Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C@H:9]2[CH2:13][O:12][C@H:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C@@H:10]2[CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C@H:9]2[CH2:13][O:12][C@H:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C@@H:10]2[CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:5][CH:6]=1
Reactant: COC(=O)CC/C=C\CC[C@@H]1[C@@H](OCc2ccc(-c3ccccc3)cc2)CO[C@@H]1c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC/C=C\CC[C@@H]1[C@@H](OCc2ccc(-c3ccccc3)cc2)CO[C@@H]1c1cccnc1

Procedure:
A solution of 28.2 g (0.0597 mol) of methyl (Z)-(2S,3S,4R)-7-[4-(1,1'-biphenyl-4-ylmethoxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]-4-heptenoate, 433 ml of methanol and 172.8 ml (0.173 mmol) of 1N sodium hydroxide is stirred at 45° C. for two h and at room temperature for 11/2 h. The solvent is evaporated, the residue is taken up in water and extracted twice with ethyl ether. The aqueous layer is adjusted to pH 5.5 and extracted with ethyl acetate (3×10 ml). The combined extracts are washed with brine, dried (MgSO4), evaporated and the residue is crystallized from methylene chloride and ether to give (Z)-(2S,3S,4R)-7-[4-(1,1'-biphenyl-4-ylmethoxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]-4-heptenoic acid, having mp. 96°-98° C. and [α]D 25=+98.58 (MeOH).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:11])[CH:8]=2)[C:3]1=O.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([NH2:25])=[S:24])[CH2:15][CH2:14]1>C(O)C>[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]2[S:24][C:2]3[CH2:10][C:9]4[CH:8]=[C:7]([F:11])[CH:6]=[CH:5][C:4]=4[C:3]=3[N:25]=2)[CH2:15][CH2:14]1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C1c2ccc(F)cc2CC1Br
Solvent: CCO
Product: Fc1ccc2c(c1)Cc1sc(NCCCN3CCOCC3)nc1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
3.5 g of 2-bromo-5-fluoro-1-indanone and 3.1 g of N-(3-morpholinopropyl)thiourea were added to 40 ml of ethanol. The resulting mixture was refluxed for 10 minutes, agitated for 24 hours at room temperature to precipitate crystals which were collected by filtration. The thus collected crystals were washed with ethanol, dried, incorporated with 40 ml of a 5% aqueous solution of NaOH, extracted with ethyl acetate, washed with water, dried, distilled at a reduced pressure and then recrystallized from ethyl acetate-isopropyl ether thereby to obtain 3.9 g of 2-(3-morpholinopropyl)amino-6-fluoro-8H-indeno[1.2-d]thiazole. The thus obtained compound had a melting point of 113° to 115° C. and the following analysis.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[O:4][CH:3]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:16][C:13]1[O:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([C:23]4[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=4)=[CH:3][O:4][C:5]3=[CH:6][N:7]=2)=[N:15][N:14]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nnc(-c2cc3c(Br)coc3cn2)o1
Product: Cc1nnc(-c2cc3c(-c4ccc(OC(F)(F)F)cc4)coc3cn2)o1
Yield: 25 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole and using [4-(trifluoromethoxy)phenyl]boronic acid instead of (4-fluorophenyl)boronic acid, the title compound (yield 25%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(CCl)c(C)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1ccc(Cn2ccc3ccc(CC(=O)O)cc32)c(C)c1

Procedure:
The titled compound (22 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,4-dimethylbenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)=[N:15][CH:16]=1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Reactant: Nc1ccc(F)cn1
Product: Cc1ccc2ccnc(Nc3ccc(F)cn3)c2n1

Procedure:
The title compound, MS: m/e=255.3 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 2-amino-5-fluoropyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cnn2c(-c3cccc(Br)c3)cnc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cnn2c(-c3cccc(-c4nccs4)c3)cnc2n1
Temperature: 65 °C
Reaction time: 12 h
Yield: 31.8 %

Procedure:
A mixture of 7-(3-bromophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.2 g, 0.58 mmol), 2-tributylstannylthiazole (0.44 g, 1.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.06 mmol) in THF (2 ml) was degassed with a stream of N2 for 10 min and stirred at 65° C. for 12 h. After allowing to cool to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane) and triturated with Et2O to give 64 mg (32%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 7.42 (1H, d, J 3.2 Hz), 7.65 (1H, t, J 7.9 Hz), 7.94 (1H, d, J 3.2 Hz), 8.04 (1H, dq, J 7.9, 1.0 Hz), 8.06 (1H, dq, J 7.9, 1.0 Hz), 8.71 (1H, s), 8.76 (1H, t, J 1.6 Hz), 8.86 (1H, s); MS (ES+) m/z 348 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:25]2[CH2:26][CH2:27][N:28]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)=[O:12])[CH2:29][CH2:30]2)=[O:24])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Yield: 14.6 %

Procedure:
Using 4-methanesulfonylaminobenzoic acid (136 mg) and (4-methylphenyl)(piperidin-4-yl)methanone hydrochloride (152 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (37 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]Br.[O:8]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:8]([C:15]1[CH:16]=[CH:17][C:18]([N:19]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: BrCCNCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1

Procedure:
To a solution of 62.4 parts of bis-(β-bromoethyl)amine dihybromide in 160 parts of methanol there were added 37 parts of para-phenoxyaniline. The mixture was refluxed for 10 hours. 10.6 parts of Na2CO3 were then added and the reaction mixture was refluxed for a further 10 hours. After cooling, the precipitate was filtered off, washed with 80 parts of methanol and dried.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].Cl.[CH3:27][NH:28][CH3:29].C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH3:27][N:28]([CH3:29])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25]
Reactant: CNC
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Agent: Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN(C)C)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.27 g), dimethylamine hydrochloride (0.30 g), N,N-diisopropylethylamine (0.53 ml) and KI (0.25 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emmys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 3-[6-{2-[dimethylamino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.10 g); NMR Spectrum: (DMSOd6) 2.12 (s, 3H), 2.25 (s, 6H), 2.69 (m, 2H), 4.19 (m, 2H), 7.49 (m, 2H), 7.57 (s, 1H), 7.69 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 368.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].C(N(CC)CC)C.[Cl:18][CH2:19][CH2:20][SH:21].O>C(Cl)(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([S:21][CH2:20][CH2:19][Cl:18])=[N:5][OH:6]
Reactant: ON=Cc1ccccc1Cl
Reactant: SCCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: ON=C(SCCCl)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chlorobenzaldoxime (46.7 g, 0.3 mol) in chloroform (350 ml) was cooled and stirred in an ice/salt bath. Chlorine gas was bubbled into the reaction until an excess was present. Excess chlorine and solvent were removed and the remaining 2-chloro-N-hydroxybenzenecarboximidoyl chloride dissolved in ether (250 ml). Solutions of triethylamine (30.3 g, 0.3 mol) in ether (50 ml) and 2-chloroethanethiol (29 g, 0.3 mol) in ether (50 ml) were added simultaneously with stirring and cooling. After the addition, the reaction was allowed to warm to room temperature and left overnight. Water was added, and the ether layer was washed with additional water, then dried with anhydrous magnesium sulphate. Evaporation left a white solid, 2-chloroethyl 2-chloro-N-hydroxybenzenecarboximidothioate, m.p. 115°-117° C., (Found: C, 43.29; H, 3.58; N, 5.59. C9H9Cl2NOS requires C, 43.21; H, 3.62; N, 5.60).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[NH2:23]>>[C:22]([C:25]1[CH:26]=[C:27]([C:2]2[C:14]3[C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[CH:7]=[N:6][C:5]=3[NH:4][N:3]=2)[CH:28]=[CH:29][CH:30]=1)(=[O:24])[NH2:23]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Product: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(-c4cccc(C(N)=O)c4)c23)C1

Procedure:
The compound, tert-butyl 1-(3-carbamoylphenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate was prepared using tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate and 4-carbamoylphenylboronic acid as described in step-1 of general procedure U. The compound was obtained as a white solid (0.070 g, 39%); 1H NMR (400 MHz, DMSO-d6) δ13.98 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.58 (m, 1H), 7.45 (s, 1H), 4.65 (s, 2H), 3.49 (m, 2H), 2.82 (m, 2H), 1.43 (s, 9H); LC-Mass [M+H]: 394.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:39]3[CH:38]=[CH:37][C:36]([CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[CH:41][CH:40]=3)[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, a 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the desired compound (0.02 g, 16%). LCMS: 543.22 (M+1)+; HPLC: 99.53% (@ 254 nm) (Rt; 4.181; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% Bin 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.17 (t, 1H, J=4.4 Hz), 7.98 (s, 1H), 7.73 (d, 1H, J=7.6 Hz), 7.57 (d, 2H, J=7.6 Hz), 7.37 (s, 2H), 7.17 (s, 1H), 5.85 (s, 1H), 4.27 (d, 2H, J=4.8 Hz), 3.44-3.57 (m, 7H), 2.54 (s, 3H), 2.32-2.36 (m, 4H), 2.23 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H), 1.69-1.72 (m, 2H), 1.61 (m, 2H), 1.43-1.50 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([C:8]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][N:27]([CH2:29][CH3:30])[CH3:28])[CH:20]=3)[O:16][N:15]=2)[CH:11]=[C:10]([CH3:31])[C:9]=1[OH:32])[CH3:7].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:6]([C:8]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][N:27]([CH2:29][CH3:30])[CH3:28])[CH:20]=3)[O:16][N:15]=2)[CH:11]=[C:10]([CH3:31])[C:9]=1[O:32][CH2:2][CH2:3][CH2:4][OH:5])[CH3:7]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1OCCCO
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3-bromo-1-propanol (55 mg, 398 μmol) was added to a suspension of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (97 mg, 265 μmol) and K2CO3 (88 mg, 637 μmol) in DMF (2 mL). The mixture was stirred at 60° C. for 3 h before it was filtered. The filtrate was separated by prep. HPLC (XBridge 30×75 mm, eluting with a gradient of MeCN in water containing 0.5% of sat. aq. ammonia) to give the title compound as a colourless resin (67 mg). LC-MS**: tR=0.61 min; [M+1]+=424.25; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.3 Hz, 3H), 1.90-1.98 (m, 2H), 2.15 (s, 3H), 2.34 (s, 3H), 2.41-2.49 (m, 5H), 2.71 (q, J=7.3 Hz, 2H), 3.55 (s, 2H), 3.65 (q, J=5.8 Hz, 2H), 3.90 (t, J=6.0 Hz, 2H), 4.55 (t, J=4.8 Hz, 1H), 7.47 (s, 1H), 7.80 (s, 2H), 7.90 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:10]=1.Br>C(O)(=O)C>[NH:19]1[C:15]([C:11]2[CH:10]=[C:9]([C:4]3[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:14]=[CH:13][CH:12]=2)=[N:16][N:17]=[N:18]1
Reactant: COc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
5-(2′-Methoxy-biphenyl-3-yl)-1H-tetrazole 8c (15.5 g, 61.5 mol) was dissolved in 195 mL of acetic acid followed by addition of 195 mL of hydrobromic acid under argon atmosphere. The reaction mixture was heated to reflux for 5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature overnight. The mixture was filtered and the filter cake was dissolved in 500 mL of ethyl acetate. The mixture was washed with water (500 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from 100 mL of ethyl acetate to obtain the title compound 3′-(1H-tetrazol-5-yl)-biphenyl-2-ol 8d (12 g, yield 82.8%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][C:12]=1[C:20](Cl)=[O:21]>>[CH2:1]([NH:8][C:17](=[O:18])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[C:12]([C:20]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1C(=O)Cl
Product: COc1ccc(C(=O)NCc2ccccc2)cc1C(=O)NCc1ccccc1

Procedure:
By following the general method of Example 1, benzyl amine was reacted with 4-methoxy-1,3-benzenedicarbonyl dichloride to give the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: NC(=O)[C@@H](c1ccccc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@@H](c1ccccc1)n1ccc2c(N)cccc2c1=O
Reaction time: 1.5 h

Procedure:
A round bottom flask was charged with (R)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)-2-phenylacetamide (2.3 g, 0.0071 mol), methanol (30 mL, 0.7 mol) and palladium, 10% weight on charcoal (110 mg, 0.00090 mol) was added and the flask is evacuated of air and stirred under hydrogen atmosphere (1 atm) for 1.5 hours. The reaction mixture was filtered over celite and the solvent removed under pressure. The residue was purified by flash chromatography (40 g silica gel, 0-10% MeOH/DCM) to obtain the product as a light yellow solid. MS m/z=294.5(M+H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C:10]1([CH:41]([Br:43])[Br:42])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O[C@H]([C@H]([C@@H]([C@@H](COCC1C=CC=CC=1)O)OCC1C=CC=CC=1)OCC1C=CC=CC=1)C(C(SC)SC)O)C1C=CC=CC=1>O1CCCC1>[CH2:1]([O:8][C@H:9]([C@H:15]([C@@H:14]([C@@H:13]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:12])[O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]([CH:41]([Br:43])[Br:42])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(C(Br)Br)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CSC(SC)C(O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(C(Br)Br)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3,4,6-tetra-O-benzyl-1-C-(dibromomethyl)-D-glucopyranose (3.15 g) in tetrahydrofuran (32 mL) was added sodium borohydride (1.6 g) under cooling with ice-water and the mixture was stirred at the same temperature for 1 hour and then at room temperature overnight. The mixture was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was washed with 2N hydrochloric acid and saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (400 mL) with toluene-ethyl acetate (6:1). The eluate was evaporated to dryness under reduced pressure to give a mixture of (1R)- and (1S)- isomers of 2,3,4,6-tetra-O-benzyl-1-C-(dibromomethyl)-D-glucitol (2.13 g) as a colorless syrup. NMR (CDCl3 +D2O) δ: 3.5-4.9 (15H, m), 5.68 (d, J=8 Hz) and 6.13 (d, J=3 Hz) (total 1H), 7.1-7.5 (20H, m). Elemental analysis for C35H38Br2O6 : Calc.(%): C, 58.84; H, 5.36; Br, 22.37,. Found(%): C, 59.15; H, 5.23; Br, 21.94.
Reaction SMILES: C1(CO[C:9](=[O:16])[NH:10][C@H:11]2[CH2:14][NH:13][C:12]2=[O:15])C=CC=CC=1.C(N(CC)CC)C.CN(C=O)C.[C:29]1([CH2:35]C(Cl)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Pd].C(O)C>[O:15]=[C:12]1[C@@H:11]([NH:10][C:9](=[O:16])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][NH:13]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@H]1CNC1=O
Reaction time: 2.5 h
Yield: 36.4 %

Procedure:
A mixture of 5.50 g (0.025 mol) of (S)-(2-oxo-3-azetidinyl) carbamic acid phenylmethyl ester, 250 mL of ethanol, and 2.0 g of 10% palladium on carbon catalyst was hydrogenated (2 hours) on a Parr apparatus at an initial gauge pressure of 50 psi. After filtration of the catalyst, the solution was concentrated to dryness under reduced pressure. A mixture of the residue with 4.2 mL (0.03 mol) of triethylamine and 30 mL of DMF was stirred and cooled in ice. A solution of 3.88 g (0.025 mol) of phenylacetyl chloride in 25 mL of ethanol-free chloroform was added over a period of 30 minutes. The mixture was stirred another 30 minutes with cooling, and then for 2.5 hours at room temperature. The chloroform was evaporated under reduced pressure, and 300 mL of ether was added to the residue. The mixture was cooled in ice for 20 minutes. The precipitate was filtered and washed successively with ether, aqueous NaHCO3 solution, water, and ether. After drying in the air, the solid (2.15 g) was recrystallized from 50 mL of ethanol to obtain 1.86 g of pure (S)-N-(2-oxo-3-azetidinyl)benzeneacetamide, m.p. 194°-195° C.