Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=C)=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC.CO>[CH2:21]([NH:28][C:12]1[C:11](=[CH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:15][C:14](=[O:16])[C:13]=1[N+:17]([O-:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NC(=Cc2ccccc2)C(O)=C1[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: O=C1NC(=Cc2ccccc2)C(NCc2ccccc2)=C1[N+](=O)[O-]
Yield: 60 %

Procedure:
An excess of diazomethane in ether is added to a suspension of 0.46 g (2 mmol) benzylidene-4-hydroxy-3-nitro-3-pyrrolin-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 20 ml methanol. When the evolution of nitrogen has subsided, the solvent is stripped off, the residue is dissolved in methanol and the solution is heated under reflux with an excess of benzylamine for five minutes, whereupon yellow crystals precipitate out, which are filtered off with suction and washed with methanol. 4-Benzylamino-5-benzylidene-3-nitro-1,5-dihydropyrrol-2-one was obtained with a melting point of 218° C. in a yield of 60%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH2:15][C:16]([O:18][N:21]2[C:25](=[O:26])[CH2:24][CH2:23][C:22]2=[O:27])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)Cn1cccc(OCc2ccccc2)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Cn1cccc(OCc2ccccc2)c1=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 82.2 %

Procedure:
3-Benzyloxy-1-carboxymethylpyrid-2-one (2 g) is dissolved in dimethylformamide (DMF) (25 ml) and to this solution is added N-hydroxysuccinimide (1 g). The resultant solution is cooled and to it is added dicyclohexylcarbodiimide (DCCI) (11.8 g) in DMF (5 ml). The mixture is allowed to stand overnight to give a brown supernatant and a white precipitate. The precipitate is filtered off, washed with a little DMF and then evaporated to dryness under high vacuum. The crude product is dissolved in a minimum volume of dichloromethane and diethyl ether is added to this solution until it becomes cloudy. The solution is then cooled and the resultant precipitate is filtered off and washed with a little diethyl ether to give 3-benzyloxy-1-(succinimido-oxycarbonylmethyl)-pyrid-2-one (2.26 g, 82%), m.p. 187°-188° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN1CCOCC1>CO>[CH2:21]([NH:29][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccccc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3ccccc3)cc2s1
Yield: 7.3 %

Procedure:
the title compound (9 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), phenethylamine (76 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 414.5 (M+1, 100%). Yield=7%.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>C(O)(=O)C>[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Potassium permanganate (0.6 g, 3.8 mmol, 2.0 eq), is added at room temperature to a stirred solution of 3,4-dimethoxy-2-nitro-benzaldehyde (0.4 g, 1.9 mmol, 1.0 eq) in acetic acid (10 mL). After stirring overnight at room temperature, the reaction mixture is quenched with saturated sodium sulfite aqueous solution and extracted with ethyl acetate (3×20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 3,4-dimethoxy-2-nitro-benzoic acid as a white solid (0.35 g, 81% yield).
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O>CN1CCCC1=O>[Cl:1][CH2:5][C:4]([F:21])([F:3])[C:17]([F:20])([F:19])[F:18]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)CCl

Procedure:
These solvents are readily prepared from commercially available materials by standard and well-known organic syntheses techniques. For example, to prepare 1,1-dichloro-2,2,3,3,3-pentafluoropropane, 2,2,3,3,3-pentafluoro-1-propanol and p-toluenesulfonate chloride are reacted together to form 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate are reacted together to form 1-chloro-2,2,3,3,3-pentafluoropropane. Chlorine and the 1-chloro-2,2,3,3,3-pentafluoropropane are then reacted together to form 1,1-dichloro-2,2,3,3,3-pentafluoropropane.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][SnH:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.CC(C)=O>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Sn:18]([CH3:20])([CH3:19])[CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[SnH](C)C
Reactant: C=CCCCCS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)CCCCCC[Sn](C)(C)C)cc1

Procedure:
The procedure described in Example 5 was employed except that 10.1 g (42.5 mmoles) of 5-hexenyl p-tolyl sulfone and 14.0 g (85 mmoles) of trimethyltin hydride were the reactants. The reaction mixture was irradiated for 232 hours. The excess trimethyltin hydride was allowed to evaporate from the reaction mixture under a flow of nitrogen. The unreacted 5-hexenyl p-tolyl sulfone was removed from the reaction mixture by distillation at 1×10-3 mm Hg leaving 3.25 g of crude product. Column chromatography of the distillation residue over silica gel, employing toluene and 1% acetone in toluene as eluents, afforded an oil, 6-(p-tolylsulfonyl)hexyltrimethylstannane. The presence of both the sulfonyl and trimethyltin moieties was indicated by the strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1285 cm-1 and 1140 cm-1 (--SO2 --) and 760 cm-1 [(CH3)3Sn--]. NMR showed the following:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]([NH2:10])=[O:9].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:11]([NH:19][C:20]([NH:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]([NH2:10])=[O:9])=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1cnc(C(N)=O)c1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cn1cnc(C(N)=O)c1NC(=S)NC(=O)c1ccccc1
Yield: 92.4 %

Procedure:
5-Amino-1-methyl-1H-imidazole-4-carboxamide (6.5 g, 45 mM) and benzoylisothiocyanate (7.7 g, 47 mM) were refluxed in acetone (90 ml) for 4 hours under N2. After cooling in an ice bath the formed product was filtered off, washed with acetone and dried. Hereby was isolated 13.0 g (95%) of the title compound as a white powder, mp 194°-196° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH:13]1(B(O)O)[CH2:15][CH2:14]1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH:13]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]3)[CH2:15][CH2:14]1
Reactant: OB(O)C1CC1
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCCc2cc(C3CC3)ccc21
Temperature: 100 °C
Yield: 97.2 %

Procedure:
To a round bottomed flask charged with 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (16.9 g, 74.7 mmol), cyclopropylboronic acid (9.45 g, 1.5 equiv), tricyclohexylphosphine (1.04 mg, 0.025 equiv), and K3PO4 hexahydrate (50 g, 2 equiv) in toluene (210 mL) and H2O (15 mL) was added Pd(OAc)2 (100 mg, 0.05 equiv).The combined mixture was heated for 4 h at 100° C. The reaction mixture was cooled, filtered and washed with toluene. The organic phase was partitioned and washed with water and brine, dried over Na2SO4, filtered and concentrated to an oil. Addition of hexanes produced 6-Cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one as a tan solid (13.6 g). MS (ESI) 187.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15](#[N:20])/[CH:16]=[CH:17]/[C:18]#[N:19]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:17]([CH2:16][C:15]#[N:20])[C:18]#[N:19]
Reactant: N#C/C=C/C#N
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: CS(C)=O
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 2,6-dichloro-4-trifluoromethylphenylhydrazine (1.0 g) and fumaronitrile (1.0 g) in dimethylsulfoxide (10 ml) was heated at 100° C. for 7 hours. The cooled mixture was diluted with water and extracted (ether) to give, after evaporation and crystallization from dichloromethane/hexane, the title compound (0.828 g, 63%), m.p. 101-102° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Br:10]N1C(=O)CCC1=O>O1CCCC1.N1C=CC=CC=1>[Br:10][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc[nH]c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c(Br)c1
Reaction time: 72 h
Yield: 49.7 %

Procedure:
A solution (70 mL) of methyl 1H-pyrrole-3-carboxylate (4.48 g) in tetrahydrofuran was cooled to −78° C., N-bromosuccinimide (6.30 g) was added, pyridine (5 drops) was added, and the mixture was left standing in a freezer (−20° C.) for 3 days. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a pale-yellow solid (yield 3.59 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH:9]([NH:11]C(=O)OCC2C=CC=CC=2)[CH3:10])=[O:7])=[CH:4][CH:3]=1.[ClH:24].[H][H]>CO.[Pd]>[ClH:24].[NH2:11][CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: Cc1ccc(C(=O)NC(C)NC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(C(=O)NC(C)N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of Example 29B (66 mg, 0.21 mmol) in methanol (9 mL) at ambient temperature was treated with 10% Pd/C (20 mg) aid sufficient 1M HCl to solubilize the substrate (ca. 0.20 mL). The system was equipped with a hydrogen balloon and stirred for 4 hours at ambient temperature. The reaction mixture was purged with nitrogen, filtered through diatomaceous earth (Celite®), rinsed with methanol and water, and the aqueous filtrate was washed with diethyl ether (2×15 mL). The aqueous layer was lyophilized providing 38 mg of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.Cl.Cl.[NH:13]1[C:17]2[CH2:18][CH2:19][CH2:20][NH:21][C:16]=2[N:15]=[CH:14]1.C(N(C(C)C)C(C)C)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([N:21]2[CH2:20][CH2:19][C:18]3[N:15]=[CH:14][NH:13][C:17]=3[CH2:16]2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: c1nc2c([nH]1)CCCN2
Reactant: COc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cnc(Cl)nc1N1CCc2nc[nH]c2C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1 g 2,4-dichloro-5-methoxy-pyrimidine are dissolved in 4 mL butanol and combined with 1.04 g 4,5,6,7-tetrahydroimidazopyridine dihydrochloride and 2.96 mL ethyldiisopropylamine. This mixture is stirred for 16 h at 50° C. and then the solvent is eliminated in vacuo. The crude mixture is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 95% water and 5% acetonitrile and at the finishing point of 70% water and 30% acetonitrile. 0.2% formic acid is added to both eluants. The suitable fractions are freeze-dried.
Reaction SMILES: Cl.C(O[C:10]([N:12]([CH2:14][C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)C)=O)C1C=CC=CC=1.[BrH:20]>C(O)(=O)C.CCOCC>[BrH:20].[BrH:20].[CH3:10][NH:12][CH2:14][C:15]1[NH:19][CH2:18][CH2:17][N:16]=1
Reactant: CN(CC1=NCCN1)C(=O)OCc1ccccc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CNCC1=NCCN1
Reaction time: 0.5 h

Procedure:
A solution of 4,5-dihydro-2-(N-benzyloxycarbonyl-N-methylaminomethyl)imidazole hydrochloride (2.0 g) in 2 ml glacial acetic acid was added dropwise to 10 ml of a 30% solution of HBr in acetic acid. After stirring 0.5 hour the reaction was diluted gradually with 15 ml of ether. The mixture was then stirred 24 hours at ambient temperature. The product separated as a white solid which was collected on a filter, washed with ether, and dried. The yield was 1.97 g, m.p. 181°-183° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=2)[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:25].CCN(C(C)C)C(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[CH2:18]([N:4]1[C:5]2[C:10](=[N:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[CH2:11][CH:2]([NH:1][S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:3]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2nc(-c3ccccc3)ccc2N1Cc1ccccc1
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
To a solution of 2B (63 mg, 0.19 mmol) in CH3CN (2 mL) at RT was added DIPEA (50 μL, 0.285 mmol), followed by benzenesulfonyl chloride (27 μL, 0.21 mmol). After 5 min, white precipitates formed. The reaction was stirred for additional 15 min. The product was collected by filtration and the solid washed with CH3CN (2-3 mL) to give the title compound as a white solid (62 mg, 70%). LC/MS (method A): RT=3.58 min, (M+H)+=470. 1H NMR (CDCl3, 400 MHz): δ 8.41 (d, J=7.4 Hz, 1H), 8.04 (d, J=7.3 Hz, 2H), 7.96 (d, J=7.3 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.62-7.70 (m, 3H), 7.50 (t, J=7.3 Hz, 2H), 7.44-7.47 (m, 2H), 7.25-7.44 (m, 5H), 5.16 (s, 2H), 4.4-4.55 (m, 1H), 3.25-3.31 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:20]1COC[CH2:21]1>O>[CH2:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[CH3:21]
Reactant: O=C1OCc2ccc(Br)cc21
Reactant: C1CCOC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1ccc2c(c1)C(=O)OC2
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-3H-isobenzofuran-1-one (Intermediate 72, 0.7 g) and potassium phosphate (1.9 g) in THF (7.3 ml) and water (3.7 ml) was degassed and palladium chloride dppf adduct with DCM (0.134 g) and triethyl borane (1M solution in THF, 4.3 ml) were added. The resultant mixture was stirred and heated at 100° C. for 1.5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine then dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give 6-ethyl-3H-isobenzofuran-1-one (0.435 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[C:23]([NH:26][CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:25])[CH3:24]>>[C:23]([NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:33][CH:34]=1)(=[O:25])[CH3:24]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(=O)NCc1ccc(N)cc1
Product: CC(=O)NCc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-[4-(Acetylaminomethyl)phenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(acetylaminomethyl)aniline using method I. LCMS; retention time 2.97 min, MH+ 441.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>>[CH:2]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH:17]3[O:19][CH2:18]3)=[CH:12][CH:13]=2)[CH2:3][CH2:1]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(CCOCC2CC2)cc1
Product: c1cc(OCC2CO2)ccc1CCOCC1CC1

Procedure:
reaction 4-[(2-Cyclopropylmethoxy)-ethyl]-phenol with epichlorohydrin in presence of base to form 1-{4-[2-(Cyclopropylmethoxy)-ethyl]-phenoxy}-2,3-epoxypropane;
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([NH:22][C:23]5[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C=O.[CH2:33]([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][C:2]1([CH3:30])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([N:22]([CH3:33])[C:23]5[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: Cc1ccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: C=O
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(N(C)c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Yield: 1148 %

Procedure:
A stirred solution of Example 60 (0.017 g, 0.04 mmol), paraformaldehyde (0.04 g, 0.28 mmol), dibutyltin dichloride (0.0015 g, 0.004 mmol) and phenyl silane (0.01 g, 0.08 mmol) in THF (4 mL) was heated to 100° C. under microwave irradiation in a sealed tube for 1 h. The reaction mixture was concentrated in vacuo. Purification by preparative HPLC (Method 7) gave the title compound (0.020 g, 34%) as an off-white solid. δH (CDCl3) 8.20 (1H, d, J 2.8 Hz), 7.70 (1H, d, J 2.5 Hz), 7.16 (1H, d, J 8.5 Hz), 7.05-6.99 (1H, m), 6.93-6.87 (1H, m), 6.78 (1H, dd, J 8.7 and 2.5 Hz), 5.15 (1H, s), 4.36-4.29 (2H, m), 4.18-4.10 (2H, m), 3.20 (3H, s), 2.80 (2H, s), 2.50 (3H, s), 1.40 (6H, s). LCMS (ES+) 436 (M+H)+, RT 3.30 minutes (Method 2).
Reaction SMILES: [CH3:1][C:2]1[C@H:7]([C:8]([O:10]C(C)(C)C)=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:5]2[S:4][CH:3]=1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:5]2[S:4][CH:3]=1
Reactant: CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 82.7 %

Procedure:
A stirred solution of tert-butyl (4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4-carboxylate (0.776 g, 2.0 mmol) in dichloromethane (30 ml) was cooled to 0° C. Titanium tetrachloride (0.6 ml, 5.5 mmol) was added in 1 min. After stirring for 2.5 h at 0° C., the suspension was mixed with a chilled 2 M solution of hydrochloric acid in water (40 ml). The organic phase was separated and washed with a 1 M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was concentrated to give 0.55 g of (4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4-carboxylic acid (yield 82.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:39](=[O:54])[C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:41]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:39](=[O:54])[C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:43]=[C:42]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:41]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cc(C)ncc1NCC(F)(F)F
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from 4-(4-fluoro-2-methoxyphenyl)-6-methyl-N-(2,2,2-trifluoroethyl)pyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (example 223, intermediate d) after a reaction time of 42 hours. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (32%). MS (ESI): m/z=565.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16].ClC(Cl)C>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[CH3:13]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1cnc2ccccc2c1Cl
Temperature: 70 °C

Procedure:
A mixture of 3-amino-4-chloroquinoline (8.00 g, 1 eq), trimethylacetyl chloride (11 mL g, 2 eq), and anhydrous dichloroethane (150 mL) was heated at 70° C. After 6 hours more trimethylacetyl chloride (2 eq) was added and heating was continued for a total of 23 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with hexanes and then filtered to provide 7.16 g of N-(4-chloroquinolin-3-yl)trimethylacetamide as a solid. The filtrate was concentrated under reduced pressure to provide 5 g of crude N-(4-chloroquinolin-3-yl)trimethylacetamide.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:19]2[N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:21]=[C:22]3[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][N:6]=3)=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)nc1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-6-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-nicotinic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless oil. MS: m/e=476.1 [M+H+].