Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:47].[K+].Cl>O1CCOCC1.O.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]>[OH:47][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: [OH-]
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2.0 g (6.11 mmol) of the compound of Example 15A were dissolved in 20 ml of dioxane and 2 ml of water, the mixture was degassed with argon, 280 mg (0.31 mmol) of tris(dibenzylideneacetone)dipalladium, 325 mg (0.76 mmol) of 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl and 1.37 g (24.5 mmol) of powdered potassium hydroxide were added and the mixture was stirred at 100° C. for 2 h. The reaction was then stirred into 50 ml of 1 M hydrochloric acid and extracted twice with in each case 50 ml of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in dichloromethane/pentane (9:1), the solid was filtered off and the filter cake was dried under high vacuum. This gave 980 mg (59% of theory) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7]Br.C(O)C>O>[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc(Cl)c(CBr)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)c(CC#N)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium cyanide (10.4 g) was added portionwise to a stirred solution of the above benzyl bromide (25 g) in a 2:1 mixture of ethanol and water (250 ml). The mixture was stirred for one hour at 50° C., poured into water and extracted with ether. The extract gave 2-chloro-5-methoxy-phenylacetonitrile (m.p. 62°-65° C.). 10M Boranemethylsulphide complex (11.3 ml) was added dropwise under nitrogen to a refluxing solution of the above phenylacetonitrile (18.6 g) in tetrahydrofuran (150 ml). The mixture was heated under reflux for 2 hours and dilute hydrochloric acid was added dropwise and the acidified mixture heated at 95° C. for one hour. The cooled mixture was washed with ether, basified with dilute sodium hydroxide solution and extracted with ether. The extract yielded 2 -chloro-5-methoxyphenethylamine as a yellow oil.
Reaction SMILES: [Mg].[F:2][C:3]([O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)=[C:4]([F:6])[F:5].[CH2:15]([O:17][Si:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])Cl)[CH3:16].C(=O)=O>CCCCCCC.C(#N)C.O1CCCC1>[F:2][C:3]([O:7][C:8]1[CH:9]=[C:10]([Si:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1)=[C:4]([F:6])[F:5]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: FC(F)=C(F)Oc1cccc(Br)c1
Agent: O=C=O
Agent: [Mg]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: CCO[Si](OCC)(OCC)c1cccc(OC(F)=C(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Magnesium (0.12 mol) and tetrahydrofuran were put in a 2-bulb flask purged with nitrogen. Then, 3-[(trifluorovinyl)oxy]bromobenzene prepared in (2) was dropped very slowly maintaining the reactor temperature at 0° C. The reactor was put in an ice bath to prevent the temperature from rising rapidly. After adding 3-[(trifluorovinyl)oxy]bromobenzene, the reactor was heated to room temperature, and reaction was performed for 2 hours. Then, triethoxychlorosilane (0.95 mol) was dropped keeping the reactor temperature at −48° C. with a constant temperature bath filled with dry ice and acetonitrile. The reaction mixture was mixed at room temperature for 24 hours. After the reaction was completed, excess heptane was added to remove the obtained salt and unreacted magnesium. The filtrate was removed by filtering with filter paper. Heptane remaining in the filtrate was removed using a vacuum evaporator and vacuum-distilled to obtain [3-[(trifluorovinyl)oxy]phenyl]triethoxysilane (PFCBSI) (yield: 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C@H:13]3[CH2:16][C@@H:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([CH:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CO[C@H]1C[C@@H](n2c([C@H](C)N)nc3ccc(F)cc32)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC1CC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccc(F)cc32)C1
Temperature: 90 °C
Yield: 51.6 %

Procedure:
To a solution of (S)-1-[6-fluoro-1-(cis-3-methoxycyclobutyl)-1H-benzoimidazol-2-yl]ethylamine (160 mg, 0.61 mmol) in IPA (1.5 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (150 mg, 0.61 mmol) and DIPEA (0.53 mL, 3.1 mmol) and the reaction mixture heated at 90° C. for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford 396 as a white solid (120 mg, 52%). 1H NMR 6 (DMSO-d6): 8.24 (1H, s), 8.14 (1H, s), 7.90 (1H, d, J=7.84 Hz), 7.63 (1H, dd, J=8.82, 5.11 Hz), 7.54 (1H, dd, J=9.80, 2.47 Hz), 7.11-7.02 (1H, m), 5.84 (1H, s), 4.99-4.89 (1H, m), 3.81-3.72 (1H, m), 3.23 (3H, s), 2.96-2.59 (4H, m), 1.64 (3H, d, J=6.70 Hz)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)nn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(Oc2ccc(Cl)nn2)cc1
Yield: 75.7 %

Procedure:
3-Chloro-6-(4-formylphenoxy)pyridazine (4.06 g, 17.3 mmol) and 200 mL of methanol were mixed, and after sodium borohydride (654 mg, 17.3 mmol) was added under cooling with ice and stirring, the mixture was stirred for 15 minutes. Water was added to the reaction mixture and methanol was distilled off. The residue was poured into water, which was extracted with ethyl acetate. The extracted solution was washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:2 v/v) to obtain 3.10 g (76%) of the title compound as a colorless oily product.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[Zn](CC)[CH2:14][CH3:15]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:14]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])[CH3:15]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCc1ccc(C(=O)O)cc1OC
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-3-methoxy-benzoic acid (2.49 g, 10.9 mmol) and Pd(dppf)Cl2 (158 mg, 0.216 mmol) were stirred in dioxane (25 mL) and Et2Zn (22 mL, 1 M in hexanes, 22 mmol) was added. The reaction mixture was heated at 70° C. for 1 h. The mixture was cooled to room temperature and was quenched with MeOH (1.1 mL). The solution was diluted with ethyl acetate (20 mL) and was washed with 1 N HCl (10 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness to give 4-ethyl-3-methoxybenzoic acid. ESI-MS m/z calc. 180.1, found 179.1 (M−1)−; Retention time: 1.77 minutes (3 min run).
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[C:3]([O:5]CC)=O.[NH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:31]=2)[CH2:25][CH2:24]1>O1CCCC1>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([NH:29][CH:26]2[CH2:25][CH2:24][CH:23]([O:22][CH2:21][CH2:20][NH:19][C:3](=[O:5])[C:2]([NH:8][C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)=[O:1])[CH2:28][CH2:27]2)=[CH:31][C:32]=1[C:39]([F:40])([F:41])[F:42])([O-:38])=[O:37]
Reactant: NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2n1
Solvent: C1CCOC1
Product: O=C(NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)C(=O)Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
The mixture of ethyl 2-oxo-2-(quinolin-2-ylamino)acetate (56 mg, 0.23 mmol) and N—(-4-(2-aminoethoxy)cyclohexyl)-4-nitro-3-(trifluoromethyl)benzenamine (80 mg, 0.23 mmol) in tetrahydrofuran (2 mL) was stirred overnight at room temperature and then concentrated under vacuum to give a residue, which was purified by HPLC to afford N1-(2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino) cyclohexyloxy)ethyl)-N2-(quinolin-2-yl)oxalamide as a yellow solid (58.8 mg, 46%). (ES, m/z): [M+H]+ 546.10; 1H NMR (400 MHz, CDCl3): δ 10.11 (br s, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.73 (t, J=7.2 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.65 (dd, J=8.8, 2.4 Hz, 1H), 4.48 (d, J=7.2 Hz, 1H), 3.68-3.58 (m, 4H), 3.42-3.36 (m, 2H), 2.19-2.10 (m, 4H), 1.48-1.38 (m, 2H), 1.34-1.24 (m, 2H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11](F)([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(C([O-])=O)CN>>[CH:1]1([N:6]2[CH2:12][CH:11]([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: NCC(F)C(=O)[O-]
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)C(=O)N2C

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with Compound 3 except that 2-fluoro-beta-alaninate was used as the starting material. The final product was purified on reversed phase HPLC as TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.87 (m, 11H) 1.91-2.08 (m, 3H) 2.18 (s, 3H) 2.79 (d, J=11.4 Hz, 2H) 3.24 (s, 3H) 3.61-3.83 (m, 3H) 3.94 (s, 3H) 4.77 (quin., J=8.3 Hz, 1H) 5.52 (qd, 1H) 7.47 (dd, J=1.8 Hz, 1H) 7.49 (s, 1H) 7.86 (s, 1H) 8.11 (d, J=7.8 Hz, 1H) 8.16 (s, 1H) 8.33 (d, J=8.34 Hz, 1H). [M+H] calc'd for C27H36FN7O3 526. found 526.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([O:17]C)=[O:16])[CH2:12][C:11]([F:14])([F:13])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-]>C1COCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=[O:16])[CH2:10][C:11]([F:14])([F:13])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)C1(c2ccc(C#N)cc2)CC(F)(F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(C(=O)O)CC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
To a stirred solution of Intermediate 314E (300 mg, 1.194 mmol) in THF (2 mL) and water (2 mL) was added LiOH (57.2 mg, 2.388 mmol) and the reaction mixture was stirred at RT for 12 h. The reaction mixture was concentrated to remove THF and the aq. layer was acidified to a pH of 2 with a 1.5N aq. solution of HCl and extracted with EtOAc (3×15 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 314F (230 mg, 81%) as a colorless semi-solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.39 (br. s., 1H), 7.91-7.79 (m, 2H), 7.62-7.49 (m, 2H), 3.50-3.25 (m, 2H), 3.11 (d, J=14.0 Hz, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([OH:14])=O)[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].C(O)(=O)C(O)=O.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH:48][C:49]([C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[N:53]([CH:60]([CH3:62])[CH3:61])[N:52]=2)=[O:50])[CH2:42][CH2:41]1>CN(C)C=O>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([NH:39][CH:40]4[CH2:41][CH2:42][N:43]([CH2:46][CH2:47][NH:48][C:49]([C:51]5[C:59]6[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=6)[N:53]([CH:60]([CH3:62])[CH3:61])[N:52]=5)=[O:50])[CH2:44][CH2:45]4)=[O:14])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: O=C(O)C12CC3CC(C1)C(O)C(C3)C2
Agent: O=C(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C34CC5CC(C3)C(O)C(C5)C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
A mixture of 0.50 g (2.55 mmol) of 4-hydroxy-1-adamantylcarboxylic acid and 0.44 g (2.71 mmol) of 1,1'-carbonyldiimidazole in 10 mL of dimethylformamide was stirred for 2 hours at ambient temperature. To this solution was dropwise added 0.90 g (2.75 mmol) of the product of Example 23 in 7 mL of dimethylformamide. The reaction was stirred for 18 hours and then concentrated in vacuo, diluted with dichloromethane and solids removed by filtration. The crude product was purified by chromatography (silica, 9:1 dichloromethane-methanol) to provide 0.71 g (55%) of the desired product as a foam. Further treatment of 500 mg of the product with 88 mg of oxalic acid in 15 mL of ethanol provided, upon concentration of the solution, 580 mg of the oxalate salt (LSN343032). 1H NMR (300 MHz, DMSO-d6) d 8.47 (t, 1H), 8.11 (d, 1H), 7.75 (d, 1H), 7.40 (t, 1H), 7.28 (d, 1H), 7.21 (t, 1H), 6.3 (br s, 3H), 5.04 (m, 1H), 3.74 (m, 1H), 3.59 (m, 3H), 3.40 (m, 2H), 3.13 (m, 2H), 2.95 (m, 2H), 1.95 (d, 2H), 1.69 (m, 13H), 1.47 (d, 6H), 1.25 (d, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10]([C:12]3[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=3)=[O:11])[S:7][CH:8]=2)[CH2:3][CH2:2]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=1>>[CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10]([C:12]3[C:17]([NH:18][C:21]4[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=3)=[O:11])[S:7][CH:8]=2)[CH2:2][CH2:3]1
Reactant: Fc1cncc(Br)c1
Reactant: Cc1ccc(N)c(C(=O)Nc2nc(C3CC3)cs2)n1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2nc(C3CC3)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-cyclopropyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 3-Bromo-5-fluoropyridine instead of 3-bromopyridine to yield the final compound as a yellow solid, MS (ISP): m/e=370.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O1C=[CH:29][CH:28]=[C:27]1P(C1OC=CC=1)C1OC=CC=1.CN1C(=O)CCC1.C([Sn](CCCC)(CCCC)CCCC)C=C>CCOC(C)=O>[CH2:29]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:28]=[CH2:27]
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Reactant: COC(=O)c1cc(Br)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCc1cc(C(=O)OC)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Reaction time: 64 h
Yield: 774.4 %

Procedure:
Methyl 3-bromo-5-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}benzoate (Intermediate 104, 300 mg, 0.73 mmol), tris(dibenzylidineacetone)dipalladium (0) (26 mg, 0.03 mmol), trifurylphosphine (14 mg, 0.06 mmol) were weighed into a flask and placed under argon. NMP (3 ml) was added, followed by the dropwise addition of allyltributyl tin (0.25 ml, 0.80 mmol). The mixture was stirred at 100° C. After 64 h, the mixture was diluted with EtOAc and washed sequentially with water followed by brine. The organic phase was dried over MgSO4 and concentrated to dryness. The crude material was purified by chromatography on silica gel using 25% EtOAc/hexanes to give 174 mg of the title product.
Reaction SMILES: [H-].[Na+:2].[CH3:3][C:4]([CH3:33])([CH3:32])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.Cl[C:35]1[CH:40]=[C:39]([C:41]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:42])[CH:38]=[CH:37][N:36]=1.[OH-].[Na+]>C1COCC1.C(OCC)C>[CH3:33][C:4]([CH3:32])([CH3:3])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([O-:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([O:31][C:37]3[CH:38]=[C:39]([C:41]([N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)=[O:42])[CH:40]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.[Na+:2]
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(O)CC2)CC1
Reactant: O=C(c1ccnc(Cl)c1)N1CCCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3cc(C(=O)N4CCCC4)ccn3)CC2)CC1
Temperature: 25 °C
Yield: 16 %

Procedure:
NaH (50 mg of a 60% oil dispersion, 1.14 mmol) was added in portions to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (128 mg, 0.287 mmol) and (2-chloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone from the previous step (300 mg, 1.42 mmol) in THF (5.0 mL) at 0° C. After 5 min the reaction was warmed to room temperature and then heated at 85° C. overnight. The reaction was cooled, aqueous NaOH (0.5 mL of a 1.0 N solution) was added and the reaction evaporated to dryness to give a solid residue. The solid was suspended in ethyl ether and sonicated for several minutes. The ether layer was removed to give an orange solid that was dried under vacuum and purified by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water). Fractions containing product were pooled and lyophilized to give the desired product as a colorless solid (30 mg, 16%). MS (m/z): 618.0 [M−H]−; HPLC retention time: 6.43 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH2:30]([OH:33])[C:31]#[CH:32]>[Cu]I>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:11]1[CH2:12][CH:9]([O:8][C:3]2[C:2]([C:32]#[C:31][CH2:30][OH:33])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: C#CCO
Reactant: Clc1nccnc1OC1CN(c2ccc3ccccc3n2)C1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCC#Cc1nccnc1OC1CN(c2ccc3ccccc3n2)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 600 %

Procedure:
A microwave tube was charged with 2-(3-((3-chloropyrazin-2-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.6; 150 mg, 0.5 mmol), triethylamine (100 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), Pd (PPh3)2Cl2 (35 mg, 0.05 mmol), prop-2-yn-1-ol (28 mg, 0.05 mmol). After several cycles of vacuum/purge with argon, 2 mL of DMF are added. The reaction mixture is then stirred at 110° C. under microwave for 2 hours. The reaction mixture is poured onto a solution of NaHCO3 and diluted with EtOAc and the layers are separated. The organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in petroleum ether) to give the title product (99 mg, 0.3 mmol, 61% yield) as white solid. ESI-MS (M+1): 333 calc. for C19H16N4O2 332.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+:12]>C(O)C>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+:12]
Reactant: O=C(O)c1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccccc1S
Yield: 61 %

Procedure:
To a solution of 15.4 g (0.1 mole) of 2-mercaptobenzoic acid in 20 ml of ethanol was added a solution of 3.8 g (95 moles) of sodium hydroxide in 10 ml of ethanol. The ethanol was removed on a rotary evaporator at 50 mm and the residual solid was triturated several times with ethanol to remove any unreacted 2-mercaptobenzoic acid. The washed solid was dried under vacuum overnight to yield sodium 2-mercaptobenzoate: 10.8 g (61% yield).
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])([O-:3])=[O:2]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=CC(=O)OCCCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.22 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Heptyl acrylate (9.5 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 3 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid heptyl 4,4-dinitropentanoate (4.8 g, yield: 83%).
Reaction SMILES: CCOCC.[CH:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])[CH2:8][CH2:7]1.[CH2:18]([OH:28])[C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[CH:25]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([O:16][CH2:15][C:14]#[C:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:6][CH2:7][CH3:8])=[O:28])[CH2:27][CH2:26]1
Reactant: CCCCCCCC#CCO
Reactant: O=C(Cl)CCCCCCC1CC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCC#CCOC(=O)CCCCCCC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 60 ml. anhydrous ether and 1.5 g. 7-cyclopropylheptanoyl chloride is added 1.2 g. 2-decyn-1-ol. The mixture is cooled to 0° and 0.8 ml. pyridine is added. The solution is stirred at room temperature for 1 day. The product is worked up using the procedure of Example 1C to yield 2-decynyl 7-cyclopropylheptanoate.