Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=[C:42]([Cl:48])[C:41]=1[NH:49][C:50]1[N:54]([CH3:55])[C:53]2[CH:56]=[C:57]([N:63]3[CH2:68][CH2:67][CH:66]([C:69]([F:72])([F:71])[F:70])[CH2:65][CH2:64]3)[C:58]([C:60]([OH:62])=[O:61])=[CH:59][C:52]=2[N:51]=1>CN(C=O)C>[Cl:39][C:40]1[C:45]([CH2:46][NH:47][C:3](=[O:4])[C:2]([F:1])([CH3:7])[CH3:6])=[CH:44][CH:43]=[C:42]([Cl:48])[C:41]=1[NH:49][C:50]1[N:54]([CH3:55])[C:53]2[CH:56]=[C:57]([N:63]3[CH2:68][CH2:67][CH:66]([C:69]([F:72])([F:71])[F:70])[CH2:65][CH2:64]3)[C:58]([C:60]([OH:62])=[O:61])=[CH:59][C:52]=2[N:51]=1
Reactant: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: CC(C)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)F)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Reaction time: 0.17 h

Procedure:
A mixture of 2-fluoroisobutyric acid (191 mg, 1.80 mmol), TBTU (578 mg, 1.80 mmol), DIPEA (1.00 mL, 5.7 mmol) and 10 mL DMF is stirred for 10 min and then the mixture is added to 2-{2,6-dichloro-3-[aminomethyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (929 mg, 1.80 mmol) in 10 mL DMF and it is stirred overnight. Then the mixture is concentrated and purified via prep HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-])=O)=[C:5]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:6]=[CH:7][N+]([O-])=O>C(O)C.C(O)=O.[OH-].[OH-].[Pd+2]>[CH3:16][O:15][C:12]1[CH:11]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:13]=1[OH:14])[NH:17][CH:7]=[CH:6]2
Reactant: COc1cc(C=C[N+](=O)[O-])c([N+](=O)[O-])c(OC)c1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Product: COc1cc2cc[nH]c2c(OC)c1O
Yield: 14 %

Procedure:
A mixture of 10 g (0.037 mole) of 3,5-dimethoxy-4-hydroxy-2,β-dinitrostyrene and 10 g of palladium hydroxide on charcoal in 400 cm3 of ethanol and 7 cm3 of formic acid is heated under reflux for 3 hours. After cooling, the reaction mixture is filtered through Celite. The filtrate is evaporated to dryness. The residue is redissolved in dichloromethane and the solution is filtered on silica gel. After distillation of the solvent under reduced pressure and recrystallization from diisopropyl ether, 1 g of the desired product is obtained in the form of a whitish solid (yield=14%).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:19]([OH:21])=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]([C:24]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=1)[NH2:23].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:19]([NH:23][NH:22][C:24]2[N:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][N:25]=2)=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN(CC1(C(=O)O)CCCCC1)OCc1ccccc1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cyclohexanecarboxylic acid (0.10 g, 0.34 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.06 g, 0.34 mmol), NMM (0.17 g, 1.7 mmol) and HOAt (0.046 g, 0.34 mmol) in DMF (2 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.067 g, 0.34 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.070 g, 47%). MH+452.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccccn2)cc1
Reaction time: 6 h
Yield: 9.9 %

Procedure:
4-Aminothiophenol (0.065 moles, 8.1 g) in 275 ml DMF was stirred at room temperature for 1 hr with sodium hydride (0.065 moles previously washed with hexane). 2-Chloropyridine (0.06 moles, 6.8 g) was added and the reaction mixture was stirred for 6 hr. An additional 5.2 g of 4-aminothiophenol was added and the reaction stirred at room temperature for 16 hr. Water was added and the product extracted with ethyl acetate. The solution was washed thoroughly with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 30% ethyl acetate/hexane to yield 2-(4-aminophenylthio)pyridine 1.2 g, 10%. Mass spec (FD) 202. Calculated for C11H10N2S: C, 65.32; H, 4.98, N, 13.85 Found: C, 65.23; H, 5.09; N, 13.63.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cccnc1C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccnc1CBr

Procedure:
Ethyl 2-methylpyridine-3-carboxylate is refluxed with N-bromosuccinimide in carbon tetrachloride with 1% equivalent dibenzyl peroxide to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
4-Hydroxy-benzoic acid methyl ester (3.19 g, 21 mmol) was dissolved together with pyridine (1.97 g, 25 mmol) in dry THF (20 mL) and after cooling down to 0° C., methanesulfonyl chloride (2.29 g, 20 mmol) was added dropwise. The ice bath was removed and mixture was stirred at r.t. for 5 h. After diluting with DCM and extraction with water and aq. HCl (2N), the organic layer was dried (MgSO4) and evaporated to afford the crude but highly pure product as a solid which was used in the next step without further purification (4.38 g, 95.1%). 1H NMR (400 MHz, CDCl3): δ 8.07-8.09 (d, 2H), 7.32-7.34 (d, 2H), 3.90 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23]O.C([O-])=O.[Na+].O>C(O)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
35.7 g (118 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde are heated to boiling under reflux for 6 hours together with 9.52 g (137 mmol) of hydroxylamine hydrochloride and 14.6 g (214 mmol) of sodium formate in 178 ml of formic acid. The solution obtained is then poured into 2.5 l of water; the precipitated product is filtered off under suction and rinsed with water. After recrystallization from methylene chloride/ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile of melting point 236°-237°.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][C@@H:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C@H:7]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:3].[H][H]>[Pd]>[NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][C@@H:19]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:18][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](N)C(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Product: C[C@H](N)C(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O

Procedure:
A solution of 10 grams of 1-(L-alanyl)-4-(S)-(phenylmethyl)-L-proline, phenylmethyl ester (liberated from its hydrochloride salt) in 150 ml. of absolute alcohol is hydrogenated in the presence of 1.5 grams of 10% palladium on carbon until the uptake of hydrogen ceases. The mixture is filtered to remove the catalyst and the filtrate is concentrated under reduced pressure to yield the desired 1-(L-alanyl)-4-(S)-(phenylmethyl)-L-proline.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH3:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[NH2:9].Cl.[Sn](Cl)Cl>O.C(O)C>[CH3:25][C:11]1[CH:10]=[C:8]([NH:9][NH2:1])[CH:7]=[C:6]([CH3:5])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:23])[CH3:24])[CH:15]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Oc2c(C)cc(N)cc2C)cc1C(C)C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2c(C)cc(NN)cc2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of sodium nitrite (155 mg, 2.24 mmol) in water (1 mL) was added to a suspension of 3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)-aniline (J. Med. Chem. 1995, 38, 695, 640 mg, 2.24 mmol) in ethanol (3 mL) and concentrated hydrochloric acid (12 M, 1.12 mL, 13.44 mmol) at 0° C. The yellow heterogeneous solution slowly turns to an orange clear solution. After stirring at 0° C. for 30 minutes, a solution of tin dichloride (1.53 g, 8.06 mmol) in hydrochloric acid (12 M, 1.3 mL, 15.68 mmol) was added. The orange solution turned green and a white precipitate formed. Ethanol (3 mL) was added to dissolve most of the precipitate and the heterogeneous reaction mixture was stirred at 0° C. After 2 hours, water was added and the precipitate collected by filtration. The sticky solid was dissolved in ethyl acetate and washed with water, 1 N sodium hydroxide then brine. The organics were dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, dichloromethane/methanol 95/5 to 90/10) to give 3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)-phenyl hydrazine (305 mg, 45%): 1H NMR (300 MHz, CDCl3) δ 6.77 (d, J=3.0 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H) 6.58 (s, 2H), 6.37 (dd, J=9.0, 3.0 Hz, 1H), 3.77 (s, 3H), 3.27 (heptuplet, J=6.9 Hz, 1H), 2.09 (s, 3H), 1.18 (d, J=6.9 Hz, 6H); TLC conditions: Merck silica gel, 250 microns; Mobile phase=dichloromethane-methanol (9:1), Rf=0.6.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[NH2:4].C([O:12][C@@H:13]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[C@@H:16]([CH2:27][O:28]C(=O)C)[O:15][C@H:14]1[O:32][C:33]1[C:37]([CH2:38][C:39]2[CH:44]=[CH:43][C:42](/[CH:45]=[CH:46]/[C:47](O)=[O:48])=[CH:41][CH:40]=2)=[C:36]([CH:50]([CH3:52])[CH3:51])[NH:35][N:34]=1)(=O)C.C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OC1C(CC2C=CC(/C=C/CC(O)=O)=CC=2)=C(C(C)C)NN=1)(=O)C>>[C@@H:14]1([O:32][C:33]2[C:37]([CH2:38][C:39]3[CH:44]=[CH:43][C:42](/[CH:45]=[CH:46]/[C:47](=[O:48])[NH:4][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH2:2][OH:1])=[CH:41][CH:40]=3)=[C:36]([CH:50]([CH3:52])[CH3:51])[NH:35][N:34]=2)[O:15][C@H:16]([CH2:27][OH:28])[C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:13]1[OH:12]
Reactant: NC(CO)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/C(=O)NC(CO)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using tris(hydroxymethyl)-aminomethane and 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of ammonium chloride and 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.C1(C)C=CC=CC=1.BrC1C=CC(C2N(C3C=CC(Cl)=CC=3)C(=O)C3C=NN(C4C=CC=C(SC)C=4)C=3N=2)=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([Cl:20])=[N:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: CSc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 170 °C

Procedure:
4-Bromo-N-(4-chloro-phenyl)-benzimidoyl chloride is prepared by heating 4-bromo-N-(4-chloro-phenyl)-benzamide (13.39 g, 43.2 mmol) and thionyl chloride (100 mL) for 1 h. The clear solution is concentrated and the residue obtained is coevaporated with toluene (100 mL). A solution of 5-amino-1-(3-nitro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (1, 4.00 g, 14.4 mmol) in dry chloroform (50 mL) is then added and the resulting mixture is concentrated to afford a dry residue. It is heated to 170° C. with out solvent for 6 h. The crude product obtained is purified by column chromatography to afford the product as greenish black solid as product (6).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[N:23]([CH2:26][CH2:27][CH3:28])=[C:24]=[O:25]>ClCCl>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([NH:15][C:24]([NH:23][CH2:26][CH2:27][CH3:28])=[O:25])[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCCN=C=O
Reactant: CCN1CCN(c2cc(N)ccn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccnc(N2CCN(CC)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
A mixture of 20.6 mg (0.1 mmol) 2-(4-ethyl-piperazin-1-yl)-pyridin-4-ylamine, 15 mg (0.15 mmol) triethylamine and 9.4 mg (0.11 mmol) 1-isocyanato-propane in 1 ml dichloromethane was stirred at room temperature for 16 h. After evaporation the residue was taken up in 1 ml methanol/acetonitrile 1/1 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 7.2 mg (25%) of the title compound. (m/e): 292.3 (MH+; 100%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[CH:8](OC(=O)C)[O:7][C@@H:6]1[C:18]1[CH:22]=[C:21]([CH2:23][CH3:24])[O:20][N:19]=1)(=[O:3])[CH3:2].[Cl:25][C:26]1[N:34]=[C:33]2[C:29]([NH:30][CH:31]=[N:32]2)=[C:28]([Cl:35])[N:27]=1.N12CCCN=C1CCCCC2.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[C:11]([O:10][C@@H:9]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:6]([C:18]2[CH:22]=[C:21]([CH2:23][CH3:24])[O:20][N:19]=2)[O:7][C@H:8]1[N:32]1[CH:31]=[N:30][C:29]2[C:33]1=[N:34][C:26]([Cl:25])=[N:27][C:28]=2[Cl:35])(=[O:13])[CH3:12]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCc1cc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 60 °C
Reaction time: 21 h

Procedure:
(2R,3 R,4R)-4,5-bis(acetyloxy)-2-(5-ethyl isoxazol-3-yl)tetrahydrofuran-3-yl acetate isomer 1 (193 mg) was dissolved in acetonitrile (5 ml) and treated sequentially with 2,6-dichloropurine (213 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.186 ml) and trimethylsilyl trifluoromethanesulphonate (TMSOTf) (0.225 ml) via a syringe over 5 min. The clear yellow solution was stirred at 22° C. for 40 h, at 60° C. for 21 h, and at 80° C. for 6 h. The mixture was cooled to room temperature and more DBU (0.186 ml) and TMSOTf (0.225 ml) were added. After stirring at 22° C. for 36 h the yellow mixture was heated at 60° C. overnight and at 80° C. for 6 h. The solvents were removed in vacuo and the resultant brown oily solid taken up in ethyl acetate and washed with water (20 ml, 3:1). The aqueous layer was extracted with ethyl acetate and the combined organic layers dried (MgSO4) and evaporated in vacuo to afford a brown oily solid. The residue was triturated with dichloromethane and a white solid removed by filtration. Evaporation of the filtrate afforded a tan solid. Purification by flash chromatography on silica gel eluting with ether:cyclohexane (1:1) afforded the title compound as a white solid (161 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>O1CCCC1>[Si:18]([O:10][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (40 mL) of 3-acetylphenol (5.0 g, 37 mmol) in tetrahydrofuran were added triethylamine (7.7 mL, 55 mmol) and tert-butyldimethylsilylchloride (6.6 g, 44 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=9/1) to give the title compound (9.4 g, 100%) as a colorless oil.
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].C([O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[C:16]([NH:18][C:19]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[OH:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[C:16]([NH:18][C:19]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1cccc(O)c1
Reaction time: 2 h
Yield: 61.6 %

Procedure:
0.50 mL of methanol, 0.50 mL of tetrahydrofuran and 4.2 mg of potassium carbonate were added sequentially to 8.0 mg of 2-(3-acetoxybenzamido)-4-phenoxybenzoic acid at room temperature and stirred at the same temperature for 2 hours. 10% citric acid aqueous solution was added to the reaction mixture and a solid substance was separated by filtration to obtain 4.4 mg of 2-(3-hydroxybenzamido)-4-phenoxybenzoic acid as whine solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 50 ml round-bottomed flask, 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.6 mmol) was dissolved in dichloromethane 912 ml). The colorless solution was cooled to 0° C. and triethylamine (0.34 ml, 2.44 mmol) and methanesulfonyl chloride (0.14 ml, 1.8 mmol) were added. The reaction mixture was stirred at 0° C. for 1.5 h then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil which was used without further purification.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[Cl-].[NH4+]>CC1C=CC=CC=1.O1CCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[OH:18])=[CH:15][CH:16]=1
Reactant: CN1CCC(Cl)CC1
Reactant: O=C(c1ccc(F)cc1)c1cccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CCC(C(O)(c2ccc(F)cc2)c2cccnc2)CC1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred and cooled Grignard-complex previously prepared starting from a mixture of 134 parts of 4-chloro-1-methylpiperidine, 25 parts of magnesium and 652.5 parts of tetrahydrofuran was added dropwise a solution of 170 parts of (4-fluorophenyl)(3-pyridinyl)methanone in 405 parts of tetrahydrofuran at a temperature between 10°-20° C. Upon completion, stirring was continued for 1 hour at room temperature and for 30 minutes at minutes at reflux. After cooling, the whole was decomposed by pouring onto a mixture of crushed ice and ammonium chloride. 270 Parts of methylbenzene were added. The organic layer was separated, dried, filtered and evaporated. The residue was boiled in acetonitrile with activated charcoal. The latter was filtered off over Hyflo and the filtrate was evaporated, yielding 240 parts (95%) of α-(4-fluorophenyl)-α-(1-methyl-4-piperidinyl)-3-pyridinemethanol as a residue (intermediate 18).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:9][C:10]([CH3:15])([CH3:14])[C:11]([NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)=[O:12]
Reactant: Cc1ccnc(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccnc(NC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methyl-pyridin-2-ylamine (30 g, 0.28 mol) was dissolved in DCM (300 mL) and treated with TEA (41 mL) followed by trimethylacetyl chloride (38 mL) via a dropping funnel over 30 min. The mixture was allowed to stir overnight at RT, then poured into a separatory funnel with water (100 mL) and satd. aq. NaHCO3 (75 mL). The organic layer was extracted, washed with satd. aq. NaHCO3 (75 mL), dried over Na2SO4, and concentrated to give solid 2,2-dimethyl-N-(4-methyl-pyridin-2-yl)-propionamide (42 g, 0.22 mol). 1H NMR (CDCl3) δ 8.09 (m, 2 H), 7.93 (br s, 1 H), 6.83 (m, 1 H), 2.33 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[CH:27])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24](/[CH:26]=[CH:27]/[C:27]#[C:26][C:24]3[CH:23]=[CH:22][C:20]4[NH:21][C:17]([C@@H:12]5[CH2:13][CH2:14][CH2:15][CH2:16][N:11]5[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[O:10])=[N:18][C:19]=4[CH:25]=3)=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Agent: Cl[Ru]Cl
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(C#C/C=C/c3ccc4[nH]c([C@@H]5CCCCN5C(=O)OCc5ccccc5)nc4c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A mixture of (S)-2-(5-ethynyl-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (41 mg, 0.115 mmol) and dichloro(p-cymene)ruthenium(II) dimer (5 mg) is purged with N2. AcOH (1 mL) is added and the mixture is stirred at room temperature overnight and concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (EtOAc/hexanes 5% to 100%) and repurified by reverse phase HPLC using a gradient of CH3CN/water to afford the title compound (5.9 mg, 7%).