Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc([N+](=O)[O-])cc43)c2cc1OC
Yield: 91 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 91% yield from 6-nitro-indoline (1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 275° C. (dec); GC-MS: 352 (M+); anal. RP18-HPLC RT: 4.30 min.).
Reaction SMILES: [CH:1]([C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[CH2:10]1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>>[C:31]1(=[O:32])[N:27]([O:15][CH2:14][C@H:13]2[O:12][C@@H:11]([N:16]3[C:25]4[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=4[N:18]=[CH:17]3)[CH2:10][C@@H:9]2[CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:28](=[O:37])[C:29]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](C=Cc2ccccc2)[C@@H](CO)O1
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](C=Cc2ccccc2)[C@@H](CON2C(=O)c3ccccc3C2=O)O1
Yield: 76 %

Procedure:
2',3'-Dideoxy-3'-C-styryladenosine underwent standard Mitsunobu reaction with N-hydroxyphthalimide to provide 2',3'-dideoxy-5'-O-phthalimido-3'-C-styryladenosine in 76% yield with a melting point of 145°-147° C. Anal.: C26H22N6O4.1/4 H2O Calcd.: C% 64.12; H% 4.65; N% 17.25; Found: C% 63.96; H% 4.58; N% 17.51.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:13])=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>O1CCCC1>[SH:15][C:14]1[NH:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]=2[N:13]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1cccc(N)c1N
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc2[nH]c(S)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.2 %

Procedure:
To a solution of 3-ethoxycarbonyl-1,2-phenylenediamine (790 mg) in tetrahydrofuran (10 ml) was added 1,1′-thiocarbonyldiimidazole (1.02 g) in ice water bath and the mixture was stirred for 20 hours at ambient temperature. The reaction solvent was concentrated in vacuo and the residue was washed with chloroform and collected by vacuum filtration to give ethyl 2-mercapto-1H-benzimidazole-4-carboxylate (665 mg).
Reaction SMILES: FC1C=C(C2C=CC=CC=2)C(S(N)(=O)=O)=CC=1S(N)(=O)=O.C(N)C1OC=CC=1.C([NH:35][C:36]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:38][C:37]=1[S:52]([NH2:55])(=[O:54])=[O:53])C1OC=CC=1.FC(F)(F)C(O)=O>C(O)(=O)C>[NH2:35][C:36]1[CH:41]=[C:40]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:39]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:38][C:37]=1[S:52]([NH2:55])(=[O:54])=[O:53]
Reactant: NS(=O)(=O)c1cc(S(N)(=O)=O)c(-c2ccccc2)cc1NCc1ccco1
Agent: NCc1ccco1
Agent: NS(=O)(=O)c1cc(S(N)(=O)=O)c(-c2ccccc2)cc1F
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-c2ccccc2)c(S(N)(=O)=O)cc1S(N)(=O)=O
Temperature: 0 °C

Procedure:
1.68 G. of 4-fluoro-6-phenyl-1,3-benzenedisulfonamide and 3.1 g. of furfurylamine is heated to 95° C. for 1 1/2 hours. This mixture is cooled in ice, diluted with 30 ml. of ice water and acidified with acetic acid affording a brown precipitate of 4-furfurylamino-6-phenyl-1,3-benzenedisulfonamide which is collected by filtration and dried affording 2.14 g. of material with a m.p. of 168° to 171° C. This material is stirred with 22 ml. of trifluoroacetic acid at room temperature for 1 hour. The trifluoroacetic acid is removed in vacuo and the residue treated with 100 ml. of water and extracted with ethylacetate. The ethylacetate is dried and evaporated to dryness in vacuo affording 2.6 g. of material which is purified on a chromatography column of silica gel affording 1.6 g. of a light foam. This material is crystallized from water affording 4-amino-6-phenyl-1,3-benzenedisulfonamide with a m.p. of 197° to 198° C.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:18]([O:19]CC3C=CC=CC=3)[C@@H:17]([CH2:27][O:28][C@H:29]3[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@@H:30]3[OH:31])[O:16][C@@H:15]([O:40][CH2:41][CH2:42][NH:43]C(=O)OCC3C=CC=CC=3)[C@@H:14]2[OH:54])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]>O.[Pd]>[C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:27][O:28][C@H:29]3[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@@H:30]3[OH:31])[O:16][C@@H:15]([O:40][CH2:41][CH2:42][NH2:43])[C@@H:14]2[OH:54])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=C(NCCO[C@@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@H]1O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: NCCO[C@@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of benzyl (2-{[α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-4-O-benzyl-β-D-glucopyranosyl]oxy}ethyl)carbamate (0.96 g, 1.244 mmol) and Pd/C (124 mmol) in water (20 mL) was allowed to stir under a balloon of H2 at rt for 16 h. The catalyst was filtered off and washed with H2O (3×10 mL). The Titrate was concentrated to give the title compound. UPLC Method B: calculated for C20H37NO16 547.21, observed m/e: 548.29 [M+1]; Rt=0.87 min. 1H NMR (D2O) δ 5.20-5.19 (1H, m), 4.88-4.87 (1H, m), 4.51-4.49 (1H, m), 4.05 (1H, m), 4.00-3.90 (4H, m), 3.85-3.70 (9H, m), 3.70-3.60 (5H, m), 3.40-3.30 (1H, m), 3.05-3.00 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[C:30]1([C:36]2[N:37]=[N:38][S:39][C:40]=2[C:41](O)=[O:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:41]([C:40]2[S:39][N:38]=[N:37][C:36]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:42])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1snnc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3snnc3-c3ccccc3)c2F)c1
Reaction time: 8 h
Yield: 37.5 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 4-phenyl-1,2,3-thiadiazole-5-carboxylic acid (16.57 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.015 g, 35%) as a tan solid. 1H NMR (400 MHz, Acetone-d6): 6 ppm 8.51 (br. s., 1H), 7.80-7.90 (m, 2H), 7.63 (t, 1H), 7.45-7.51 (m, 3H), 7.38-7.45 (m, 2H), 7.33-7.38 (m, 2H), 4.65 (d, 2H). LCMS m/z 498.9 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1Cl)(=[O:4])=[O:3].[C:16]([C:20]1[O:24][N:23]=[C:22]([OH:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:16]([C:20]1[O:24][N:23]([C:6]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])[C:22](=[O:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: CS(=O)(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(=O)n(-c2ccc(S(C)(=O)=O)cc2S(C)(=O)=O)o1
Reaction time: 4 h
Yield: 61.2 %

Procedure:
After mixing 1 g of 2,4-bismethanesulfonylchlorobenzene, 1 g of 5-t-butyl-3-hydroxyisoxazole, 1 g of potassium carbonate, and 8 ml of dimethyl sulfoxide, the reaction was performed for 4 hours at 80° C. After the reaction was over, the reaction mixture obtained was poured into water and extracted with ethyl acetate. Then, the ethyl acetate was distilled off from the extract under reduced pressure and the residue thus formed was recrystallized from a mixture of water and methanol to provide 0.85 g of the desired compound with a yield of 61.2%. The melting point thereof was 166° C. to 168° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=[O:22])C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:10]2[C:9]([CH3:11])([CH3:12])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[C:4]([CH:14]=[O:22])[CH:3]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: Cc1cc(F)c2c(c1)B(O)OC2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2cc(C=O)cc(F)c21
Temperature: 25 °C
Yield: 894.3 %

Procedure:
To a solution of 4-fluoro-3,3,6-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (1.94 g, 10 mmol) in CCl4 (19.4 mL) at rt was added benzoyl peroxide (0.24 g, 1.0 mmol) and NBS (3.56 g, 20 mmol). The reaction mixture was refluxed for 16 h, cooled to rt and treated with Na2CO3. The aqueous layer was acidified with 3 N HCl to pH of 3 and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (2:1) to give 4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (1.86 g, 89.4% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (d, J=1.6 Hz, 1H), 9.53 (s, 1H), 8.09 (s, 1H), 7.77 (m, 1H), 1.55 (d, J=5.6 Hz, 6H) ppm.
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11]O)[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:18]>C(OCC)C>[Br:18][CH2:11][C:8]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=1[Cl:10]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Solvent: CCOCC
Product: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of 9.2 g (35.7 mmoles) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 11.6 g (42.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 10.0 g (yield: 87.3%) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyra-zole.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=1.[OH-].[K+].C(O)C.Cl>O>[F:1][C:2]([F:30])([F:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A mixture of 6.0 g. of ethyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate, 4.0 g. of potassium hydroxide and 50 ml. of ethanol is stirred at 80° C. for 4 hours. The mixture is diluted with water and adjusted to pH 5.5 by the addition of concentrated hydrochloric acid. Cooling and filtration affords a solid which is recrystallized from acetone to yield the product as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1)C(=O)C>Cl>[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)N(CCCN)c1ccc(C2=NNC(=O)CC2C)cc1
Agent: Cl
Product: CC1CC(=O)NN=C1c1ccc(NCCCN)cc1

Procedure:
2.8 g (8.3 mmol) of 6-[4-[N-(3-aminopropyl)acetamido]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone hydrochloride are boiled under reflux in 30 ml of 2N hydrochloric acid for 2 hours. The solution is concentrated by evaporation under vacuum and the residue is taken up with 20 ml of saturated potassium carbonate. After this residue has been extracted twice with 30 ml portions of isopropanol, the combined organic phases are dried over potassium carbonate and concentrated by evaporation under vacuum. The residue is chromatographically purified with ethyl acetate/ethanol/conc. ammonia (15:10:2) on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([OH:13])=O)=[C:4]([CH3:19])[CH:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][NH2:27].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:27][O:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)=[O:13])=[C:4]([CH3:19])[CH:3]=1
Reactant: NOC1CCCCO1
Reactant: Cc1cc(Br)ccc1CCC(C)(C(=O)O)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1CCC(C)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
4-(4-Bromo-2-methylphenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (3.28 g, 9.39 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (2.19 g, 18.7 mmol), 1-hydroxy benzotriazole monohydrate (3.68 g, 24 mmol), triethylamine (3.35 mL, 24 mmol) and (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.59 g, 18.7 mmol) were combined followed by the addition 60 mL of dichloromethane. The reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with 20 mL of dichloromethane and 60 mL of water. The aqueous layer was extracted with dichloromethane (2×40 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel. Silica chromatography (30% ethyl acetate 70% heptane for 10 minutes, then 30% ethyl acetate 70% heptane to 60% ethyl acetate 40% heptane for 40 minutes) afforded the title compound as a white solid (2.11 g, 50.1%).
Reaction SMILES: [CH:1]([Li])([CH3:3])[CH3:2].Br[C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[CH:7]=1.CO>C1COCC1.O1CCOCC1.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:1]([C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: [Li]C(C)C
Reactant: Cc1cc(Br)c2cccc(O)c2n1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(C)C)c2cccc(O)c2n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of ZnCl2 (0.29 g, 2.1 mmol) in anhydrous THF (2.1 mL) was added dropwise to a stirred solution of isopropyllithium (0.7 M in pentane, 1.6 mL, 1.1 mmol) at −92° C. The reaction mixture was allowed to reach room temperature and was than transferred to a suspension of dichloro(1,2-bis(diphenylphosphino)ethane)palladium (II) (36 mg, 0.063 mmol) and 4-bromo-2-methyl-quinolin-8-ol (75 mg, 0.32 mmol) in anhydrous dioxane (1.1 mL). After stirring for 2 h at 80° C., the reaction mixture was cooled to room temperature, MeOH (5 mL) was added and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/MeOH 20:1) to give the title compound. MS (m/z): 202.2 [M+H+].
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH2:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:18](=[O:19])[NH2:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=1)=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of Boc-tyrosine amide (0.960 g, 3.4 mmol) in pyridine (10 mL) stirred under argon was added acetic anhydride (808 μL, 8.56 mmol). After 18 hrs of stirring the solvent was evaporated, the residue taken in EtOAc (30 mL) washed with 5% aqueous citric acid (3×20 mL) and brine. The solution was dried (MgSO4) and the solvent evaporated to yield 949 mg (86%) of the title compound.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1ccncc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nc(-c2ccncc2)[nH]c1-c1ccc(C)cc1
Yield: 395.1 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (10.5 g) and 4-aminomethylpyridine (5.8 g) were dissolved in xylene (100 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(4-pyridyl)imidazole-4-carboxylate (54.2 g), melting point 182-185° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.O1CCCC1.C([Li])CCC.[CH3:25][C:26](=O)[CH2:27][CH2:28][CH2:29][CH3:30]>CCCCCC.[I-].[Zn+2].[I-].O>[CH3:14][Si:2]([CH3:13])([CH3:1])[C:3]#[C:4][CH:5]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:26]([CH3:25])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: C[Si](C)(C)C#CCOC1CCCCO1
Reactant: CCCCC(C)=O
Agent: [I-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCC(C)C(C#C[Si](C)(C)C)OC1CCCCO1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To 13.6 parts of the above ether in 100 parts by volume of tetrahydrofuran at -70° C is added 37 parts by volume of 2.4 molar butyl lithium in hexane. This mixture is stirred for 20 minutes at -70° C and the solution is allowed to stand for 45 minutes and then 17.8 parts of zinc iodide in 350 parts by volume of tetrahydrofuran is added while maintaining the temperature at -70° C. The resulting yellow solution is stirred for 1 hour and 8 parts of 2-hexanone in 50 parts by volume of tetrahydrofuran is added while retaining the temperature at -70° C. The reaction mixture is allowed to warm to -30° C, water is carefully added, and the reaction mixture is allowed to come to room temperature. The reaction mixture is extracted with ether, washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent is stripped and the residual oil is distilled at 107°-110° C/0.5 mm to provide 1-trimethylsilyl-3-tetrahydropyranyloxy-4-methyl-1-octyne.
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:34])[CH:14]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:13]2[C:21]([CH3:33])=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:23]([CH3:26])=[C:24]([CH3:25])[C:12]=2[O:11]1.[ClH:35]>C(OCC)(=O)C>[ClH:8].[ClH:35].[CH2:1]([N:30]1[CH2:31][CH2:32][N:27]([C:22]2[C:23]([CH3:26])=[C:24]([CH3:25])[C:12]3[O:11][C:10]([CH3:34])([CH3:9])[CH:14]([N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)[C:13]=3[C:21]=2[CH3:33])[CH2:28][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2N1CCCCC1
Yield: 64 %

Procedure:
Using Benzyl chloride and (2,2,4,6,7-pentamethyl-3-piperidino-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 152, the free base was obtained in the same manner as in Example 2. The free base was treated with a 4 N hydrogenchloride in ethyl acetate solution (10 ml) to obtain the title compound. Yield 64% Amorphous powder.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1)[CH3:26]>[Zn].CCOC(C)=O>[CH2:17]([N:14]([CH2:15][CH3:16])[C:12]([C:11]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:9]([NH:8][C:35](=[O:36])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:25][CH3:26])=[CH:29][CH:30]=2)[CH:10]=1)=[O:13])[CH3:18]
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Reactant: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c(N)c1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirring toluene solution (100 mL) of 3-amino-N,N-diethyl-4-nitro-benzamide (1.00 g, 4.21 mmol) were added 4-ethoxyphenylacetyl chloride (1.25 g, 1.5 eq) and zinc dust (415 mg, 1.5 eq). The solution was stirred at rt overnight. Another 0.5 eq of acid chloride and zinc dust were then added and the solution stirred at rt for another 24 h. The solution was then filtered through celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 1:1/hex:EtOAc on silica gel to furnish the desired product (1.52 g, 90% yield). 1H NMR (400 MHz, CDCl3) d 8.81 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.26 (m, 3H), 7.15 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 4.06 (q, J=7.2 Hz, 2H), 3.75 (s, 2H), 3.54 (q, J=6.8 Hz, 2H), 3.24 (q, J=6.8 Hz, 2H), 1.59 (br s, 1H), 1.42 (t, J=6.8 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 1.16 (t, J=6.8 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([NH:21][C@@H:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[OH:28])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Cc1c(N[C@@H]2CCOC[C@H]2O)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(NC2CCOCC2=O)ccc(C#N)c1Cl
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of oxalyl chloride (1.22 mL, 14.1 mmol) in dichloromethane (15 mL) at −60° C. is added dropwise a solution of dimethyl sulfoxide (2.08 mL, 29.3 mmol) in dichloromethane (15 mL) and stirred at −60° C. for 15 min. trans-2-chloro-4-[(3-hydroxytetrahydropyran-4-yl)amino]-3-methyl-benzonitrile (3.13 g, 11.7 mmol, Example 9) in dichloromethane (30 mL) is added to the solution and stirred at −60° C. for 30 min. Triethylamine (9 mL, 64.5 mmol) is added and the mixture is warmed to room temperature and stirred for 3 h. The mixture is diluted with EtOAc and washed twice with 1 N hydrochloric acid. The organic portion is dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude title compound as an orange semi-solid (2.53 g, 81%). LC-ES/MS m/z 265.2 (M+1).