Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H]1c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CC1c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ester from step 2 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent was evaporated, the aqueous layer was acidified with HCl 1N and the acid extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried and evaporated to afford 2-(4-bromophenyl)cyclopropanecarboxylic acid. Optically active intermediates were obtained by separation on chiral column (Chiral Pak AD) using hexane:EtOH (90:10 with 0.2% TFA)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].Br[CH2:23][CH:24]=[CH2:25]>CN(C=O)C>[CH2:25]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])[CH:24]=[CH2:23]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1.0 g, 3.3 mmol) in DMF (10 mL), NaH (0.25 g, 10 mmol) was added at 0° C. and the mixture stirred for 20 minutes. 3-bromoprop-1-ene (1.7 g, 14.13 mmol) was added and the mixture was heated at 80° C. for 15 h. On completion, the reaction was quenched with ice cold water and extraction was carried out using DCM. The combined organic layers were dried, concentrated and resulting crude was purified by column chromatography giving the title compound (0.50 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[Cl:12].CN(C(OC)[O:17]C)C>CN(C=O)C.CN(C=O)C.O>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([CH:11]=[O:17])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 14 h
Yield: 23 %

Procedure:
A mixture of 1,2-dichloro-4-methyl-5-nitrobenzene (2 g, 9.71 mmol) and DMF-DMA (3 g, 25.2 mmol) in DMF (50 mL) was stirred at 140° C. for 14 h. The dark solution was cooled to 0° C., and then added to a solution of NaIO4 (10.8 g, 50.5 mmol) in DMF/water (1:4, 25 mL) at 0° C. After stirring at room temperature for 8 h, the mixture was filtered and the cake was rinsed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether=1:20) to afford the desire product (480 mg, 23% yield, 2 steps)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)[N:11]=[C:10]2[OH:12]
Reactant: COc1ccc2nc(Cl)nc(O)c2c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc2nc(-c3cccnc3)nc(O)c2c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a mixture of 2-chloro-6-methoxyquinazolin-4-ol (1.20 g, 5.7 mmol, 1.0 eq.), pyridin-3-ylboronic acid (1.27 g, 8.6 mmol, 1.5 eq.), K2 CO3 (2.37 g, 17.1 mmol, 3.0 eq.) in dioxane (100 mL) and 1H2O (10 ml) was added Pd(PPh3)2Cl2 (230 mg, 0.29 mmol, 0.05 eq.) under N2 atmosphere. The resulting mixture was stirred at 105° C. under N2 atmosphere overnight. After reaction was completed, the mixture was cooled to room temperature, and the resultant precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was partitioned between H2O (30 mL) and ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over MgSO4. After filtration and evaporation, the crude product was obtained, which was combined with the filter cake and dried in vacuo to give 1.35 g of 6-methoxy-2-(pyridin-3-yl) quinazolin-4-ol as a gray solid. LCMS m/z=254.1 (M+1) (Method B) (retention time=1.39 min). The crude product was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[N:8][C:9]([CH3:11])=[CH:10][C:5]=2[N:4]([C:12]([OH:14])=[O:13])[CH2:3]1.C([O:19][C:20](=[O:22])[CH3:21])(=O)C>>[C:2]([O:13][C:12]([N:4]1[C:5]2[CH:10]=[C:9]([CH2:11][O:19][C:20](=[O:22])[CH3:21])[N:8]=[CH:7][C:6]=2[C:2]([CH3:15])([CH3:1])[CH2:3]1)=[O:14])([CH3:6])([CH3:3])[CH3:1]
Reactant: Cc1cc2c(cn1)C(C)(C)CN2C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Temperature: 125 °C
Yield: 65 %

Procedure:
3,3,6-Trimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid, 5-oxide, tert-butyl ester (0.375 g, 1.34 mmol) was dissolved in acetic anhydride (1.68 mL) and heated to 125° C. for 1 h. The reaction was cooled to ambient temperature and concentrated in vacuo. Chromatography (SiO2, gradient elution, 0-100%, EtOAc/petrol), gave the title compound (0.280 mg, 65%) as a yellow oil. MS: [M+H]+=321.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(F)c1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1F

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3-Difluorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 505.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[N:46]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34](=[O:36])[NH:54][CH2:53][CH2:52][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(/C=C/C(=O)NCCN4CCCCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A mixture of Example 271 (30.6 mg, 0.044 mmol), N,N-diisopropylethylamine (35 μL, 0.20 mmol), 2-piperidin-1-ylethylamine (14.3 μL, 0.10 mmol), and DMF (1 mL) was treated sequentially with 0.5M (0.09 mL) of HBTU in DMF and 0.5M (0.09 mL) of HOBT in DMF. The reaction was stirred for 24 hours at ambient temperature and partitioned between 1N NaOH and ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product (20.4 mg, 0.034 mmol). LCMS m/e 609.2; retention time: 2.93 min.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)=O.FC(F)(F)C([O-])=O.[NH4+:31].O>C(Cl)Cl>[C:18]1([CH2:17][N:13]2[CH2:14][CH2:15][O:16][CH:11]([C:9]3[NH:8][C:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=4[N:31]=3)[CH2:12]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [NH4+]
Reactant: O=C(N[C@@H]1CCCCC1=O)C1CN(Cc2ccccc2)CCO1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: c1ccc(CN2CCOC(c3nc4c([nH]3)CCCC4)C2)cc1
Temperature: 150 °C
Yield: 75.4 %

Procedure:
A mixture of N-[(1R)-2-oxocyclohexyl]-4-(phenylmethyl)-2-morpholinecarboxamide (1.1 g, 3.48 mmol) and ammonium trifluoroacetate (2.069 g, 17.38 mmol) was heated at 150° C. for 20 minutes. After cooling, to the mixture was added water (30 mL) and CH2Cl2 (50 mL). The organic layer was separated and washed with brine, dried (MgSO4), and concentrated to afford the crude title compound (0.78 g). LC-MS (ES) m/z=298 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=4)[C:15](=[O:28])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:29]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:32].[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CNC>CN1CCCC1=O>[CH3:30][N:31]([CH3:32])[C:25]([C:23]1[N:24]=[C:20]([CH2:19][N:16]2[CH2:17][CH2:18][N:13]([S:10]([C:8]3[S:7][C:6]4[CH:29]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH:9]=3)(=[O:12])=[O:11])[CH2:14][C:15]2=[O:28])[S:21][CH:22]=1)=[O:26]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl-carboxylic acid (14 mg, 0.03 mmol) in N-methyl-pyrolidinone (0.3 mL) is added TBTU (0.05 mmol) and diisopropylethylamine (0.06 mmol) and dimethylamine hydrochloride (0.06). The reaction is stirred 3 h and an additional aliquot of TBTU, DIEA and amine are added. The reaction is stirred 1 h and the reaction is concentrated and purified by column chromatography (silica, 2% MeOH/EtOAc) to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazole-4-carboxylic acid dimethylamide. 1H NMR (300 MHz, CDCl3) δ 7.87-7.77 (m, 4H), 7.47 (dd, 1H), 4.83 (s, 2H), 3.92 (s, 2H), 3.63-3.60 (m, 2H), 3.47-3.43 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H); MS (Ion Spray) 499 (M+H)+.
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[C:11](F)[CH:12]=[CH:13][C:6]=2[S:5][CH2:4][CH2:3]1.[CH3:15][N:16]([CH3:33])[S:17]([NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30]([NH2:32])=[S:31])[CH2:24][CH2:23]1)(=[O:19])=[O:18]>>[N:32]1[C:8]2[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[S:5][CH2:4][CH2:3][C:2]=2[S:31][C:30]=1[NH:29][CH2:28][CH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][NH:20][S:17]([N:16]([CH3:33])[CH3:15])(=[O:19])=[O:18])[CH2:23][CH2:24]1
Reactant: O=C1c2cc(F)ccc2SCCC1Br
Reactant: CN(C)S(=O)(=O)NCC1CCC(CNC(N)=S)CC1
Product: CN(C)S(=O)(=O)NCC1CCC(CNc2nc3c(s2)CCSc2ccccc2-3)CC1

Procedure:
4-Bromo-7-fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one (0.200 g, 0.720 mmole) and N-[4-([(dimethylamino)sulfonyl]aminomethyl)-cyclohexyl]methylthiourea (0.250 g, 0.810 mmole) were heated at reflux for 18 hours, the solvent removed under reduced pressure and the crude product chromatographed (silica) to afford N′-(4-[(4,5-dihydrobenzo[2,3]thiepino[4,5-d][1,3]thiazol-2-ylamino)methyl]cyclohexylmethyl)-N,N-dimethylsulfamide.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>>[Cl:19][CH2:20][CH2:21][CH2:22][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: ClCCCI
Reactant: O=C1COc2cc(F)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2cc(F)ccc2N1CCCCl
Yield: 104.6 %

Procedure:
7-Fluoro-4H-benzo[1,4]oxazin-3-one (81MF763) (0.263 g, 1.57 mmol), Cs2CO3 (0.769 g, 2.36 mmol) and 3-chloro-1-iodopropane (0.354 g, 1.73 mmol) were mixed according to GP5 giving the crude title compound (0.40 g); 1H NMR (CDCl3) δ 7-01-6.91 (m, 1H), 6.79-6.73 (m, 2H), 4.60 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.4 Hz, 2 H), 2.18-2.11 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH2:16][CH2:15][NH:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]=[CH:26]C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH2:16][CH2:15][N:14]2[CH:26]=[O:25])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccc(CC3NCCC4=C3CCCC4)cc2)cc1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=CN1CCC2=C(CCCC2)C1Cc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.6 %

Procedure:
To a solution of 0.78 g (0.002 mol) of (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline in 5 ml of chloroform was added 0.42 g of chloral in 1 ml of chloroform dropwise. After the mixture had been stirred at room temperature for 3 hrs it was diluted with 15 ml of chloroform and washed with 4 N hydrochloric acid (10 ml) and water (10 ml). After drying, the solvent was removed under reduced pressure to give 0.81 g (96%) of crude (±)-1-(p-phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For characterization, a sample of this compound was distilled, bp 225°-227° (0.08 mm Hq).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:22][NH:23][CH3:24]>C1COCC1.O>[CH3:22][N:23]([CH3:24])[CH2:2][CH2:1][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: C=CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 86.9 %

Procedure:
A solution of the above vinylsulfonamide (3.10 g, 10 mmol) in 20 mL of THF was treated with an excess (10 mL, 80 mmol) of 40% aqueous dimethylamine. After 5 min, the mixture was diluted with water to give 3.09 g (87% yield) of benzyl 4-{[2-(dimethyl-amino)ethyl]sulfonyl}-1-piperazinecarboxylate as a white solid: mp (aq. MeOH) 101-103° C.; 1H NMR (CDCl3) δ 7.40-7.30 (m, 5H), 5.15 (s, 2H), 3.59 (m, 4H), 3.26 (m, 4H), 3.07 (dd J=8.1, 6.4 Hz, 2H), 2.74 (dd, J=8.0, 6.4 Hz, 2H), 2.25 (s, 6H); Anal. Calcd. for C16H25N3O4S: C, 54.1; H, 7.1; N, 11.8. Found: C, 53.8; H, 6.9; N, 11.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:32]\[OH:33])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(N)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(S(N)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzenesulfonamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=460.2 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>C1COCC1.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[N:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Reactant: N#Cc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccccc2C#N)nc1
Yield: 68.6 %

Procedure:
A mixture of [5-(tert-Butyldimethylsilyloxymethyl)pyridin-2-yl]tri-n-butylstannane (11.5 g, 0.022 mol), 2-iodobenzonitrile (5.1 g, 0.022 mol), CuI (0.43 g, 0.002 mol), and bis(triphenylphosphine)palladium(II) chloride (0.80 g, 0.001 mol) in THF (40 mL) was heated under reflux for 48 h. The mixture was diluted with ether and washed with saturated aqueous NH4Cl, aqueous NH4OH, water, and brine, dried (MgSO4), and concentrated to give 4.9 g (67%) of product as a brown oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][C:20]#[N:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[F:27][C:25]([F:26])([F:28])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([C:2]([F:30])([F:29])[F:1])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][CH2:20][NH2:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: N#CCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)propanenitrile (190 mg, 0.44 mmol) and nickel(II) chloride hexahydrate (158 mg, 0.66 mmol) in methanol (4 mL) at 0° C. was added sodium borohydride (117 mg, 3.1 mmol) in several portions over 30 minutes. The ice bath was removed and stirring continued for 1 h. Very clean and mostly complete conversion to product (by LC/MS) was observed. The reaction was cooled to 0° C. and treated with concentrated hydrochloric acid (85 μL). After 5 min, celite was added, and the mixture was filtered. The solution was made basic by addition of solid sodium bicarbonate, and filtered again. The organics were concentrated to give the crude amine which was purified by column chromatography (10% MeOH/DCM-->10:90:0.5 MeOH/DCM/Me3N in EtOH) to give 114 mg (59%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.73 (s, 1H), 7.63 (s, 2H), 7.05-7.40 (m, 4H), 5.11 (s, 2H), 4.61 (qAB, JAB=13.1 Hz, 2H), 3.66 (s, 2H), 2.64 (m, 2H), 1.70-2.10 (m, 4H), 1.50 (m, 1H), 1.20 (m, 1H); 13C-NMR (CDCl3, 126 MHz) δ 141.42, 141.39, 140.1, 131.7 (q, J=33.6 Hz), 128.1, 127.5, 127.1, 123.4 (q, J=273 Hz), 121.6, 121.4, 121.1, 90.3, 76.8, 72.9, 72.0, 42.3, 34.1, 27.3. Mass spec.: 434.25 (MH)+. Accurate mass spec.: m/z 434.1542 [MH]+, Δ=1.3 ppm.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:18])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>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.C(O)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([CH2:2][C:25]3[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)[C:4]=2[F:18])[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(Cc2ccc([N+](=O)[O-])cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 60 °C
Yield: 76 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed 3-bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (I-33, 400 mg, 1.21 mmol), 4-nitrophenylboronic acid (420 mg, 1.45 mmol), potassium phosphate (tribasic) (514 mg, 2.42 mmol), dimethoxyethane (3.5 mL) and 50% aqueous ethanol (3.5 mL). After degassing with nitrogen for 15 minutes, tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.121 mmol) was added. The mixture was heated to 60° C. for 18 hours and then the palladium catalyst was removed by filtering through Celite. To the filtrate were added water (50 mL) and a saturated ammonium chloride solution (50 mL). After extracting with ethyl acetate (3×50 mL), the organic portions were combined, washed with brine (75 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel chromatography utilizing 20% ethyl acetate/hexanes as eluent to produce 342 mg (76%) of 3′-chloro-2-fluoro-6-methoxy-3-(4-nitro-benzyl)-biphenyl (I-34) as a yellow solid. MS (APCI−): 370.1 (M−1).
Reaction SMILES: CS[C:3]1[C:9]2=[CH:10][C:11]3[C:16]([N:8]2[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.[N:21]1([CH2:27][CH2:28][CH2:29][OH:30])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl>[CH:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]1[N:8]2[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=[C:3]1[N:24]1[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][CH2:29][OH:30])[CH2:22][CH2:23]1
Reactant: OCCCN1CCNCC1
Reactant: CSC1=Nc2ccccc2Cn2c1cc1ccccc12
Solvent: ClCCl
Product: OCCCN1CCN(C2=Nc3ccccc3Cn3c2cc2ccccc23)CC1

Procedure:
A mixture of 5.39 g of 12-methylthio-6H-indolo[2,1-c][1,4]benzodiazepine, the product of Example 1c., and 17 g of 1-piperazinepropanol in a pressurized bottle was heated to 220° C. overnight. The reaction mixture was dissolved in CH2Cl2 and then was washed with water. Removal of solvent in vacuo followed by recrystallization from EtOH gave the title compound, a colorless solid, mp 174°-175° C.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>C(O)C>[CH3:20][O:21][CH2:22][CH2:23][NH:24][C:5]1[C:4]2[N:8]=[CH:9][N:10]([C:3]=2[N:2]=[CH:1][N:6]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: COCCN
Solvent: CCO
Product: COCCNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 90 °C
Yield: 98 %

Procedure:
547 mg 6-chloropurine riboside, 0.882 mL 2-methoxyethylamine, and 5.0 mL ethyl alcohol are combined and heated to 90° C. in a sealed reaction vessel for about 22 hours. The ligand is then purified by silica gel chromatography using 8:1 methylene chloride:methanol to yield N6-(2-methoxyethyl)-adenosine (0.61 g, 98% yield.