Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:31])[CH:4]=1.[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:5]6[CH:4]=[C:3]([CH3:2])[O:7][N:6]=6)[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: Cc1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cc(C)on5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(5-methylisoxazol-3-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg; compound B31) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (238 mg; compound C10) and HBTU (246 mg) in DCM (15 ml) in the presence of DIPEA (0.38 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 3/2 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]([O:16][C:17](=[O:23])[N:18]([CH2:20][CH2:21][NH2:22])[CH3:19])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CC(O)C>[C:12]([O:16][C:17](=[O:23])[N:18]([CH2:20][CH2:21][NH:22][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Fc1ccc2ncc(Br)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(CCNc1ccc2ncc(Br)n2n1)C(=O)OC(C)(C)C
Yield: 58.9 %

Procedure:
A solution of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (1.4 g, 6.3 mmol), N-(2-aminoethyl)-n-methyl carbamic acid tert-butyl ester [121492-06-6] (961 mg, 5.5 mmol), and Hunig's base [7087-68-5] (1.1 mL, 6.4 mmol) in 2-propanol (28 mL) was heated to reflux for 4d, cooled, preloaded onto silica gel and flash chromatographed (silica gel eluted with 10% (v/v) methanol/ethyl acetate). The isolated light yellow solid product was recrystallized (ethyl acetate/heptane) to yield 1.2 g of [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester as a white powder, mp. 128-129° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotamers present) 1.16 (s, 6H) 1.33 (br. s., 3H) 2.84 (s, 2H) 2.90 (br. s., 1H) 3.34-3.44 (m, 3H) 3.45-3.52 (m, 1H) 6.68 (d, J=9.60 Hz, 1H) 7.31 (br. s., 1H) 7.49 (s, 1H) 7.72 (d, J=9.35 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 28.22, 28.45, 34.02, 35.07, 39.02, 39.97, 46.23, 47.06, 78.52, 78.87, 99.57, 113.35, 125.92, 130.80, 137.01, 154.37, 155.39. LRMS (ESI) m/z 370.1/372.1 [(M+H)]+, calc'd for C14H20BrN6O2: 370.25.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][O:6][C:5]([CH3:8])=[N:4]1.C([O-])([O-])=O.[Cs+].[Cs+].[O:24]([CH2:31][CH2:32]Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOC(C)=O>CN(C=O)C.O>[CH3:8][C:5]1[O:6][CH2:7][C:3]([CH2:2][OH:1])([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:32][CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:15][CH:16]=2)[N:4]=1
Reactant: BrCCOc1ccccc1
Reactant: CC1=NC(CO)(CCc2ccc(O)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1=NC(CO)(CCc2ccc(OCCOc3ccccc3)cc2)CO1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in DMF (5 ml) was added Cs2CO3 (1.2 g, 3.83 mmol) and 2-phenoxyethyl bromide (770 mg, 1.27 mmol). The reaction mixture was stirred at 85° C. for 4 hours. AcOEt and water were then added, the organic layer was separated and the aqueous phase was extracted with AcOEt (3×50 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hx 9:1) afforded (2-Methyl-4-{2-[4-(2-phenoxy-ethoxy)phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil. To a solution of (2-methyl-4-{2-[4-(2-phenoxy-ethoxy)phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (50 mg, 0.14 mmol) in ethanol (2 ml) was added conc. HCl (2 ml). The reaction mixture was stirred at 85° C. for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford 2-amino-4-{4-[2-phenoxy-ethoxy]-phenyl}-2-ethoxy-butan-1-ol hydrochloride as a colorless powder. ESI+MS: m/z=332.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C:6]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].CC(C)=O>CCCCCC>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C:6]=2[CH:18]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Oc1ccc2c(c1)CC(CCc1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C=CCOc1ccc2c(c1)CC(CCc1ccccc1)O2
Yield: 82 %

Procedure:
A mixture 5-hydroxy-2-(2-phenylethyl)-2,3-dihydrobenzoruan, E5, (50 gm; 208 mmoles), potassium carbonate (55 gm; 400 mmoles), allyl bromide (48 gm; 400 mmoles) and acetone (500 mL) was refluxed for 18 hours. The mixture was cooled, diluted with hexane (250 mL) and filtered through celite. The filtrate was concentrated in vacuo and the residue chromatographed in silica gel using 10% ethylacetate in hexane as eluent to obtain 47.8 gm (82%) of 5-allyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran E6 as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:20][N:19]=2)[C:3]1=[O:31].C([SiH2][O:37][C:38](C)(C)[C:39]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=[CH:41][C:40]=1[N:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([CH:64]3[CH2:66][CH2:65]3)[CH:60]=2)[C:55]1=[O:67])(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O.ClCCl>O1CCOCC1>[CH:64]1([C:59]2[CH:60]=[C:61]3[C:56](=[CH:57][CH:58]=2)[C:55](=[O:67])[N:54]([C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([CH2:24][N:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[CH:20][N:19]=5)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=4)[C:39]=2[CH2:38][OH:37])[CH:63]=[CH:62]3)[CH2:66][CH2:65]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ccc2cc(C3CC3)ccc2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(CN3CCOCC3)cn2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)ccc4c3=O)c2CO)cc(Nc2ccc(CN3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl-3-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (96 mg, 0.25 mmol), 2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one (124 mg, 0.233 mmol), 2 mL dioxane, and a 0.86 mg/μL solution of cesium carbonate in water (450 μL, 1.2 mmol) were charged into a 4 mL reaction vial fitted with a stir bar and septum. Sparged mixture with nitrogen for 5 min. Added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (10 mg, 0.012 mmol). The reaction was sparged with nitrogen for 5 min. Sealed the vial and stirred at 90° 16 hr. Cooled to room temperature and filtered the reaction mixture through a 300 mg C18 cartridge. Washed the cartridge with 4 mL EtOAc, 4 mL water, and 4 mL EtOAc. Separated filtrate phases and washed the organic phase with 5 mL of water and 5 mL of brine. Dried the solution over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile+0.1% TFA/water+0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one as an off-white solid. (73 mg, 0.12 mmol). MS (ESI) 590 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=1.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([NH2:36])[CH2:34][CH3:35])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O>C1(C)C=CC=CC=1>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]([NH:36][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=2)[CH2:34][CH3:35])=[CH:31][CH:32]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Reactant: CCCCOc1ccc(C(N)CC)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(C(CC)Nc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
Triethylamine (0.33 g, 3.26 mmol) was added to a solution of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (0.40 g, 1.86 mmol) in toluene (10 ml). The mixture was stirred at room temperature. Then, 1-(4-butoxyphenyl)-1-propylamine (0.46 g, 2.22 mmol) was added. After stirring at 80° C. for 3 hours, water (40 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give The desired ethyl 4-(1-(4-butoxyphenyl)-1-propylamino)-6-ethylpyrimidine-5-carboxylate (0.32 g, 44%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=3)[C:39]([C:48]([C:50]3[CH:55]=[C:54]([O:56][CH3:57])[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[CH:51]=3)=[O:49])=[CH:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[C:17][C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=4)[C:39]([C:48](=[O:49])[C:50]4[CH:51]=[C:52]([O:60][CH3:61])[C:53]([O:58][CH3:59])=[C:54]([O:56][CH3:57])[CH:55]=4)=[CH:38]3)(=[O:35])=[O:36])=[CH:30][CH:29]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(Br)cc3)c2c1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Yield: 56 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step C was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 56% yield, as yellow paste. 1H-NMR (CDCl3) 1.41 (s, 3H); 1.43 (s, 9H); 1.45 (s, 3H); 3.88 (s, 3H), 3.90 (s, 6H), 3.95 (s, 3H); 3.96 (d, 2H, J=11.58 Hz); 4.05 (d, 2H, J=11.45 Hz); 7.0 (dd, 1H, J=2.25, 8.82 Hz); 7.00 (s, 2H); 7.44 (broad s, 1H); 7.46 (d, 2H, J=8.7 Hz); 7.80 (d, 2H, J=8.61 Hz); 7.89 (s, 1H); 8.08 (d, 1H, J=8.82 Hz),
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:2]([N:19]1[CH2:20][CH2:21][N:16]([C:15]2[CH:14]=[CH:13][C:12]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:11][C:10]=2[Cl:9])[CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)c(Cl)c1)c1ccccn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)c(Cl)c1)c1ccccn1
Yield: 192.2 %

Procedure:
According to Scheme 5 Step 5 Method B: A suspension of (bromomethyl)benzene (0.61 mmol, 74 μL), N-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.51 mmol, 161 mg) and of K2CO3 (0.51 mmol, 70 mg) in ACN (3 mL) was stirred at 80° C. for 30 minutes. After evaporation of the solvent, water and AcOEt were added. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using DCM/AcOEt (80:20) as eluent and finally crystallized in pentane to obtain N-(4-(4-benzylpiperazin-1-yl)-3-chlorophenyl)picolinamide (0.98 mmol, 40 mg, 20%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14](I)[CH:13]=2)=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Zn+]>>[C:1]([C:4]1[S:8][C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:13]=2)=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(I)c2)s1
Reactant: [Zn+]c1ccccn1
Agent: [Br-]
Product: CC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)s1

Procedure:
5-Acetyl-N-(4-chloro-3-iodophenyl)thiophene-2-carboxamide (202 mg, 0.5 mmol) was used in Procedure B with 2-pyridylzincbromide (2.5 mL, 1.25 mmol, 0.5 M in THF). Purified by silica gel chromatography (10-100% ethyl acetate/hexanes) to yield 5-acetyl-N-(4-chloro-3-(pyridin-2-yl)phenyl)thiophene-2-carboxamide as a yellow solid: TLC Rf=0.19 (50% ethyl acetate/hexanes); 1H NMR (CDCl3, 400 MHz) δ 8.96 (bs, 1H), 8.67 (d, 1H), 7.79 (dt, 1H), 7.68 (m, 3H), 7.61 (d, 1H), 7.58 (d, 1H), 7.37 (d, 1H), 7.32 (m, 1H), 2.58 (s, 3H); MS (Q1) 357.0 (M)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([OH:12])[CH2:9][CH2:10][OH:11].S(O[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[C:20]=1[N+:27]([O-:29])=[O:28])(C)(=O)=O>CCCCCC.O>[OH:11][CH2:10][CH2:9][CH2:8][O:12][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: CSc1cccc(COS(C)(=O)=O)c1[N+](=O)[O-]
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CSc1cccc(COCCCO)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
33 mg (0.76 mmol) of sodium hydride (as a 55% w/w suspension in mineral oil) were washed twice with hexane, and then 1 ml of dimethylformamide was added to the suspension. The resulting suspension was cooled in an ice bath, and then 0.8 ml (11 mmol) of 1,3-propanediol was added. The mixture was then stirred for 30 minutes at this temperature and then for 30 minutes at room temperature. 1 ml of a dimethylformamide solution containing the whole of the 2-mesyloxymethyl-6-methylthio-1-nitrobenzene prepared as described in step (i) above was then added to the resulting solution, whilst ice-cooling, and the mixture was stirred for 2 hours at the ice-cooling temperature and then for 1.5 hours at room temperature. At the end of this time, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic extract was washed with water several times, and then the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 10 g of silica gel using mixtures of methylene chloride and ethyl acetate in ratios ranging from 10:1 to 8:1 by volume as the eluent, to obtain 95 mg (yield 74%) of the title compound as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)([CH3:4])([CH3:3])C.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>[Cu]I.CS(C)=O>[CH:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:10]=1)([CH3:3])[CH3:4]
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)NCc1cccc(I)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)OC(=O)NCc1cccc(NCCN2CCOCC2)c1
Temperature: 85 °C
Yield: 76.3 %

Procedure:
A mixture of (3-iodo-benzyl)-carbamic acid tert-butyl ester (272 mg, 0.816 mmol), 4-(2-aminoethyl)morpholine (0.16 mL, 1.225 mmol), K2CO3 (232 mg, 1.679 mmol), CuI (19 mg, 0.10 mmol), L-proline (19 mg, 0.163 mmol) and DMSO (5 mL) was heated at 85° C. for 1 h. The reaction was cooled, poured onto water and the aqueous layer extracted with EtOAc (×3). The organic layers were combined and washed with water, brine and dried (Na2SO4). Chromatography (MeOH/EtOAc) afforded [3-(2-morpholin-4-yl-ethylamino)-benzyl]-carbamic acid isopropyl ester (200 mg) as an orange viscous oil. m/z (M+1) 336.16.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])(=[O:14])=[O:13])[N:11]=[C:4]2[N:3]=1.[CH3:24]C(C)([O-])C.[K+].CI>C(#N)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12]([N:15]([CH3:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])(=[O:13])=[O:14])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CC#N
Product: Cc1cc(C)n2nc(S(=O)(=O)N(C)c3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A mixture of 3.00 g (8.06 mmol) of 5,7-dimethyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]-pyrimidine-2-sulfonamide and 0.90 g (8.1 mmol) of potassium t-butoxide in 30 ml of acetonitrile was heated at reflux for 40 minutes. After cooling to room temperature 1.14 g (8.06 mmol) of methyl iodide was added, and the reaction was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was diluted with methylene chloride and washed with 1% aqueous NaOH. The organic phase was separated, dried (MgSO4) and evaporated at reduced pressure. The brown solid residue was recrystallized from acetone to give 1.60 g (51%) the desire product as a tan solid, mp 220°-222° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2C([C:51]([O:53][CH:54]([CH3:65])[C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)=[O:52])N)=CC=CC=1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:51]([O:53][CH:54]([CH3:65])[C:55]2[CH:56]=[CH:57][C:58]([C:61]([F:62])([F:64])[F:63])=[CH:59][CH:60]=2)=[O:52])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(OC(=O)C(N)c1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)c1ccc(C(F)(F)F)cc1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Product: CC(OC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)c1ccc(C(F)(F)F)cc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and α-methyl-4-trifluoromethyl)benzyl N-succinimidocarbonate (precursor 4c), according to the general working procedure 170 mg of 2′-(α-methyl-4-(trifluoromethyl)benzyloxycarbonyl-aminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained as a racemate. MS (ES+): m/e=548 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:33][C:9]2[N:10]=[C:11]([NH2:32])[N:12]=[C:13]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16](S(C4C=CC=CC=4)(=O)=O)[CH:15]=3)[C:8]=2[CH:7]=1)=[O:5])C.[OH-].[K+].O>C(O)C>[NH2:32][C:11]1[N:12]=[C:13]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:33][C:9]=2[N:10]=1
Reactant: CCOC(=O)c1cc2c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)nc(N)nc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2c[nH]c3ccccc23)c2cc(C(=O)O)sc2n1
Reaction time: 8 h

Procedure:
A solution of 2-amino-4-(1-benzenesulfonyl-1H-indol-3-yl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (80 mg, 0.17 mmol) in ethanol (6 ml) was heated to 65° C., 2M potassium hydroxide added (0.25 ml, 3 equiv.) and stirred overnight. Water was added and the volatile removed in vacuo. The solution was then neutralised and freeze dried.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=1)[C:13]([CH3:29])=[C:12]2[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])C1C=CC=CC=1.Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([N:14]3[C:15]4[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=4)[C:12]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:13]3[CH3:29])=[N:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(OCc3ccccc3)cc12
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 5-benzyloxy-1-(7-chloroquinazolin-4-yl)-2-methylindol-3-ylacetate (1.5g) in glacial acetic acid (5ml.) was treated with a 50% w/v solution of hydrogen bromide in glacial acetic acid (5ml.). The resulting dark red solution was stirred at room temperature for 10 minutes and then neutralised by the addition to a mixture of saturated sodium acetate solution (50ml.) and water (150ml.). The mixture was extracted with ethyl acetate (3 × 50ml.) and the extracts washed successively with water (2 × 40ml.), saturated sodium hydrogen carbonate solution (2 × 40ml.), water (40ml.) and then saturated sodium chloride solution (40ml.). After drying (MgSO4), the extracts gave on evaporation in vacuo a yellow-brown oil. Purification by chromatography on silica gel (200g.) in a mixture of 50% v/v ether and 50% v/v petroleum ether (b.p 40°-60° C.), gave ethyl 1-(7-chloroquinazolin-4-yl)-5-hydroxy-2-methylindol-3-ylacetate as a pale yellow glass [NMR: 2-CH3 at 7.7 τ; pure by TLC (systems A, C and D)].