Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[CH:27]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)C1CCCCC1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
3-(5-(2-Chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (200 mg, 0.510 mmol) was suspended in pyridine (2 mL) and after 5 min, cyclohexanesulfonyl chloride (0.148 mL 1.021 mmol) was added. The mixture was stirred overnight. Additional cyclohexanesulfonyl chloride (0.100 mL 0.69 mmol) was added and stirred overnight. Silica gel was added the reaction mixture and concentrated. The crude product was chromatographed on silica gel eluting with DCM and 9:1 (EtOAc:MeOH). The product was chromatographed again with 9:1 hexane:EtOAc increasing to 1:1 gradient. The clean fractions were concentrated to yield the title compound of Step A (102 mg, 37% yield). A second reaction was run (46 mg, 17% yield) same scale and combined to yield the title compound of Step A (148 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H) 8.34 (d, J=5.5 Hz, 1H) 7.55 (td, J=7.6, 2.0 Hz, 2H) 7.14-7.38 (m, 3H) 6.65 (d, J=5.5 Hz, 1H) 3.68 (t, J=4.7 Hz, 4H) 3.52 (t, J=4.6 Hz, 4H) 2.79-3.04 (m, 1H) 2.01 (d, J=11.4 Hz, 2H) 1.69 (d, J=13.0 Hz, 3H) 1.47-1.63 (m, 2H) 1.26-1.42 (m, 3H) 0.84 (t, J=7.4 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([OH:11])[CH:10]=1)#[N:4].Br[CH2:16][O:17][CH3:18]>C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([O:11][CH2:16][O:17][CH3:18])[CH:10]=1)#[N:4]
Reactant: N#Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To sodium hydride (60% oil dispersion, 260 mg, 6.5 mmol), previously washed with hexanes, in THF (5 ml) was added dropwise at rt 5-cyano-2-nitro-phenol (978 mg, 5.96 mmol) in THF (10 ml). The solution turned bright orange and a large prepipitate formed. After stirring 15 min at rt bromomethylmethylether was added dropwise to this stirred slurry and the reaction was stirred for 18 h at rt. The yellow-colored mixture was then partitioned between t-butyl-O-methylether and water and the aqueous portion was extracted (×3) and washed with 5% sodium bicarbonate solution (×4) and brine. After drying (MgSO4), filtration and evaporation under reduced pressure afforded the title compound as a pale yellow solid (1.05 g, 85%).1H NMR(400 MHz, CDCl3) δ 7.84 (d, J=8.4 Hz, 1H), 7.66 (d, J=1.4 Hz 1H), 7.35 (dd, J=8.4 Hz J=1.5 Hz, 1H), 5.34 (s, 2H), 3.55 (s, 3H).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[C:16]([CH3:24])=[N:17][C:18]([CH3:23])=[C:19]([Cl:22])[C:20]=1[S-:21].[Na+]>>[Cl:14][C:15]1[C:16]([CH3:24])=[N:17][C:18]([CH3:23])=[C:19]([Cl:22])[C:20]=1[S:21][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Cc1nc(C)c(Cl)c([S-])c1Cl
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)c(C)nc(C)c2Cl)s1

Procedure:
Prepared according to the procedure described for example 18 from methyl 5-chloro-4-nitrothiophene-2-carboxylate (300 mg, 1.36 mmol) and sodium 3,5-dichloro-2,6-dimethylpyridine-4-thiolate (282 mg, 1.36 mmol) from above. The titled product was obtained as a solid (380 mg, 77% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.27 (1H, s), 3.83 (3H, s), 2.07 (3H, s), 2.05 (3H, s).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36][C:37]([F:47])([F:46])[O:38]C1C=CC(S)=CC=1>>[CH3:26][C:22]([S:21][C:18]1[S:17][C:16]([NH:15][C:14]([N:13]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][C:7]([O:38][C:37]([F:47])([F:46])[F:36])=[CH:6][CH:5]=2)=[O:28])=[N:20][CH:19]=1)([CH3:27])[C:23]([OH:25])=[O:24]
Reactant: FC(F)(F)Oc1ccc(S)cc1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccc(OC(F)(F)F)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 4-trifluoromethoxy-thiophenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl-].[NH4+]>[Fe].O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2ccoc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: Nc1cc(Br)cc2ccoc12

Procedure:
A mixture of 5-bromo-7-nitro-1-benzofuran (1.9 g, 7.9 mmol; obtained in Step 3), iron powder (2.3 g) methanol (20 mL), 1,4-dioxane (20 mL) and ammonium chloride (2.3 g dissolved in 10 mL of water), was refluxed overnight. The warm mixture was filtered through wetted Celite, which was further washed with hot methanol and the solvents were evaporated. The crude product was dissolved in hot ethanol/water (100 mL) and then water added so that product began to crystallize out. The product was collected by filtration, washed with water and dried in a vacuum oven. Yield: 1.1 g (65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.63 (s, 2H) 6.68 (d, J=2.0 Hz, 1H) 6.81 (d, J=2.3 Hz, 1H) 6.96 (d, J=2.0 Hz, 1H) 7.92 (d, J=2.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.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.O>[F:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([O:8][C@H:9]3[CH2:14][CH2:13][C@H:12]([C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)=[O:16])[CH2:11][CH2:10]3)=[N:6][CH:7]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)N1CCN(C(=O)C2CCC(Oc3ccc(Br)cn3)CC2)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: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4ccc(F)c(F)c4)cn3)CC2)CC1

Procedure:
A mixture of 120 mg (0.29 mmol) of [4-(5-bromo-pyridin-2-yloxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 69 mg (0.44 mmol) of 3,4-difluorophenylboronic acid, 34 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium, and 93 mg (0.88 mmol) of sodium carbonate, 1.5 ml of toluene and 0.5 ml of water was refluxed for 5 hr under Ar. The mixture was diluted with AcOEt, washed with saturated NaHCO3 solution and brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica eluting with cyclohexane and ethyl acetate=from 100:0 to 4:1. The combined product fractions were evaporated to dryness to yield 22 mg (17%) of the title compound. MS (m/e): 444.2 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]CC)=[O:7])#[N:2].CO.[OH-].[Na+]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)c1cccc(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(C(=O)O)c1
Temperature: 82 °C
Yield: 93 %

Procedure:
A mixture containing ethyl m-cyanobenzoate (87.5 g, 0.5 mol), methanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask, and heated to 82° C. with stirring by use of a mechanical stirrer. When the temperature became stable, a 20% aqueous solution of sodium hydroxide was added thereto so as to adjust the pH of the mixture at 9.0-9.3. Four hours after the reaction started, 20% sodium hydroxide (98.2 g) was added to the mixture. Liquid chromatographic analysis revealed that the reaction mixture contained 68.4 g of m-cyanobenzoic acid (yield 93%). The reaction mixture was cooled to 30° C., and hydrochloric acid was added thereto to lower the pH of the mixture to 3.1. The mixture was heated again to 82° C., and methanol was added thereto until the mixture dissolves. The mixture was cooled so as to crystallize, to thereby obtain 63.8 g of m-cyanobenzoic acid crystal (purity 96.8%, yield 84%).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>N.CO>[C:29]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:37])=[O:36])[CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cccc(-c2ccccc2)c1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Biphenyl-3-sulfonyl chloride (25 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (2.0 mg). MS m/z 405 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](C=O)[N:9]=1.Cl[CH2:17]Cl>>[Cl:7][C:8]1[N:9]=[CH:10][C:11]([CH:17]=[N:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:12][CH:13]=1
Reactant: ClCCl
Reactant: O=Cc1cccc(Cl)n1
Reactant: Nc1nccs1
Product: Clc1ccc(C=Nc2nccs2)cn1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
2-Aminothiazole (0.75 g, 7.5 mmol) was added to 2-chloropyridine-6-carboxaldehyde (1.0 g, 7.1 mmol) in dichloromethane (25 mL) at room temperature. The suspension was stirred an additional 10 min and then concentrated to dryness under vacuum. The resulting residue was heated to 90° C. on a rotary evaporator with a non-returning bump trap to facilitate water removal. After 30 min the resultant yellow solid was checked by NMR to verify reaction completion (by disappearence of the characteristic aldehyde peak at 10.10 ppm (s, 1H)). The title compound was obtained as a yellow solid (1.55 g) and used in the next step without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.OS(O)(=O)=O>>[F:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of HNO3 (0.55 mL) was added a mixture of (3-fluorophenyl)acetic acid (2 g, 13 mmol) and H2SO4 (4 mL) at 0° C. dropwise. After 2 hours, the mixture was diluted with ice-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give (3-fluoro-4-nitrophenyl)acetic acid. 1H-NMR (400 MHz, MeOD) δ ppm 8.2˜8.24 (m, 1H), 7.26˜7.3 (m, 2H), 4.06 (s, 2H).
Reaction SMILES: [H-].[Na+].O1C=CN=[C:4]1[C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1.[S:15]([O-:19])(=[O:18])(=[O:17])C.[O:20]1[CH2:24][C:23](=O)[N:22]=[C-:21]1>CN(C)C=O>[S:15]([C:11]1[CH:12]=[CH:13][C:8]([CH3:4])=[CH:9][CH:10]=1)([OH:19])(=[O:18])=[O:17].[O:20]1[CH2:24][CH2:23][NH:22][CH2:21]1
Reactant: Oc1ccc(-c2ncco2)cc1
Reactant: CS(=O)(=O)[O-]
Reactant: O=C1CO[C-]=N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1COCN1
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 40.7 %

Procedure:
A solution of 2-phenyl-3-(3,4-dimethoxyphenylethyl)-5-(hydroxymethyl)oxazolidine 1 (25.76 g, 0.075 m) in pyridine (30 ml) was cooled to 10° C. and p-toluenesulfonyl chloride (14.30 g, 0.075 m) was added over 30 minutes, keeping the temperature below 25° C. After stirring at 25° C. for 3 hours, a cold solution of K2CO3 (10.37 g, 0.075 m) in H2O (70 mL) was added and the mixture was extracted with CHCl3 (3×125 mL). The extracts were washed with H2O, dried and concentrated under reduced pressure below 50° C., initially using water aspiration and finally high vacuum to yield the tosylate 2 (35.83 g, 96%). Sodium hydride (3.36 g, 0.070 m, 50% dispersion in mineral oil) was added to a solution of p-(2-oxazolyl)phenol 3 (11.29 g, 0.070 m) prepared according to the procedure of H. Jones, et al. [J. Med. Chem., 21, 1100 (1978)] in dimethylformamide (125 mL) under nitrogen and the mixture was heated at 60° C. for 30 min. A solution of the tosylate 2 (35.83 g., 0.072 m) in dimethylformamide (110 mL) was added and the mixture was refluxed for 16 hours. The solvent was removed under reduced pressure, saturated Na2CO3 solution (210 mL) added and the mixture extracted with ethyl acetate (2×250 mL) and CHCl3 (2×250 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was heated on a steam bath for 1.5 hours with 1.5N HCl (685 mL), the resulting solution cooled, and extracted with ether (2×300 mL). The acid layer was rendered alkaline with 20% NaOH solution and extracted with CHCl3 (3×500 mL). The solvent was concentrated under reduced pressure and the residue was chromatographed on silica gel and eluted with 5% MeOH--CHCl3 saturated with NH3. The product was crystallized from acetonitrile to yield 4 (7.0 g, 25%, m.p. 122°-3° C.).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:28])=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][N:18]=1)C1C=CC=CC=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:28][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[OH:8])=[N:18][CH:19]=[N:20]2)=[C:25]([CH3:27])[CH:24]=1
Reactant: Cc1cc(Br)cc2ncnc(Nc3ccc(F)cc3OCc3ccccc3)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)cc2ncnc(Nc3ccc(F)cc3O)c12
Temperature: 0 °C

Procedure:
A mixture of 10 g (22.8 mmol) of N-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine (Intermediate V.1 step 1) and DCM is cooled to 0° C. and 34.2 ml (34.2 mmol) 1M BBr3 in DCM are added dropwise. After 6 h water is added carefully and the precipitate is filtered off, suspended in water and neutralized with 32% aq. ammonia solution. After 2 h the precipitate is filtered off and dried furnishing 2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:31])[CH2:14][CH2:15][C:16]1([OH:30])[CH2:21][CH:20]2[CH2:22][CH2:23][CH:17]1[CH:18]=[C:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:31])[CH2:14][CH2:15][C@:16]1([O:30][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C@H:20]2[CH2:22][CH2:23][C@@H:17]1[CH:18]=[C:19]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(CCCc1nc2ccccc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc3ccccc3[nH]2)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 150 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and 0.176 mL of NEt3 in 4 mL DCM 0.1 mL of isobutyrylchloride was added at 0° C. The yellow reaction mixture was stirred for 3 h at rt and then quenched with sat. aq. NaHCO3. The product was extracted with DCM, the organic phase was evaporated to dryness. The residue was dissolved in EtOAc, silica gel and a few drops of MeOH were added and the mixture was stirred vigorously for 5 h. The mixture was filtered, the filtrate evaporated and the residue purified by CC with EtOAc-MeOH (3:1) to yield 86 mg of pure rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as colorless foam.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-tert-butyl-phenyl acetic acid (5.0 g, 26.04 mmol) in DMF (30 mL) at rt were added Cs2CO3 (12.72 g, 39.06 mmol) and benzyl bromide (4.89 g, 28.6 mmol). The reaction mixture was stirred for overnight at room temperature and then the reaction mixture was heated at 100° C. for 1 h and cool to rt. The solvent was removed under reduced pressure and poured into cold 1 N HCl (50 mL). The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure, dried under vacuum. (4-tert-butyl-phenyl)acetic acid benzyl ester was obtained as a yellowish liquid. (5.96 g, 81%): 1H NMR (300 MHz, CDCl3): δ 7.37-7.33 (m, 7H), 7.25 (dd, J=5.4, 13.2 Hz, 2H), 5.14 (s, 2H), 3.65 (s, 2H), 1.32 (s, 9H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:11])[CH3:10]>>[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: NCc1ccccc1
Reactant: CC(=O)O
Product: CC(=O)NCc1ccccc1
Temperature: 115 °C

Procedure:
Benzylamine (1 mL) and acetic acid (20 mL) may be mixed together. The mixture may be heated at 115° C. for 17 hours. The excess acetic acid may be distilled from the reaction mixture using a rotary evaporator. The product may be crystallized from toluene. The mixture may be cooled to 0° C. and then filtered.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].Cl[C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:11]=[CH:10][N:9]=1>O.O1CCOCC1>[OH:6][CH2:5][CH2:4][S:3][C:8]1[C:13]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:12][CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2SCCO)CC1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
Sodium hydroxide (0.92 g, 23 mmol) was dissolved in water (9 mL) and dioxane (15 mL). 2-Mercaptoethanol (0.54 mL, 7.7 mmol) was added while stirring and 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (2.3 g, 7.7 mmol, from Example 52, step 1) in dioxane (10 mL) was added. The reaction mixture was heated at 100° C. for 22 h. After cooling to room temperature, it was extracted with EtOAc. The organic layer was dried (K2CO3) and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel using hexane/ EtOAc (1:1) as eluent to give 1.71 g (65%) of the title compound as an orange oil. MS m/z 341 (M+H)+.
Reaction SMILES: [C:1]([C@H:4]1[CH2:10][C@H:9]2[C@:7]([CH3:11])([O:8]2)[C@H:6]([OH:12])[CH2:5]1)([CH3:3])=[CH2:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C)C=O>[C:21]([Si:18]([O:12][C@@H:6]1[CH2:5][C@@H:4]([C:1]([CH3:3])=[CH2:2])[CH2:10][C@H:9]2[C@:7]1([CH3:11])[O:8]2)([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(C)[C@@H]1C[C@@H](O)[C@@]2(C)O[C@H]2C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)[C@H]1C[C@@H]2O[C@]2(C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
The compound of Example 16A (11.0 g, 65 mmol) in 66 mL of dimethylformamide was treated with 5.37 g (1.2 equivalents) of imidazole followed by 11.2 g (1.14 equivalents) of tert-butyldimethylsilyl chloride. The reaction was stirred for 20 hours at ambient temperature. The reaction solution was mixed with 200 mL of water and the resulting layers were separated. The aqueous layer was extracted three times with 120 mL each of tert-butyl methyl ether. The organic layers were combined, and washed twice with 125 mL each of 10% aqueous NaCl. The tert-butyl methyl ether solution was dried over MgSO4 then filtered and concentrated in vacuo. The product was purified on 2.00 kg of Silica Gel 60 with a gradient of hexanes:tert-butyl methyl ether from 19:1 (8 L) to 9:1 (4 L) to afford 16.2 the titled compound (16.2 g, 91 %).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-])=[O:5].C1N=CN(C(N2C=NC=C2)=O)C=1.O/[N:23]=[C:24](\[NH2:32])/[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([C:24]1[N:32]=[C:4]([CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[O:5][N:23]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CCC(=O)[O-]
Reactant: N/C(Cc1ccccc1)=N\O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Butanedioic acid, monomethyl ester (4.0 g, 30.3 mmole) and CDI (5.40 g, 33.3 mmole) were dissolved in anhydrous DMF (15 ml) and stirred at room temperature for 3 hours. (1Z)-N′-hydroxy-2-phenylethanimidamide (5.0 g, 33.3 mmole) was added to above solution and the mixture was stirred at 90° C. for 20 hours. The reaction mixture was concentrated and the residue was diluted with water and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (elution with 1:3 ethyl acetate:hexane) to give the desired product as light yellowish oil (5.2 g, 70% yield). LCMS calculated for C13H15N2O3 (M+H): 247.1. found: 247.1.