108 mg (0.79 mmol) of zinc chloride, 5.1 mg (0.0087 mmol) of bis(benzylideneacetone)-palladium(0), and 4.2 mg (0.018 mmol) of tri(2-furyl)phosphine was added a solution of 132 mg (0.416 mmol) of vinyl(tri-n-butyl)tin in N-methylpyrrolidinone (6 ml), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added ethyl acetate, and the organic layer was washed with water followed by saturated aqueous sodium chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography (elution with ethyl acetatehexane system) to give 60.3 mg (yield: 47.9%) of the title compound.
Reaction SMILES: [Na].[CH:2]([OH:5])([CH3:4])[CH3:3].Br[CH2:7][C:8]1[C:15]([F:16])=[C:14]([F:17])[C:11]([CH2:12][OH:13])=[C:10]([F:18])[C:9]=1[F:19].Cl>O>[F:17][C:14]1[C:15]([F:16])=[C:8]([CH2:7][O:5][CH:2]([CH3:4])[CH3:3])[C:9]([F:19])=[C:10]([F:18])[C:11]=1[CH2:12][OH:13]
Reactant: CC(C)O
Reactant: OCc1c(F)c(F)c(CBr)c(F)c1F
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(C)OCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Sodium (1.0 g) was added to dry isopropanol (200 cm3), maintained at 40° C. under an atmosphere of dry nitrogen. After dissolution was complete, 4-(bromomethyl)-2,3,5,6-tetrafluorobenzyl alcohol (10.9 g) was added and the reaction was stirred for 16 hours, at the ambient temperature. The reaction mixture was poured into water, acidified with dilute aqueous hydrochloric acid, and extracted into ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The residue was combined with the product of a similar reaction and distilled under reduced pressure to give 2,3,5,6-tetrafluoro-4-[(1-methylethoxy)methyl]-benzyl alcohol (0.8 g).
Reaction SMILES: O.[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([I:10])=[CH:5][C:4]=1[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:19]([O:21][CH:22](OCC)OCC)[CH3:20].C(OC(=O)C)(=O)C>C(O)C.C(OCC)(=O)C>[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([I:10])=[CH:5][C:4]=1[C:11]([C:12](=[CH:22][O:21][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:18]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(I)cc(F)c1F
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(I)cc(F)c1F
Temperature: 150 °C
Yield: 98.3 %

Procedure:
A flask equipped with a Dean-Stark trap and cold water condenser, is charged with ethyl 3-(2,3-difluoro-5-iodophenyl)-3-oxopropanoate (Preparation 20, 14.8 g), triethylorthoformate (12.4 g), and acetic anhydride (14.92 g). The contents are placed in an oil bath initially at 115° C. and the temperature quickly raised to 150° C. where it is maintained until the volume of ethyl acetate and ethanol distillate collected remained constant (ca. 1.25 h). The reaction mixture is cooled and concentrated at reduced pressure to obtain 16.86 g (98.5%) of the title compound as a dark golden oil. Physical characteristics: 1H NMR (CDCl3) δ8.98, 7.87-7.75, 7.71, 7.69-7.51, 4.36, 4.29-4.08, 3.75, 1.48, 1.35, 1.26, 1.21-1.02; MS (ESI+) m/z 411 (M+H)+.