Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1([C:5]2([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH2:7][O:6]2)[CH2:4][CH2:3]1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1([C:5]([OH:6])([CH2:7][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(OCC2(C3(Cl)CC3)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC(COc1ccc(Cl)cc1)(Cn1cncn1)C1(Cl)CC1
Yield: 37.9 %

Procedure:
A solution 27.9 g (0.11 mol) of 2-(1-chlorocyclopropyl)-2-(4-chloro-phenoxymethyl)-oxirane in 50 ml of acetonitrile is added dropwise under a nitrogen atmosphere to a mixture of 29 g (0.42 mol) of 1,2,4-triazole, 19 g (0.14 mol) of potassium carbonate and 100 ml bf acetonitrile, and the reaction mixture is boiled under reflux. After completion of the addition, the mixture is heated for a further 8 hours under reflux. The mixture is then filtered off from the solid residue with suction and the filtrate is concentrated under reduced pressure. The remaining residue is taken up in ethyl acetate. The resultant solution is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The product thus obtained is purified chromatographically through silica gel using chloroform/ethanol=97:3 as eluent. In this manner, 13.7 g (39% of theory) of 2-(1-chlorocyclopropyl)-1-(4-chlorophenoxy)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of an oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([F:18])([F:17])[F:16].[CH3:20][C:21]1([CH3:42])[O:25][CH:24]([C:26]2[CH:35]=[C:34]3[C:29]([C:30]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][CH2:32][O:33]3)=[CH:28][CH:27]=2)[CH2:23][O:22]1.C(N(CC)CC)C>ClCCl>[CH3:20][C:21]1([CH3:42])[O:25][CH:24]([C:26]2[CH:27]=[CH:28][C:29]3[C:30]4([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH:31]([C:3]([C:4]5[O:8][N:7]=[C:6]([C:9]6[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=6)[C:5]=5[C:15]([F:18])([F:17])[F:16])=[N:2][O:1]4)[CH2:32][O:33][C:34]=3[CH:35]=2)[CH2:23][O:22]1
Reactant: CC1(C)OCC(c2ccc3c(c2)OCC=C3N2CCOCC2)O1
Reactant: ON=C(Cl)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC(c2ccc3c(c2)OCC2C(c4onc(-c5ccccc5)c4C(F)(F)F)=NOC32N2CCOCC2)O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of the N-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazole-5-carbimidoyl chloride (Intermediate 1-12, 0.340 g, 1.170 mmol) in dichloromethane (3.5 mL) was added 4-(7-(2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromen-4-yl)morpholine (Preparation 60C, 0.473 M in dichloromethane) (2.47 mL, 1.17 mmol). The reaction mixture was cooled to 0° C., and triethylamine (0.324 mL, 2.34 mmol) was added dropwise over 10 min. The ice-bath was removed, and the resulting cloudy solution was stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (25 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude product as an orange oil. The compound was purified by flash silica gel chromatography using a mixture of ethyl acetate and hexane (5%-12%-20%) to give 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazole (0.080 g, 0.140 mmol, 12% yield) as a yellow solid. The product had an HPLC ret. time=3.25 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=572.1.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=4)[N:13](COCC[Si](C)(C)C)[C:11]=3[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F-].[Cs+]>CC(C)=O>[N:1]1([C:7]2[N:8]=[C:9]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[C:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=4)[NH:13][C:11]=3[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(-c2cccc(O)c2)cc2c(N3CCOCC3)nc(N3CCOCC3)nc21
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)=O
Product: Oc1cccc(-c2cc3c(N4CCOCC4)nc(N4CCOCC4)nc3[nH]2)c1
Temperature: 40 °C
Yield: 67.2 %

Procedure:
To a round bottom flask were added 3-[2,4-di-morpholin-4-yl-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (8.1 mg, 0.016 mmol) and cesium fluoride (72.4 mg, 0.477 mmol, 30 equiv) followed by acetone (6 mL). The reaction was heated for 6 hours at 40° C. The reaction was then quenched by adding aqueous saturated ammonium chloride solution (10 mL). Acetone was removed under reduced pressure and the aqueous phase was extracted with DCM (3×15 mL). The combined organic phase was removed under reduced pressure and the crude product was directly purified using reverse phase preparative HPLC (5% to 70% H2O/MeCN, with n-propanol in water as modifier) to obtain the desired product as a white solid (4.1 mg, 67.8% yield). LC/MS analysis method 7, mass (ES+) m/z 382.4, retention time 1.05 min 1HNMR (CDCl3): δ 10.15 (1H, brs), 7.15 (1H, t), 7.02 (1H, d), 6.67 (1H, brs), 6.65 (2H, m), 6.52 (1H, s), 3.82 ppm (8H, dt), 3.64 (8H, m)
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([OH:3])=[O:2].[OH-].[Na+].Cl>CO.O>[C:1]([CH2:4][CH2:5][N:6]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(OCCCN(CCC(=O)O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCN(CCCOc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 23 h
Yield: 65.9 %

Procedure:
Methyl 4-[3-[N-(2-carboxyethyl)-N-(4-chlorophenyl)amino]propoxy]benzoate (1.37 g) was dissolved in methanol (20 ml) and thereto was added a solution of sodium hyroxide (0.42 g) in water (4 ml), and the mixture was heated with stirring at 60° C. for 23 hours. After the reaction mixture was cooled, a neutralizing amount of conc. hydrochloric acid was added thereto, then, concentrated under reduced pressure. The residue was allowed to stand in water (pH; about 4.5) and the resulting crystal was collected by filtration, washed with water, and recrystallized from about 30 % aqueous methanol to give the desired product (0.87 g). mp. 132°-133° C.
Reaction SMILES: CO[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].C(O)(=[O:18])C>Br>[N+:13]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:3]=1)([O-:15])=[O:14]
Reactant: COc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: CC(=O)O
Agent: Br
Product: O=[N+]([O-])c1ccc(O)c(C(F)(F)F)c1

Procedure:
A solution of 24.73 g (110.7 mmol) 6-methoxy-5-nitrobenzotrifluoride in 260 ml acetic acid and 130 ml of aqueous HBr solution (62%) was heated to reflux for 96 h, cooled down, evaporated and taken up in aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over sodium sulfate, and evaporated to dryness to yield 19.27 g of the title compound as yellow solid of mp. 103–104° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]4[N:26]=[C:25]([CH2:27][CH2:28][CH:29]5[NH:35][C:34](=O)[CH2:33][CH2:32][CH2:31][CH2:30]5)[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]4[N:26]=[C:25]([CH2:27][CH2:28][CH:29]5[NH:35][C:34](=[S:46])[CH2:33][CH2:32][CH2:31][CH2:30]5)[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=O)N5)nc4c3)cc2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=S)N5)nc4c3)cc2)CC1
Yield: 93 %

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 170 mg of 7-(2-{6-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one (compound B7) and 142 mg of Lawesson's reagent at 100° C. for 2.5 hours in 20 ml of dioxane. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 163 mg of the title compound as a waxy solid. ESI-MS: 527.3 (MH+). TLC: Rf=0.34 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(COC)OC>[C:1]([Si:5]([CH3:36])([CH3:37])[O:6][C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:20]([Cl:34])=[CH:21][C:22]([C:40]4[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=4)=[CH:23][C:24]=3[Cl:25])[C:14]2=[O:35])[CH2:11][CH2:12]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)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: COCCOC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(-c4cccnc4)cc3Cl)C2=O)CC1

Procedure:
Using the method of Example 81 and trifluoro-methanesulfonic acid 4-{1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-3-yl methyl}-3,5-dichloro-phenyl ester (Preparation 74) (0.204 g, 0.337 mmol), 3-pyridineboronic acid (0.124 g, 1.01 mmol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.0337 mmol), dimethoxyethane (5 mL) and sodium carbonate (2M, 0.9 mL) gives the title compound. Purify the crude material over silica gel (3/1 hexane in ethyl acetate to ethyl acetate) to yield 0.027 g (15%) of the title compound: mass spectrum (m/z): 535(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17].[CH3:18]O>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:18])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17]
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Reactant: CO
Product: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1

Procedure:
Synthesized in an analogous fashion as methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate, but MeOH from step 1 was removed and EtOH was used for step 2. MS (ESI) m/z: Calculated: 315.0; Observed: 316.0 (M++1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH:2]1[CH2:3][CH2:4][C:5]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[O:8]2)[CH2:6][CH2:7]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC2(CCC(O)CC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OC(=O)c1ccccc12
Yield: 88 %

Procedure:
At r.t to the mixture of 4′-hydroxy-3H-spiro[2-benzofuran-1,1′-cyclohexan]-3-one (100 mg, 0.46 mmol), triethylamine (192 μL, 1.37 mmol) in methylene chloride (2 mL) was added methanesulfonyl chloride (42.6 μL, 0.55 mmol) with stirring. The mixture was stirred at r.t. overnight, then quenched with water and extracted with ethyl acetate. The extract was washed with water, then brine once; and dried over anhydrous sodium sulfate. After removal of solid, the solution was concentrated to yield 120 mg of 3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl methanesulfonate (yield: 88%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:23][C:12]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pd].CO>[C:19]([O:18][C:16]([N:14]1[CH2:13][C:12]2([CH2:23][N:10]([C:7]3[CH:8]=[N:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:15]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc(N)nc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
In a 500 mL pear-shaped flask, tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4.54 g, 14.2 mmol) and 10% Pd/C (662 mg, 6.22 mmol) were combined with ethyl acetate (150 ml) and methanol (50 ml) to give a black suspension. The mixture was evacuated and filled with H2 twice, then stirred overnight at 25° C. under balloon pressure of H2. The mixture was filtered over celite and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo to give a purple oily solid. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 4% MeOH in DCM) to afford 1.29 g (31%) of the title compound as an impure dark red solid. (M+H)+=291 m/e.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:20])=[O:21])[CH:9]=2)[NH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: OB(O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccco3)c2c1
Yield: 32.5 %

Procedure:
N-(3-Furan-2-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 47 from 1 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 330 mg of 2-furanboronic acid, 40 ml of dimethylformamide, 3.2 ml of a saturated aqueous sodium hydrogencarbonate solution and 42.7 mg of tetrakis(triphenylphosphine)palladium[0]. 200 mg of N-(3-furan-2-yl-1 H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 248° C. (analysis C18H15N3O5S2 % calculated C, 51.79; H, 3.62; N, 10.07; O, 19.16; S, 15.36. % found C, 51.95; H, 3.75; N, 9.68; S, 14.75).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)nc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a solution of 2,5-dibromopyridine (10 g, 42.55 mmol, 1.00 equiv) in tetrahydrofuran (400 mL) under nitrogen at −78° C. was added dropwise n-BuLi (19 mL, 2.4 M in THF). After 1 h at −78° C., a solution of tert-butyl 4-oxopiperidine-1-carboxylate (9.5 g, 47.74 mmol, 1.12 equiv) in tetrahydrofuran (100 mL) was added dropwise. The resulting mixture was stirred for an additional hour at −78° C. The reaction was then warmed to −30° C. and carefully quenched by the addition of 300 mL of water. The resulting mixture was extracted with 3×200 mL of ethyl acetate and the combined organic layers were washed with 1×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:3) as eluent to yield 5 g (33%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=1[CH2:6][N:7]1[CH:12]=[C:11]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:10]=[CH:9][C:8]1=[O:14]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Yield: 100 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared from 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 16.4 mmol, 5.20 g, Example 1 Step 2) and 4-methoxyphenylboronic acid (1.5 eq, 25.0 mmol, 3.80 g) according to the procedure described for Example 1 Step 3. The crude product was purified by flash chromatography over silica gel using CH2Cl2/AcOEt 95/5 to 80/20 as eluent to afford 1-(2-fluoro-4-chlorobenzyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (16.4 mmol, 5.64 g, 100%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:48][C:49]([CH3:69])=[CH:50][CH2:51][CH2:52]/[C:53](/[CH3:68])=[CH:54]/[CH2:55][CH2:56]/[C:57](/[CH3:67])=[CH:58]/[CH2:59][S:60][CH2:61][C@H:62]([NH2:66])[C:63]([OH:65])=[O:64]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH:66][C@@H:62]([CH2:61][S:60][CH2:59]/[CH:58]=[C:57](\[CH3:67])/[CH2:56][CH2:55]/[CH:54]=[C:53](\[CH3:68])/[CH2:52][CH2:51][CH:50]=[C:49]([CH3:69])[CH3:48])[C:63]([OH:65])=[O:64])=[O:14]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)Cc1c[nH]c2ccc(O)cc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 24 mL vial, 5-hydroxyl indole-3-acetic acid (191 mg, 1.0 mmol), HATU (380 mg, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in THF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. THF was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with water (50 mL) and brain (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (210 mg, 42%) to yield Compound N-39. 1H-NMR (500 MHz, CD3OD): δ 1.49 (s, 9H), 1.56 (S, 3H), 1.85-1.98 (m, 6H), 2.62 (dd, J=8.0, 14.0 Hz, 1H), 2.80 (dd, J=4.5, 14.0 Hz, 1H), 2.88 (dd, J=7.0, 13.0 Hz, 1H), 2.98 (dd, J=8.5, 13.0 Hz, 1H), 3.55 (dd, J=6.5, 22.5 Hz, 2H), 4.49 (dd, J=5.0, 8.0 Hz, 1H), 4.98 (bs, 2H), 6.57 (d, J=8.5 Hz, 1H), 6.84 (s, 1H), 7.07 (d, J=6.5 Hz, 2H). 13C-NMR (125 MHz, CD3OD): δ 16.2, 17.8, 26.0, 27.3, 27.4, 27.8, 28.8, 30.2, 33.3, 33.8, 40.7, 40.9, 53.4, 103.7, 108.2, 112.7, 112.8, 121.5, 125.2, 125.5, 125.8, 129.3, 132.1, 133.0, 136.2, 140.5, 151.5, 173.9, 174.9; ES-MS: mass calcd for Chemical Formula: C28H38N2O4S 498.3 (M+). Found (M+1) m/z 499.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: Clc1ccnc2ccccc12
Product: O=C(O)c1cccc2cc(Oc3ccnc4ccccc34)ccc12
Yield: 51.7 %

Procedure:
The title compound (1.24 g, 52% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4-chloroquinoline (1.49 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 316 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[S:37][CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[C:33]5[S:37][CH3:38])[CH:27]=4)[CH2:23][C:22](=[O:39])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nccn1-c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (4′-fluoro-3-{3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K87) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (104 mg).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[N:15][C:14]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[CH:13][N:12]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[CH3:22][O:21][CH2:20][CH2:19][N:17]([CH3:18])[C:14]1[CH:13]=[N:12][C:11]([NH2:10])=[CH:16][N:15]=1
Reactant: COCCN(C)c1cnc(NC(=O)OCc2ccccc2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(C)c1cnc(N)cn1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
The above carbamic acid benzyl ester (316 mg, 1.0 mmol) was suspended in a mixture of methanol (25 mL) and THF (5 mL) containing 5% palladium on carbon (60 mg). The solution was placed under an atmosphere of hydrogen (hydrogen balloon) for one hour. The mixture was filtered through a thin layer of Celite and the solution was evaporated to give a green oil as N-(2-methoxyethyl)-N-methylpyrazine-2,5-diamine (180 mg, 100%). LCMS calcd for C8H14N4O (m/e) 182, obsd 183.1 (M+H).