Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]1CC1C=CC=CC=1)=[O:4].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](C(=O)OC)N1
Yield: 45 %

Procedure:
79 mg (0.3 mmol) of cis-N-benzylazetidine-2,4-dicarboxylic acid dimethyl ester and 25 mg of Pd(OH)2 (20% on C, 31% H2O, Aldrich) in 10 ml of methanol are hydrogenated under 3 atm of hydrogen in a Parr shaker for 6 hours. The catalyst is filtered off and thoroughly washed, the solution evaporated, and the residue filtered over a short column to yield 23.4 mg (45%) of cis-azetidine-2,4-dicarboxylic acid dimethyl ester. 1H NMR (CDCl3): δ4.27 (dd, 2H, J=6.5, 8.5), 3.76 (s, 6H), 2.95 (dt, 1H, J=8.5 (t), 12 (d)), 2.60 (dt, 1H, J=6.5 (t), 12 (d)). IR (neat): 3345, 2955, 1740, 1437, 1231, 1042 cm-1. Mass spectrum: m/z 173 (7%), 114 (100), 82 (44), 59 (14), 55 (32), 54 (98). Calcd. for C7H11NO4 : 173.0688, found: 173.0688.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=O)=[CH:13][CH:12]=1>C(OCC)C>[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH2:4])=[CH:13][CH:12]=1
Reactant: CCOCC
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: C[Mg]Br
Product: C=C(c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
An equivalent of methyl magnesium bromide/diethyl ether solution is reacted with 4,4′-dimethoxybenzophenone (24.2 g, 0.1 mol) dissolved in anhydrous diethyl ether over a 60 minute period at ambient temperature. The reaction mixture is poured onto ice and extracted with ether. The ether is removed by distillation and replaced with ethyl acetate (100 mL). The ethyl acetate solution is refluxed for one hour over anhydrous magnesium sulfate. Methylene chloride (300 mL) is added and the magnesium sulfate removed by filtration. The solvent is distilled leaving 16.9 g of the title compound as a white solid melting at 137° C. whose structure is consistent with 1nmr and mass spectrometry.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8])=[O:12]
Reactant: Nc1ccncc1O
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccncc1O

Procedure:
A solution of 4-amino-3-hydroxypyridine (7 g, 0.06 mol) and chloroacetyl chloride (50 ml) was refluxed for 2 hours, cooled and the excess solvent was removed by vacuum distillation. The crude material was dissolved in water, neutralized with Na2CO3 and the solid precipitated filtered and air dried to give the desired product, m.p. 155°-158° C. The structural assignment was supported by the proton NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][C:3]=1[I:14].C(N(CC)CC)C.[C:22](=O)([O:28]C(C)(C)C)[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C:22]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([I:14])[CH:4]=2)[CH2:9][C:10]1=[O:13])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1C[C@H](c2ccc(Cl)c(I)c2)CN1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(I)c2)CC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To (4R)-4-(4-chloro-3-iodophenyl)pyrrolidin-2-one (17.4 g, 54.4 mmol) was added 50 mL DCM. The solution was cooled to 0° C. Triethylamine (9.1 mL, 65.25 mmol) was added followed by di-tert butyl carbonate (13.1 g, 59.04 mmol) in 60 mL of DCM. A catalytic amount of DMAP was added, the mixture warmed to room temperature, and then stirred overnight at room temperature. A 5% solution of HCl (50 mL) was added and the organic phase separated. The DCM layers were then washed with brine and evaporated to give the title compound (43a) as a yellowish solid (18.3 g, 80% yield). 1H-NMR (400 MHz, CD3OD): δ 7.83-7.84 d, J=2 Hz, 1H), 7.35-7.46 (m, 1H), 7.31-7.33 (m, 1H), 4.11-4.15 (m, 1H), 3.62-3.67 (m, 2H), 3.45-3.61 (m, 1H), 2.80-2.84 (m, 1H), 2.69-2.74 (m, 1H) 1.52 (s, 9H); MS (ESI) m/z 443.86 (M+Na)+.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]([S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])[CH:28]=2)O)=[C:21]([F:47])[N:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:41]1([S:38]([N:29]2[C:30]3=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[C:35]3[C:27]([CH2:25][C:22]3[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=4)=[N:20][C:21]=3[F:47])=[CH:28]2)(=[O:39])=[O:40])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1cnc2c(c1)c(C(O)c1ccc(N(Cc3ccc(C(F)(F)F)nc3)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2c(c1)c(Cc1ccc(NCc3ccc(C(F)(F)F)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 105 %

Procedure:
To 5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2, 3-1)]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (576, 0.100 g, 0.15 mmol) in acetonitrile (12.6 mL) were added triethylsilane (0.34 mL, 2.10 mmol) and trifluoroacetic acid (0.17 mL, 2.20 mmol). The reaction was heated to 80° C. for 2 hours. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude compound (577, 90 mg, 100%) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][N:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH:27]([OH:30])[CH2:28][CH3:29])=[N:14]2)=[O:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][N:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH:27]([O:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:28][CH3:29])=[N:14]2)=[O:9]
Reactant: CCC(O)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OS(C)(=O)=O)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
Methanesulfonyl chloride (0.024 ml, 0.31 mmol) was added to a 0° C. solution of 3-benzyl-2-(1-hydroxy-propyl)-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.007, 0.21 mmol) and triethylamine (0.052 mL, 0.37 mmol) in CH2Cl2 (1.0 mL) and the mixture was stirred at 0° C. for 30 min. The reaction mixture was then quenched with saturated NaHCO3 (3.0 mL), extracted with EtOAc (3×3 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.043 g, 50%) which was used without further purification: MS (ESI+) 420 (M++H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[OH:27][CH2:28][CH2:29][NH:30][NH2:31]>CO>[OH:27][CH2:28][CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Reactant: NNCCO
Solvent: CO
Product: O=c1ccn(-c2ccc(N3CCOCC3)cc2)nc1-c1ccnn1CCO
Yield: 7.3 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (476 mg, 1.34 mmol) in 20 mL of methanol, 2-hydroxyethylhydrazine (414 mg, 5.36 mmol) was added, the resulting mixture was refluxed for 4 hours, and then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (36 mg, 7.3% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 320-3.22 (4H, m), 3.87-3.89 (4H, m), 4.03-4.05 (2H, m), 4.33-4.36 (2H, m), 6.69 (1H, d, J=7.6 Hz), 6.98 (2H, dd, J=6.8, 2.0 Hz), 7.34 (1H, d, J=2.4 Hz), 7.51-7.53 (3H, m), 8.14 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 95% water and 5% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=2.770 min; MS Calcd.: 367. MS Found: 368 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=1.[OH-].[Na+]>CN(C=O)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:12]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1Oc1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (12 g, 300 mmol) (60% by wt) was weighed into a flask and washed free of oil with several hexane rinsings. The hexanes were decanted and discarded and DMF was added to the flask. A solution of phenol (23.5 g, 250 mmol) in DMF (100 mL) was added dropwise and the mixture was stirred at room temperature. To the mixture was added a solution of 4-bromo-2-fluoro-benzonitrile (50 g, 250 mmol, 100 mL DMF), dropwise. Upon complete addition, the reaction was refluxed for 20 h. The reaction was cooled to room temperature and poured into cold 1 N NaOH. A fine, tan precipitate formed and was collected by vacuum filtration to give Compound 5c. MS m/z (MH+) 277.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.C[O:19][B:20](OC)[O:21]C>C1COCC1>[B:20]([OH:21])([OH:19])[CH:5]1[N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: COB(OC)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1B(O)O

Procedure:
N-acetyl-gly-boroproline 5 was prepared according to the synthetic route of FIG. 1. Metallation of tert-butyl 1-pyrrolidinecarboxylate (N-t-BOC-pyrrolidine, Sigma-Aldrich Co.) in THF with sec-butyllithium, followed by addition of trimethylborate gave 1-(tert-butoxycarbonyl)pyrrolidin-2-yl-2-boronic acid 1 after quenching with aqueous NaOH and extraction. Borate esterification with the (1S, 2S, 3R, 5S), (+)-pinanediol in methyl, tert-butyl ether (MTBE) gave borate ester 2. Acid hydrolysis of the BOC protecting group and selective crystallization in isopropyl alcohol gave (+)-pinane 1-pyrrolidin-2-yl-2-boronate 3. Coupling of 3 and N-acetyl glycine with EDC (N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide), HOBt (1-hydroxybenzotriazole), and DiPEA (diisopropylethylamine gave the pinane borate of N-acetyl-gly-boroproline 4. Borate exchange of 4 with phenylboronic acid in MTBE and water gave N-acetyl-gly-boroproline 5.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:12][C:13](=[O:27])[CH:14](OC(=O)C)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:10][CH3:11].CCOCC>O>[CH2:8]([O:12][C:13](=[O:27])[CH:14]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:10][CH3:11]
Reactant: [Li]c1ccccc1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 2 h

Procedure:
A solution containing 2.4 mmol. of phenyl lithium in benzene-ether was added dropwise at -78° under argon to a solution of 700 mg. (2.4 mmol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 15 ml. of dry ether. The mixture was stirred for 2 hours at -78°, then for 1 hour at 25°. The mixture was diluted with water, the layers were separated and the ether layer was washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel with methylene chloride to give a crude product which was rechromatographed on basic alumina to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH2:5]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH:6]=[CH2:7].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:5]([O:8][CH2:9][CH:10]1[CH2:11][O:12][C:2]([CH3:4])([CH3:1])[O:13]1)[CH:6]=[CH2:7]
Reactant: CC(C)=O
Reactant: C=CCOCC(O)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCOCC1COC(C)(C)O1

Procedure:
The 4-allyloxymethyl-2,2-dimethyl-1,3-dioxolane was prepared by mixing acetone, 225 parts, 3-allyloxy-1,2propanediol, 195 parts and toluene, 480 parts in a flask fitted with a magnetic stirring bar and a water trap mounted with a reflux condenser. Concentrated sulfuric acid, 4 parts, was added to the flask and the mixture was heated to reflux. The first 170 parts of distillate were removed via the water trap, after which reflux was conducted and water was collected in the water trap. After 13 hours the reaction mixture was cooled, neutralized with solid sodium bicarbonate, distilled to remove water and toluene and then distilled under vacuum to give 161 parts of 4-allyloxymethyl-2,2-dimethyl-1,3-dioxolane having a boiling point of 57° to 58° at 4.5 Torr.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:17]([O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])=[N:16][C:15](F)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:32]1[C:36](=O)[CH2:35][CH2:34][CH2:33]1>O>[CH2:3]([N:10]1[C:18]2[C:17]([O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])=[N:16][C:15]([NH:10][C:3]3[CH:33]=[CH:34][C:35]([C:36]#[N:32])=[CH:5][CH:4]=3)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCCC1=O
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(F)nc2ccn(Cc3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred suspension of NaH (101 mg, 4.21 mmol) in dry NMP (4 mL) was added 4-aminobenzylnitrile (299 mg, 2.53 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 4-(5-benzyl-2-fluoro-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (314 mg, 0.84 mmol) in dry NMP (4.4 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc×3. The combined organic layers were washed with water, NH4Cl, water×2, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 1% MeOH:CH2Cl2, producing the product as a tan solid (320 mg, 80%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:9])=[CH:6][CH:5]=1.I[CH3:22]>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH3:22])[CH2:11][CH2:12][C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:9])=[CH:19][CH:20]=1
Reactant: Cc1ccc(CCNC(=O)c2ccc(F)cc2)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CCN(C)C(=O)c2ccc(F)cc2)o1
Yield: 83.6 %

Procedure:
NaH (60% dispersion in oil, 65 mg, 1.63 mmol) was added portionwise to a solution of 4-fluoro-N-[2-(5-methyl-2-furanyl)ethyl]benzamide (269 mg, 1.09 mmol, 237A) in THF (5 mL). After gas evolution ceased, iodomethane (0.14 mL, 2.18 mmol) was added drop-wise. Once HPLC analysis showed the reaction to be 50% complete, the mixture was concentrated under reduced pressure and resubjected to the above conditions. After all the starting material was consumed, H2O was added and the resulting mixture was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 20% acetone/CHCl3 gave 238 mg (84%) of compound 425A. HPLC: 98% at 2.94 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z [M+H]=262.38.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[CH3:17][OH:18]>ClCCl>[CH3:17][O:18][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=c1c(CCl)c[nH]c2c([N+](=O)[O-])cccc12
Reactant: CO
Solvent: ClCCl
Product: COCc1c[nH]c2c([N+](=O)[O-])cccc2c1=O

Procedure:
A suspension of 3-chloromethyl-1,4-dihydro-8-nitro-4-oxoquinoline (2 g) in dichloromethane (70 ml) and methanol (30 ml) was refluxed for 15 minutes and concentrated in vacuo. The crystalline residue was suspended in hot methanol (30 ml), and the mixture was allowed to stand to ambient temperature. The resulting precipitates were collected by filtration to give 1,4-dihydro-3-methoxymethyl-8-nitro-4-oxoquinoline (1.5 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14](C1C=CC=CC=1)[C:15](=[O:17])[O-])(=[O:13])=[O:12])[CH:2]=[CH2:3].[NH2:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1>O1CCOCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1)=[O:17])(=[O:12])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1S(=O)(=O)N(C(=O)[O-])c1ccccc1
Reactant: COc1nc(C)nc(N)n1
Solvent: C1COCCO1
Product: C=CCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 20 °C
Yield: 52.8 %

Procedure:
A mixture of 3.33 g of N-(2-allyloxyphenylsulfonyl)phenylcarbamate and 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 30 ml of absolute dioxane is heated to reflux for 1/2 hour, then cooled to 20° C., filtered, evaporated to dryness, and the residue is crystallised from ether. Recrystallisation from ethyl acetate/petroleum ether (1:1) yields 2 g of N-(2-allyloxyphenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea with a melting point of 146°-147° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[OH:2][CH:1]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 4-methylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2-methyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].O.[CH2:37]([OH:39])[CH3:38]>>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1[O:39][CH2:37][CH3:38]
Reactant: CCO
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOc1cnn(-c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)c(=O)c1Cl
Yield: 35 %

Procedure:
To a suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in ethanol (10 mL) was added of 0.220 mg of potassium carbonate. The mixture was heated to reflux for 4 h. The suspension was poured into water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic phase were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-hexane (9:1), afforded the title compound as a solid (0.130 g, 35%). Mp 196–198° C., 1H NMR (CDCl3) 8.80 (1H, d, 3 Hz), 8.60 (1H, d, 6 (1H, s), 8.02 (2H, d, m), 7.93 (1H, s), 7.46 (1H, dd, 6 Hz, 3 Hz), 7.31 (1H,m), 7.29 (1H, d 3 Hz), 7.28 (1H, s), 4.43 (2H, q, 6 Hz), 1.56 (3H, t, 6 Hz).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:31]=[C:32]([CH2:33][CH3:34])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:31]=[C:32]([CH2:33][CH3:34])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(CC)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(CC)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C([O-])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[Br:19][CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:26][C:27]([C:31]#[N:32])=[N:28]2)=[CH:23][CH:22]=1>O.CC(C)=O>[Br:19][CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:26][C:27]([C:31]([NH2:32])=[O:2])=[N:28]2)=[CH:23][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
Sodium percarbonate (2.98 g, 9.50 mmol, 3.0 equiv.) in water (52.8 ml) was added dropwise to a solution of 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 1.08 g, 3.17 mmol, 1.0 equiv.) in acetone (106 ml) and the reaction stirred for 1 hour at rt. The reaction was quenched with saturated KH2PO4 and the mixture was extracted with EtOAc (3×). The combined organic fractions were dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (120 g SiO2, 0-100% EtOAc/hexanes) to afford 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 650 mg, 57%) as a white solid. LRMS m/z (M+H)+ 359.05 found, 359.19 required.