Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:26])[CH:16]=3)[CH2:12][NH:11][CH2:10]2)[O:6][N:5]=1)[CH3:2].C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36].O>ClCCl>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11]([C:35]([O:37][C:38]3[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=3)=[O:36])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOc1noc(C2CNCC(c3ccc(OC(F)(F)F)c(F)c3)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
195 mg (0.48 mmol) of 3-(3-ethoxy-1,2,4-oxadiazol-5-yl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine were initially charged in 4.5 ml of dichloromethane, cooled to 0° C. and admixed with 0.27 ml (193 mg, 1.91 mmol) of triethylamine and 96 mg (0.48 mmol) of 4-nitrophenyl chloroformate. The reaction mixture was stirred at RT for 1 hour and admixed with water, and the organic phase was removed. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 290 mg (94% of theory)
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[CH:11][S:12][C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][O:20][CH:21](OC)N(C)C>>[CH3:19][O:20]/[CH:21]=[C:14](\[C:13]1[S:12][CH:11]=[N:10][C:9]=1[CH:1]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)/[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cc1scnc1/C=C/c1ccccc1
Reactant: COC(OC)N(C)C
Agent: CO/C=C(/C(=O)OC)c1scnc1/C=C/c1ccccc1
Product: CO/C=C(/C(=O)OC)c1scnc1C=Cc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2.5 g of the product of Step A and 25 ml of dimethylformamide dimethyl acetal was heated to 50° C. and after 4 hours at this temperature, the mixture was allowed to return to 25° C. The reaction mixture was evaporated to dryness and the residue was dissolved in 30 ml of tetrahydrofuran and 5 ml of an aqueous solution of 2N hydrochloric acid. After standing for 2 hours at 25° C., the mixture was decanted followed by extraction with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was dissolved in 30 ml of acetone and 4 g of potassium carbonate and 6 ml of methyl iodide were added. The mixture was stirred for 16 hours at 20° to 25° C. and after filtering and evaporating to dryness, the residue was chromatogrpahed on silica, eluting with a hexane-ethyl acetate mixture (7-3) to obtain 1.1 g of the desired product. Thin layer chromatography; Rf=0.17 [eluant: hexane-acetate of ethyl (7-3)].
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]1=[O:17].Br[C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:29][CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH:31]1([CH2:30][O:29][C:20]2[CH:19]=[CH:24][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:22][C:21]=2[C:6]2[CH:5]=[CH:4][C:3](=[O:17])[N:2]([CH3:1])[CH:7]=2)[CH2:32][CH2:33]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)ccc1=O

Procedure:
1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one was treated with 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene in a manner similar to Example 94 to give the title compound. 1H NMR (CDCl3, 400 MHz): δ 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.68-765 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.64 (s, 3H), 3.07 (s, 3H), 1.28-1.25 (m, 1H), 0.69-0.65 (m, 2H), 0.34-0.38 (m, 2H). LCMS (M+H)+ 334.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=3[Cl:36])[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:37][CH2:38][CH3:39])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:36][C:30]1[C:31]([Cl:35])=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:17]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]([CH2:37][CH2:38][CH3:39])=[N:10][C:11]=2[CH:16]=1
Reactant: CCCc1nc2cc(N(Cc3cccc(Cl)c3Cl)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3cccc(Cl)c3Cl)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(2,3-Dichloro-benzyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.72 (m, 2H), 7.48 (m, 4H), 7.22 (m, 3H), 6.79 (dd, 1H), 4.99 (s, 2H), 4.51 (s, 2H), 2.67 (t, 2H), 1.72 (m, 2H), 0.94 (t, 3H). MS calculated for C25H22FCl2N3O4S—H: 548, observed: 548.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([C:15](=[CH2:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]=1[CH3:32])#[N:2].[CH2:33](Br)[CH:34]=[CH2:35].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:35]([N:17]([CH2:16][C:15]([C:6]1[C:7]2[O:11][C:10]([CH:12]3[CH2:14][CH2:13]3)=[N:9][C:8]=2[C:3]([C:1]#[N:2])=[C:4]([CH3:32])[C:5]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH2:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:34]=[CH2:33]
Reactant: C=C(CNC(=O)OC(C)(C)C)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Reactant: C=CCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CC(=C)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
tert-Butyl [2-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)prop-2-en-1-yl]carbamate (I-325) (97.0 mg, 0.226 mmol) and allyl bromide (28.7 μl, 0.339 mmol) were dissolved in dimethylformamide (2 ml), then with cooling with ice, sodium hydride (55% w/w) (11.8 mg, 0.271 mmol) was added, followed by stirring for 2 hours with cooling with ice. With cooling with ice, aqueous 10% citric acid solution was added to the reaction liquid, followed by concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (105 mg, 99%) as a colorless oily substance.
Reaction SMILES: [NH2:1][N:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.C([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=O)(=O)C>>[NH:18]1[CH2:19][CH2:20][N:16]=[C:17]1[NH:1][N:2]1[CH2:3][CH2:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8]1
Reactant: CC(=O)N1CCNC1=O
Reactant: NN1CCc2ccccc2CC1
Product: c1ccc2c(c1)CCN(NC1=NCCN1)CC2
Reaction time: 1 h

Procedure:
5 g of (0.03 M) 3-amino-2,3,4,5-tetrahydro-1H-3-benzazepin and 4.3 g of (0.034 M) 1-acetyl-imidazolidin-2-one are stirred in 50 ml POCL3 for 1 hour at 100° C. The remaining process steps are analogous to those set forth in Example 5.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]([O:17][C@H:18]3[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]3)[N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=1)=[CH2:2].[ClH:34]>C(Cl)Cl>[ClH:34].[CH:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]([O:17][C@H:18]3[CH2:22][NH:21][C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]3)[N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc2c(c1)c(O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)nc1ccccc12
Agent: Cl
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)c(O[C@H]1CN[C@H](C(=O)OC)C1)nc1ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of the product mixture from Step 4 (100 mg, 0.26 mmol) in DCM (5 mL) was bubbled HCl(g) for 10 min. After stirring for an additional 30 min, the solvent was removed in vacuo to yield methyl (4R)-4-[(8-vinylphenanthridin-6-yl)oxy]-L-prolinate hydrochloride, which was taken up in DCM (5 mL) and linker intermediate B20, (2S)-cyclohexyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acid (85 mg, 0.29 mmol), TEA (0.073 mL, 0.52 mmol), EDC (63 mg, 0.33 mmol), and HOBT (50 mg, 0.33 mmol) were added. The mixture was stirred at r.t. for 18 h, the solvent was removed in vacuo, and the residue was taken up in EtOAc and extracted with NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 10-50% EtOAc/hex) to yield the title compound as a 1:1 mixture with the expected regioisomer. LRMS (M+H)+=628.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=O)[CH2:8][C:7]=2[CH:14]=1.B>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)CC(=O)NCC2
Agent: B
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
Into a 1-neck round-bottom flask, to 8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (30.00 g, 0.16 mol) in tetrahydrofuran (200 mL) was added a 1 M solution of borane in tetrahydrofuran (450 mL) via cannula at 0° C., under an atmosphere of nitrogen. After 20 minutes the reaction was allowed to warm to room temperature and then the flask was equipped with a condenser and the reaction was heated at reflux overnight. The reaction was quenched by careful addition of concentrated aqueous HCl (37%). The tetrahydrofuran was removed in vacuo and to the aqueous reaction mixture was added an additional 50 mL of concentrated HCl and the resulting mixture was refluxed for 3 h, cooled and neutralized with 33% NaOH to pH 7-8 and further with saturated Na2CO3 to pH 11. The mixture was extracted three times with ethyl acetate, and the combined extracts were dried (MgSO4), and concentrated. The crude product was passed through a short SiO2 plug (MeOH/DCM 0-15%) to provide 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (17 g, 55%). 1H-NMR (CDCl3) δ 7.01 (d, J=8.3 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 6.65 (dd, J=2.5, 8.1 Hz, 1H), 3.79 (s, 3H), 2.96 (m, 4H), 2.88 (m, 4H), 2.50 (br s, 1H); LC/MS (ESI+): 178.05 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[CH2:4][CH:5](C(O)=O)[C:6]([OH:8])=[O:7]>CCOCC>[Br:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1Br)C(=O)O
Solvent: CCOCC
Product: O=C(O)CCc1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
[2-Bromo-4-(trifluoromethyl)benzyl]malonic acid (9.80 g, 28.7 mmol) in a round-bottom flask was heated to 180° C. and heating was continued at 180° C. for 1.5 hrs. After cooling to room temperature, the solid was dissolved in ether. The resulting solution was dried over MgSO4 and concentrated. The solid was washed with hexane to give the title compound (7.20 g, 85%). MS calculated for C10H8BrF3O2: (M+H)+ 297. found 297.0, 299.0.
Reaction SMILES: [S:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:20])[O:13][C:14]3[CH:19]=CC=CC=3)[S:10][C:6]=2[CH:5]=1)[C:2]#[N:3].[N:23]1(CCN)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[S:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:20])[O:13][CH2:14][CH2:19][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[S:10][C:6]=2[CH:5]=1)[C:2]#[N:3]
Reactant: NCCN1CCOCC1
Reactant: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Product: N#CSc1ccc2nc(NC(=O)OCCN3CCOCC3)sc2c1

Procedure:
The 2-morpholin-4-ylethyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate was prepared according to the method described in Example 9c, but using 654 mg of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate and 0.27 cm3 of 2-morpholin-4-ylethanamine. The residue obtained is chromatographed on an Analogix cartridge of 40 g of silica 15-40 μm, elution being carried out with a gradient of dichloromethane then 95/5 dichloromethane/methanol. 729 mg of 2-morpholin-4-ylethyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14](Br)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[N:26]=[CH:27][C:28](B(O)O)=[N:29][CH:30]=1>C(O)C.O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([C:28]2[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][N:29]=2)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnc(B(O)O)cn1
Reactant: COC(=O)c1c(Br)sc(Br)c1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(-c2cnc(OC)cn2)sc(Br)c1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Palladium tetrakis-triphenylphosphine is added to a degassed solution of dibromide 155 and 5-methoxypyrazin-2-ylboronic acid 156 in ethanol: water:toluene (2:1:1) and sodium carbonate. The resulting mixture is heated under N2 and stirred for 1 h at 80° C. The mixture is then cooled filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provides 157.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])=[O:4].[C:11]1(=[O:30])[N:15]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:25])[C:13]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:12]12.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH:6]([C:7](=[O:8])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][CH2:16][N:15]2[C:11](=[O:30])[C:12]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:13]3[C:14]2=[O:25])=[CH:24][CH:23]=1)[CH3:10]
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccccc1
Reactant: COC(=O)CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CC(C)C(=O)c1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
8.2 g (50 mmol) of 3-methoxycarbonyl-2-methyl-propionic acid chloride and 13.3 g (50 mmol) of 3-phthalimidopropyl-benzene are reacted with 26 g of aluminum chloride in 1,2-dichloroethane analogously to Example 4(a). The oil obtained crystallizes from ethanol as beige coloured crystals.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:55]1[C:56](=[O:63])[N:57]([CH3:62])[CH:58]=[C:59]([Br:61])[CH:60]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:61][C:59]1[CH:60]=[C:55]([NH:9][C:6]2[N:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=2)[C:56](=[O:63])[N:57]([CH3:62])[CH:58]=1
Reactant: Nc1ccc(C(F)(F)F)nn1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(C(F)(F)F)nn2)c1=O
Temperature: 90 °C
Yield: 85.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 301a (750 mg, 4.6 mmol), XantPhos (532 mg, 0.92 mmol), Pd2 dba3 (421 mg, 0.46 mmol), 2-bromo-4-chloronicotinaldehyde (H-001) (1.84 g, 6.9 mmol), Cs2CO3 (3.0 g, 9.2 mmol), and 1,4-dioxane (50 mL). The system was subjected to three cycles of vacuum/argon flush and heated at 90° C. for overnight. After the completion of the reaction, the mixture was filtered and the solid was washed with methanol (30 mL). The combined filtrate was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 301b (1.38 g, 89%) as a yellow solid. MS-ESI: [M+H]+ 350.8
Reaction SMILES: C(OC([CH:6]1[C:10](=[O:11])[CH:9]([CH3:12])[CH2:8][N:7]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C>Cl>[CH2:13]([N:7]1[CH2:8][CH:9]([CH3:12])[C:10](=[O:11])[CH2:6]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1C(=O)C(C)CN1Cc1ccccc1
Agent: Cl
Product: CC1CN(Cc2ccccc2)CC1=O
Temperature: 100 °C

Procedure:
A 30.15 g (115.4 mmol) sample of the ester from step c was hydrolyzed and decarboxylated by adding to 280 mL of 1M HCl and heating at 100° C. under reflux conditions for 12 hours. The mixture was then poured over ice and the impurities extracted into methylene chloride. The aqueous solution was then adjusted to pH 8 with potassium carbonate and the product extracted into methylene chloride, which was then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum, to yield 9.95 g of 1-benzyl-4-methylpyrrolidin-3-one, NMR (CDCl3) d 1.12 (d, 3H, J=7.5 Hz), 2.50 (m, 1H), 2.75 (m, 2H), 3.33 (m, 2H), 3.69 (d, 2H, J=7.5 Hz), 7.32 (m, 5H).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([OH:24])[CH2:21][CH2:22][OH:23]>>[NH2:2][C:3]1[N:11]=[C:10]([O:23][CH2:22][CH2:21][CH2:20][OH:24])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: OCCCO
Agent: [Na]
Product: Nc1nc(OCCCO)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 51 %

Procedure:
Sodium (80 mg, 3.5 mmol) in 3 ml of 1,3-propanediol was added 6-amino-9-benzyl-2-chloropurine (235 mg, 0.90 mmol). The mixture was heated at 100° C. for 3 hours. The reaction mixture was concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (137 mg, yield 51%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([C:13]2[S:22][C:21]3[NH:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[NH:17][C:16](=S)[C:15]=3[N:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[CH:8]1([C:13]2[S:22][C:21]3[NH:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[N:17]=[C:16]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[C:15]=3[N:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: S=C1Nc2ccccc2Nc2sc(C3CCCC3)nc21
Solvent: c1ccncc1
Product: CN1CCN(C2=Nc3ccccc3Nc3sc(C4CCCC4)nc32)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
Combine N-methyl piperazine (0.264 g, 2.64 mmol) and 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.205 g, 0.66 mmol) in 7 ml of pyridine, and heat to reflux over night. Cool to room temperature, remove pyridine, the residue purify on silica gel using 2N ammonia in methanol/ dichloromethane (1:10) as the eluent to give 165 mg foam, which recrystallize in methanol to give 110 mg of title compound: Mass spectrum (electrospray) (m/e): C20H25N5S, Cacl. Mass (M): 367.18, Found: 368.18 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm: 6.97–6.90 (m, 2H), 6.81 (dt, 1H, J=7.3 Hz, J=1.0 Hz), 6.55 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 4.96 (br, 1H), 3.2–3.17 (m, 1H), 2.49–2.47 (m, 4H), 2.28 (s, 3H), 2.03–1.97 (m, 2H), 1.71–1.55 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19]CC)=[O:18].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(C(=O)O)c2)C1
Reaction time: 2 h
Yield: 55.8 %

Procedure:
3.3 g of ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzoate (intermediate 4) were dissolved in 60 ml of methanol and admixed with 60 ml of 2 N KOH. After two hours at 50° C., the mixture was concentrated in vacuo and the residue partitioned between water and ether. The water phase was adjusted to a pH of approx. 6 using 2 N HCl and the precipitate which formed was filtered off with suction. Drying afforded 1.7 g of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:42](O)=[O:43])[CH2:32][C:33]3[CH:38]=[C:37]([Br:39])[C:36]([OH:40])=[C:35]([Br:41])[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:34]=[C:35]([Br:41])[C:36]([OH:40])=[C:37]([Br:39])[CH:38]=3)[C:42]([N:11]3[CH2:12][CH2:13][CH:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)=[O:43])=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere 55 mg (0.30 mmol) 1-methyl-4-piperidin-4-yl-piperazine was added to a solution of 151 mg (0.25 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 104 mg (0.27 mmol) HATU and 47 μL (0.27 mmol) ethyldiisopropylamine in 5 mL DMF and the reaction mixture was stirred for 3 h at RT. The reaction solution was evaporated down i.vac. and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 80:20:2).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][N:8]=2)[C:4](=[O:19])[CH2:3]1.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](I)[CH:27]=1.CCN(CC)CC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:22]1[CH:27]=[C:26]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([N:5]3[CH2:6][C:2]([CH3:20])([CH3:1])[CH2:3][C:4]3=[O:19])=[N:8][CH:9]=2)[CH:25]=[N:24][CH:23]=1
Reactant: Fc1cncc(I)c1
Reactant: CC1(C)CC(=O)N(c2ccc(C#C[Si](C)(C)C)cn2)C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3cncc(F)c3)cn2)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 37, step 2) (80 mg, 0.28 mmol) was dissolved in DMF (1 ml). 3-Fluoro-5-iodopyridine (87 mg, 0.39 mmol, 1.4 equiv.), Et3N (85 mg, 117 μl, 0.84 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (10 mg, 14 μmol, 0.05 equiv.), triphenylphosphine (2 mg, 8.4 μmol, 0.03 equiv.) and copper(I)iodide (2 mg, 8.4 μmol, 0.03 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (300 μl, 0.3 mmol, 1.1 equiv.) was added dropwise in 20 minutes at 70° C. The reaction mixture was stirred for 30 minutes at 70° C. and evaporated with isolute to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→0:100. The desired 1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one (36 mg, 42% yield) was obtained as a white solid, MS: m/e=310.2 (M+H+).