Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.S(=O)(=O)(O)O.[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH2:12][CH2:13][CH2:14][OH:15].CC([OH:22])C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH2:12][CH2:13][C:14]([OH:22])=[O:15]
Reactant: CC(C)O
Reactant: OCCCOc1cccc(F)c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCOc1cccc(F)c1
Yield: 90 %

Procedure:
Acetone (600 mL) is chilled using an ice/salt water bath, then chromium trioxide (14.45 g, 145 mmol) is added, followed by water (32 mL) and concentrated sulfuric acid (16 mL). The mixture is allowed to stir several minutes, then a solution of 3-(3-fluorophenoxy)-propan-1-ol (6.15 g, 36.1 mmol) in acetone (300 mL) is slowly added via an addition funnel over ˜1 h. The reaction is stirred at 0° C. for 5 h, and then 2-propanol (70 mL) is added. The reaction is filtered over diatomaceous earth, rinsed with acetone (˜100 mL), and the filtrate evaporated under reduced pressure, reconstituted in diethyl ether (500 mL), and washed with brine (2×500 mL). The organic layer is then dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford the sub-title compound (6.00 g, 90%) as an off-white solid which is used without further purification: Rf 0.34 (95:5:0.5 dichloromethane/methanol/ammonium hydroxide); 1H NMR (300 MHz, CDCl3), δ2.85 (t, J=6.2 Hz, 2H), 4.23 (t, J=6.2 Hz, 2H), 6.59-6.70 (m, 3H), 7.18-7.24 (m, 1H), 7.30-9.60 (br s, 1H); 19F NMR (282 MHz, CDCl3), δ-112.01; APCI MS (negative mode) m/z 183 [C9H9FO3—H]−.
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][C:7]1([OH:29])[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]1)=[N+:4]=[N-:5].[CH3:30]I.O>CN(C=O)C>[N:3]([CH2:6][C:7]1([O:29][CH3:30])[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:8]1)=[N+:4]=[N-:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)(CN=[N+]=[N-])C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(CN=[N+]=[N-])CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
Under ice-cooling, sodium hydride (60% oil, 8 mg) was added to a solution of tert-butyl (6RS,7SR)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (120 mg) in DMF (5 mL). The mixture was stirred at room temperature for 20 min, methyl iodide (122 mg) was added, and the mixture was stirred at the same temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (115 mg).
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][N:5]([C:10]([NH:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14])=[S:11])[CH2:6][CH2:7][CH2:8]C.[Si](=O)=O>>[CH3:8][CH2:7][CH2:6][N:5]([C:10]([NH:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14])=[S:11])[CH2:4][CH2:3][CH3:2]
Reactant: CCCCN(CCCC)C(=S)NC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: O=[Si]=O
Product: CCCN(CCC)C(=S)NC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
A mixture of 90 parts by mass of PET obtained above and 10 parts by mass of silicon dioxide (“Silysia 445,” average particle size 2.5 μm, manufactured by Fuji Silysia Chemical Ltd.) was kneaded at 260° C. using a vented counter-rotation twin-axis extruder (L/D=35) with 30 mmφ, to prepare a PPT master (MS-4) containing 10% by mass of silicon dioxide.
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:4][C:5]([O:7]CC)=[O:6])[O:2]1.O[Li].O.C1COCC1.Cl>O>[CH2:20]1[CH2:1][O:2][C:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:4][C:5]([OH:7])=[O:6])[O:19]1
Reactant: CCCCCCCCCC1(CC(=O)OCC)OCCO1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC1(CC(=O)O)OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a 25 mL flask were added ethyl 3,3-ethylenedioxydodecanoate (1.131 g, 3.95 mmol), LiOH.H2O (840 mg, 20 mmol), THF (5 mL), and water (5 mL). The mixture was stirred at room temperature overnight. The solution was acidified by the addition of 1 M HCl (50 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed once with brine. The organic phase was dried (MgSO4) and concentrated to give 3,3-ethylenedioxydodecanoic acid (0.824 g, 3.19 mmol) in 81% yield. 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J=7 Hz, 3H), 1.20-1.44 (m, 14H), 1.72-1.80 (m, 2H), 2.72 (s, 2H), 3.98-4.10 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 13.9, 22.5, 23.3, 29.13, 29.35, 29.39, 29.50, 31.7, 37.5, 42.2, 64.9 (2 C), 109.2, 174.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:11]2)=[CH:16][CH:15]=1)=[O:25]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COc1nccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)c3cccc(Cl)c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of 2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (30 mg, 0.11 mmol) in CH2Cl2 (5 mL) was added 3-chlorobenzoic acid (17 mg, 0.11 mmol) and HATU (42 mg, 0.11 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 3-chloro-N-[2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-benzamide (35 mg, 78%) as a white solid. MH+ 411.9.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: CCCCCC(=O)C=Cc1ccc(OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCC(=O)C=Cc1ccc(O)c(O)c1
Temperature: -78 °C
Yield: 52.5 %

Procedure:
In 1 ml of dry dichloromethane was dissolved 128 mg of 1-(3,4-dimethoxyphenyl)-3-oxo-1-octene obtained in the above Example 13-(1), and the solution was cooled at -78° C. Then, 1.5 ml of 1N boron tribromide solution in dichloromethane was added dropwise to the solution, and the temperature was restored to room temperature slowly. Then, the reaction mixture was poured in ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried with magnesium sulfate. The solvent was removed by distillation to give crude product. After recrystallization from water/ethanol, 60 mg of the above caption compound was obtained as crystals.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-[(N-Boc)amino]-4-thiazolecarboxylate (1 mmole) in CH2Cl2 (10 mL) was cooled to −78° C., and treated with DIBAL-H (1M, 5 ML). The reaction was stirred at −60° C. for 3 h, and quenched with a suspension of NaF/H2O (1 g/1 mL). The resulting mixture was filtered and the filtrate was concentrated to give 2-[(N-Boc)amino]-4-hydroxymethylthiazole as a solid.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[C:32]([F:40])=[N:33][CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1.[I-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[F:40][C:32]1[C:31]([CH2:30][N:6]2[C:5]([C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=3)[C:17]#[N:18])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]2=[O:11])=[CH:36][C:35]([N+:37]([O-:39])=[O:38])=[CH:34][N:33]=1
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: O=[N+]([O-])c1cnc(F)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc([N+](=O)[O-])cnc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
3-(5-Isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (37 mg, 0.124 mmol, 1.2 eq.) was dissolved in 1.5 mL DMF. Potassium carbonate (14 mg, 1 eq.) was added and the reaction was stirred at room temperature for 10 minutes. 3-Bromomethyl-2-fluoro-5-nitro-pyridine (27 mg, 0.103 mmol, 1 eq.) and lithium iodide (14 mg, 1 eq.) were added. The reaction was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give white powder (16 mg, 34%). LC-MS shows 449.9 (M−1). 1H NMR (300 MHz, CDCl3): δ 8.98 (d, 2H), 8.48 (m, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.78 (m, 2H), 5.08 (d, 1H), 4.56 (d, 1H), 2.50 (s, 3H), 2.22 (m, 1H), 1.22 (dd, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11]Cl)=[N:6][CH:7]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2=[O:15])=[N:6][CH:7]=1
Reactant: CC(C)(CCl)C(=O)Nc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(c2ccc(Br)cn2)C1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
(250 mg, 0.738 mmol) N-(5-Bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide (Example 97, step 1) dissolved in DMF (3 ml) was added at room temperature to a solution of NaH (29.5 mg, 0.738 mmol, 1 equiv.) in 5 ml DMF. The mixture was stirred for 3 hours at 70° C. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel column and eluting with an ethyl acetate:heptane gradient 10:90 to 15:85. The desired 1-(5-bromo-pyridin-2-yl)-3,3-dimethyl-azetidin-2-one (160 mg, 72% yield) was obtained as a white solid.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([CH2:9][N:10]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[N:19]=[CH:20][O:21][C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=3)=[O:17])[CH:12]=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH4+].[OH-:32].Cl>S(=O)(=O)(O)O>[C:1]([C:4]1[O:8][C:7]([CH2:9][N:10]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[N:19]=[CH:20][O:21][C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:32])[NH2:30])[CH:24]=3)=[O:17])[CH:12]=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C#N)c3)cn2)o1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C(N)=O)c3)cn2)o1

Procedure:
5-(3-Cyano-phenyl)-oxazole-4-carboxylic acid [1-(5-acetyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-amide (50 mg, 0.112 mmol) in 97% sulfuric acid (0.17 mL) was stirred at rt overnight. The reaction mixture was then poured onto crushed ice, adjusted to pH 9 with NH4OH, and then strongly acidified with HCl 25%. The precipitate was filtered and washed with water until neutral pH. After drying, the title compound was obtained as a beige solid. LC-MS-conditions 02: tR=0.81 min; [M+H]+=420.12.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C[O-].[Na+].[C:22]1(C)C=CC=C[CH:23]=1>C(OCC)(=O)C>[CH3:22][C:23]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 74 %

Procedure:
5.04 g. 2-(theophyllin-7-yl)-acetamidoxime, 2.16 g. of sodium methylate, 10 cm3 ethyl acetate and 200 cm3 of toluene are heated under stirring by using a water condenser for 20 hours and further 10 cm3 ethyl acetate are added to the mixture in five portions. The solvent is distilled off. After crystallization from water 4.1 g. (74% yield) 7-[(5-methyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. M.p.: 135°-136° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[N:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:19][N:20]=1
Reactant: CCOC(=O)C1(NC(=O)c2cncc3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
The mixture of 2-[(isoquinoline-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (51) (200 mg, 0.55 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (52) as white solid (170 mg, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:7][N:6]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: C1CCNCC1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccc(N2CCCCC2)cn1
Temperature: 150 °C
Yield: 34.4 %

Procedure:
5-Bromo-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.12 mmol) and piperidine (1 ml, 10.1 mmol) were placed in a microwave vial. Pd2dba3 (5 mg, 0.006 mmol), BINAP (7.2 mg, 0.012 mmol) and cesium carbonate (57 mg, 0.17 mmol) were added and the mixture was heated at 150° C. for 75 mins under microwave irradiation. The reaction mixture was concentrated in vacuo to give a crude residue that was suspended in 1:1 DMSO/MeOH (1 ml) and filtered to give an orange solution that was purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (18 mg) as a yellow gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N
Agent: Cl[Sn]Cl
Solvent: O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-dimethylamino-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example C20) (3.9 g, 12.7 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a pale brown solid (2.05 g, 58%).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)C=C.Cl[C:16]1[CH:21]=CC=C[C:17]=1Cl>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:21][CH:16]=[CH2:17]
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Reactant: Clc1ccccc1Cl
Product: C=CCc1cc(C(=O)OC)ccc1O
Temperature: 183 °C
Yield: 91 %

Procedure:
A solution of 15.05 g (78.3 mmol) of the product of Step A in 25 mL of 1,2-dichlorobenzene was magnetically stirred and refluxed (183° C.) under an argon atmosphere for 18 hours. At this point, the reaction mixture was cooled to room temperature and applied to a 6 cm diameter by 18 cm silica gel flash chromatography column and eluted with 25% ethyl acetate-hexane to separate the 1,2-dichlorobenzene, then with 40% ethyl acetate-hexane to elute the product. The product fractions were concentrated in vacuo and the residual oil was crystallized from hexane to afford 13.70 g (91%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)C(=O)[O:10][N:9]=2)=[N:5][O:6][N:7]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C.C(Cl)Cl.CN(C1C=CN=CC=1)C.CO>[Cl:20][C:15]1[CH:14]=[C:13]([NH:12][C:8]([C:4]2[C:3]([CH2:2][NH:1][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])=[N:7][O:6][N:5]=2)=[N:9][OH:10])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: O=C(NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 164.7 %

Procedure:
3-[4-(Aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (10 mg, 0.003 mmol) was dissolved in ACN (0.2 mL) and DCM (0.2 mL). Phenyl isocyanate (7.6 mg, 0.064 mmol) DIPEA(0.012 mg, 0.096 mmol) and DMAP (0.4 mg, 0.03 mmol) were added and stirred at rt for 6 hrs. The reaction was then diluted with MeOH and purified by preparative LCMS. The intermediate was stripped to dryness, redissolved in EtOH (1 mL) and 1 M of sodium hydroxide in water (0.06 mL) was added. The reaction was stirred at rt for 1 hour, quenched with acetic acid and diluted with MeOH. The crude was purified by preparative LCMS to afford the desired product (2.0 mg). MF=C17H14ClFN6O3; LCMS calculated for C17H15ClFN6O3(M+H)+: m/z=405.1.
Reaction SMILES: C(NC(C)C)(C)C.[N:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1.[C:16](OCC)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH3:14][C:12]1[CH:11]=[C:10]([CH2:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])[CH:9]=[N:8][CH:13]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: Cc1cncc(C)c1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cncc(CC(=O)c2ccccc2)c1
Temperature: -5 °C
Yield: 72.5 %

Procedure:
A solution of diisopropylamine (20.2 mL) in anhydrous tetrahydrofuran (180 mL) was cooled to −78° C., and a 1.6 M n-butyllithium-hexane solution (90 mL) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min at the same temperature, and then 3,5-lutidine (14 g) was added dropwise. The temperature was raised to −10-0° C., and after stirring for 20 min, a solution of ethyl benzoate (9.8 g) in anhydrous tetrahydrofuran (20 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The organic solvent was evaporated under reduced pressure and an oily product was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (10 g, yield 70%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:44](=[O:45])[N:14]2[C:15]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:16]([CH:20]=[CH:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:17][S:18](=O)[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].C(Cl)(=O)C.C1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:44](=[O:45])[N:14]2[C:15]([C:28]([O:30][CH:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])=[C:16]([CH:20]=[CH:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)C1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Yield: 86.8 %

Procedure:
To 1.3 g of benzhydryl 7-phenoxyacetamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate-1-oxide in 25 ml of N,N-dimethylformamide were added with stirring under cooling with a freezing mixture 2.0 g of potassium iodide and 0.7 ml of acetyl chloride, and the mixture was stirred for 5 minutes. The mixture was then stirred for another 90 minutes at room temperature and poured into ice-water. The separating oil was extracted with ethyl acetate. The extract was washed with an aqueous potassium metabisulfite solution, water, a dilute aqueous sodium hydrogencarbonate solution and water successively and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to leave a residue. The obtained residue was developed through silica gel column with a mixture of benzene and ethyl acetate (1:1) to give 1.1 g of benzhydryl 7-phenoxyacetamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.ON1C2C=CC=CC=2N=N1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:34]([NH:41][C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)O)c3)cc2)S1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)NCc4ccccc4)c3)cc2)S1
Reaction time: 24 h
Yield: 60.3 %

Procedure:
600 mg (1.84 mmol) of 4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-carboxylic acid (prepared in Example 23(c)), 5 ml of dimethylformamide, 340 mg (2.5 mmol) of 1-hydroxybenzotriazole and 250 μl (2.3 mmol) of benzylamine are introduced into a three-necked flask under a stream of nitrogen. At 0° C., 480 mg (2.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride are added portionwise. The mixture is stirred for 24 hours while allowing the temperature to rise. The reaction medium is immersed in water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue obtained is washed with dichloromethane and filtered. 460 mg (60%) of the desired product are obtained.