Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[NH:5][CH2:6]CC#N.[OH-:14].[Na+].[CH2:16]([OH:18])[CH3:17]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[NH:5][CH2:6][CH2:17][C:16]([OH:14])=[O:18]
Reactant: [OH-]
Reactant: Cc1cc(C)cc(NCCC#N)c1
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)cc(NCCC(=O)O)c1

Procedure:
β-(3,5-Dimethylanilino)propionitrile (4.5 g) was dissolved in ethanol (50 ml), and a solution of NaOH (5.1 g) in water (25 ml) was added, which was followed by refluxing for 4 hr. The solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to adjust the residue acidic, and the mixture was washed with chloroform (100 ml). The aqueous layer was concentrated to about 20 ml and allowed to stand. The precipitated crystals were collected by filtration and dried to give 4.0 g of β-(3,5-dimethylanilino)propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[Cl:28][C:29]1[C:30]([CH2:35][NH2:36])=[N:31][CH:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:28][C:29]1[C:30]([CH2:35][NH:36][C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])=[N:31][CH:32]=[CH:33][N:34]=1
Reactant: NCc1nccnc1Cl
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A THF (370 mL) solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (15.14 g, 81.30 mmol) and CDI (13.18 g, 81.30 mmol) was placed under a nitrogen atmosphere and stirred at 60° C. for 4 h. The reaction mixture was cooled to rt, then, (3-chloropyrazin-2-yl)methylamine bis-hydrochloride salt (16.00 g, 73.91 mmol) and DIEA (31.52 g, 244.00 mmol, 42.5 mL) was added. After stirring at 60° C. for 20 h, the reaction was concentrated in vacuo. The crude reaction mixture was purified by a silica gel glass column chromatography (eluted with 3:2 DCM/EtOAc) to obtain the pure desired product as a slightly yellowish creamy white powder; 1H NMR (CDCl3, 400 MHz) δ 1.43-1.65 (m, 4H), 2.01-2.14 (m, 4H), 2.25 (tt, J=12.0, 3.6 Hz, 1H), 2.34 (tt, J=11.6, 3.2 Hz, 1H), 3.68 (s, 3H), 4.70 (d, J=4.4 Hz, 2H), 6.81 (s, br, —NH), 8.32-8.36 (m, 1H), 8.46 (d, J=2.4 Hz, 1H); MS (ES+): m/z 312.17/314.12 (84/32) [MH+]; HPLC: tR=2.44 min (OpenLynx, polar—5 min).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O)[CH3:8].CN(C)C=O.[NH2:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[CH:28]=[N:27][C:26]=1[C:33]([NH2:35])=[O:34]>ClCCl.N1C=CC=CC=1>[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[CH:28]=[N:27][C:26]=1[C:33]([NH2:35])=[O:34])=[O:14])[CH3:8]
Reactant: CCOc1ccccc1C(=O)O
Reactant: CCCn1cnc(C(N)=O)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1cnc(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
Oxalyl chloride (1.74 g, 0.137 mol) was added dropwise to a stirred solution of 2-ethoxybenzoic acid (1.1 g, 0.00663 mol) and dimethylformamide (0.1 ml) in dichloromethane (20 ml) and the resulting mixture stirred at ambient temperature for 4 hours, then evaporated under vacuum. The residue was azeotroped with dichloromethane (2×20 ml), then added dropwise to a stirred solution of 5-amino-1-n-propylimidazole-4-carboxamide (0.9 g, 0.00536 mol) in pyridine (20 ml) The resulting solution was stirred at ambient temperature for 3 days, then evaporated under vacuum. The residue was dissolved in dichloromethane (50 ml), and the solution washed with 1N hydrochloric acid (30 ml), dried (Na2SO4) and evaporated under vacuum. Chromatography of the crude product on silica gel (15 g) using a methanol in dichloromethane elution gradient (2-6% methanol), followed by crystallisation from ethanol, gave the title compound as a colourless solid (1.3 g, 77%), m.p. 182°-184° C. Found: C,60.85; H,6.40; N,18.06. C16H20N4O3 requires C,60.74; H,6.37; N,17.71%.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[OH:14])=[O:5].[CH3:16][C:17]([CH3:21])=[CH:18][CH2:19]O>O1CCOCC1>[CH3:16][C:17]([CH3:21])=[CH:18][CH2:19][C:8]1[C:7]([OH:14])=[C:6]([C:4]([CH2:3][CH:2]([CH3:15])[CH3:1])=[O:5])[C:11]([CH3:12])=[C:10]([CH2:9][CH:10]=[C:11]([CH3:12])[CH3:6])[C:9]=1[O:13][CH2:4][CH:3]=[C:2]([CH3:15])[CH3:1].[OH:14][C:7]1[C:8]([CH2:19][CH:18]=[C:17]([CH3:21])[CH3:16])=[C:9]([OH:13])[CH:10]=[C:11]([CH3:12])[C:6]=1[C:4]([CH2:3][CH:2]([CH3:15])[CH3:1])=[O:5]
Reactant: Cc1cc(O)cc(O)c1C(=O)CC(C)C
Reactant: CC(C)=CCO
Solvent: C1COCCO1
Product: CC(C)=CCOc1c(CC=C(C)C)c(C)c(C(=O)CC(C)C)c(O)c1CC=C(C)C
Product: CC(C)=CCc1c(O)cc(C)c(C(=O)CC(C)C)c1O

Procedure:
To a solution of 1.04 g (5.00 mmol) of (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47) in dry 1,4-dioxane (10.0 ml), under nitrogen atmosphere, added 710 mg (5.00 mmol, 1.00 equivalent) of boron trifluoride ether complex in dioxane (5.0 ml) at 10° C. with stirring. Then, added 861 mg (10.0 mmol, 2.00 equivalents) of 3-methyl-2-butenol in dioxane (5.0 ml) slowly, allowing to elevate to room temperature, and stirred for five hours. Added ether to the reaction mixture and washed the ether layer with saturated sodium hydrogen carbonate aqueous solution and saturated brine, and dried over sodium sulfate. By removal of the solvent, obtained orange-colored oily substance as a crude product. Column chromatographic separation on silica gel (65 g of Wako Gel C-300, eluted with hexane: ethyl acetate at varying ratios=19:1-7:3) gave, in the order of elution, 246 mg of {3,5-bis(3-methyl-2-butenyl)-2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl}(2-methylpropyl) ketone (51) as a light yellow viscous oil and 95 mg of {2,4-dihydroxy-6-methyl-3-(3-methyl-2-butenyl)phenyl}(2-methylpropyl) ketone (49) as a light yellow fine needles.
Reaction SMILES: C([C@@:4]1([OH:30])[C@:8](C(=O)C)([OH:9])[C@@H:7]([CH:13](C(=O)C)[OH:14])[O:6][C@H:5]1[N:18]1[C:28]2[N:27]=[C:25](N)[NH:24][C:22](Cl)(O)[C:21]=2[N:20]=[CH:19]1)(=O)C.[N:31]([O-])=O.[Na+].[ClH:35]>O.N>[Cl:35][C:25]1[N:24]=[C:22]([NH2:31])[C:21]2[N:20]=[CH:19][N:18]([C:28]=2[N:27]=1)[C@@H:5]1[O:6][C@H:7]([CH2:13][OH:14])[C@@H:8]([OH:9])[C@H:4]1[OH:30]
Reactant: O=N[O-]
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cnc3c2N=C(N)NC3(O)Cl)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Reactant: Cl
Agent: N
Agent: [Na+]
Solvent: O
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 0 °C
Yield: 60 %

Procedure:
100 g of 2',3',5'-triacetyl-6-chloroguanosine was dissolved in 400 ml of concentrated hydrochloric acid and, after the mixture was cooled to 0°C, a solution of 20 g of sodium nitrite dissolved in 50 ml of water was then added slowly to the mixture. The resulting mixture was allowed to react for 30 minutes, neutralized with concentrated aqueous ammonia and extracted with 2 l of methylene chloride. The extract was dried over anhydrous sodium sulfate and concentrated. The concentrate thus-obtained was dissolved in 300 ml of saturated methanolic ammonia and the mixture was allowed to react at a temperature of 100°C for 5 hours in a sealed tube. The reaction mixture was then concentrated to dryness and the residue was crystallized from water to obtain 42.3 g (60% yield) of 2-chloroadenosine. Recrystallization from water was repeated to obtain crystals having the following constant physical properties. Melting Point: 161° ~ 162°C (with decomposition)
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1.C=C>C(Cl)(Cl)Cl>[Cl:1][Si:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([Cl:4])[Cl:3]
Reactant: CC1=CCCCC1
Reactant: Cl[SiH](Cl)Cl
Agent: C=C
Solvent: ClC(Cl)Cl
Product: Cl[Si](Cl)(Cl)CC1CCCCC1
Reaction time: 144 h

Procedure:
A mixture of 20 ml trichlorosilane, 25 ml chloroform, 8.1 g 1-methylcyclohexene and 0.055 g (phenazine)PtCl2 (C2H4) was refluxed and stirred under nitrogen for 6 days. Distillation of the reaction mixture afforded 2.2 g of trichlorosilylmethylcyclohexane C6H11CH2SiCl3 which was characterized by its mass and NMR spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[CH:17]([C:35]([O:37]CC)=O)[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:55]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>CN(C)C=O>[ClH:1].[C:35]([CH:17]1[CH2:16][N:15]([S:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH:8]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21](=[O:34])[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)(=[O:37])[NH2:55]
Reactant: c1ccncc1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cccnc2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cl
Product: NC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
In the same manner as in Example A-3, with 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[4-(pyridin-3-yl)benzoyl]piperazine (426 mg) as a starting material, a crude product was obtained by the hydrolysis of the ester, followed by suspension in N,N-dimethylformamide (35 ml). Under ice cooling, di-tert-butyl dicarbonate (646 mg), pyridine (370 μl) and ammonium bicarbonate (196 mg) were added to the resulting suspension. The resulting mixture was stirred at room temperature for 19 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (4% methanol—dichloromethane) and the eluate was dissolved in tetrahydrofuran. Solution of hydrochloride in ethanol was added to the resulting solution to solidify the same. The resulting solid was collected by filtration and dissolved in a mixed solvent of water and methanol. The insoluble matter was filtered off and the filtrate was distilled under reduced pressure, whereby the title compound (302 mg, 65%) was obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].C([N:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21](S(NC3C=CC=CC=3C(C3C=CC(F)=CN=3)=O)(=O)=O)=[CH:20][CH:19]=2)[C:14]1=[O:43])C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:43]=[C:14]1[NH:13][CH2:17][CH2:16][N:15]1[C:18]1[CH:23]=[CH:22][C:21]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(F)cn1)c1ccccc1NS(=O)(=O)c1ccc(N2CCN(Cc3ccccc3)C2=O)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NCCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1.5 mL (23.1 mmol) of chlorosulfonic acid in 3 mL of carbon tetrachloride at 0° C. was added slowly 500 mg (3.1 mmol) of the compound of Step 1. The reaction was almost completed after 2 h at 0° C. The reaction mixture was poured into ice water slowly, then filtered to collect the solids formed. The aqueous layer was extracted with chloroform (3×100 ml), and the combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. The filtered solid and the crude material from the extraction were combined to provide the title compound (LC/MS found: 261.1)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23]C)[CH2:6][CH2:7][N:8]([CH3:19])[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.B(Br)(Br)Br.ClCCl.CO>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[OH:23])[CH2:6][CH2:7][N:8]([CH3:19])[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(CCN(C)C(=O)/C=C/c2cccnc2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CN(CCc1ccc(O)c(O)c1)C(=O)/C=C/c1cccnc1
Reaction time: 14 h
Yield: 88.3 %

Procedure:
(E)-N-(3,4-dimethoxyphenethyl)-N-methyl-3-(3-pyridyl)-2-propenoic acid amide (2.65 g, 8.31 mmol) obtained in Example 84 was dissolved in dichloromethane (66 ml) and 1M boron tribromide-dichloromethane solution (33 ml) was dropwise added under argon at −30° C. and stirred for 14 hours. After methanol was added at the same temperature to stop the reaction, the solvent was distilled out under reduced pressure and hydrogen chloride/methanol solution was added to the residue and heated and refluxed for 1 hour. The solvent was distilled out under reduced pressure and potassium hydroxide/methanol solution was added to the residue to neutralize. The precipitated inorganic salts were filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1) and recrystallized to yield the titled compound (2.19 g, 90%).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)([O-])C.[K+].[C:25]1([C:31]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:32]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[CH:48]=[CH:47][C:46]([CH2:49]Br)=[CH:45][CH:44]=3)[N:34]=[N:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C.O>CN(C)C(=O)C>[C:57]1([C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:32]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[CH:48]=[CH:47][C:46]([CH2:49][N:7]([C:8]4[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=4)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:45][CH:44]=3)[N:34]=[N:33]2)[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CCCCC(=O)Nc1cccc(C(=O)OCC)c1
Reactant: BrCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)c1cccc(C(=O)OCC)c1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution of ethyl 3-aminobenzoate (5.02 g) in N,N-dimethylacetamide (DMA, 50 ml) was added dropwise pentanoyl chloride (4.0 ml), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was stirred for 1 hr. The mixture was partitioned and extracted by adding ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give ethyl 3-(N-pentanoyl)aminobenzoate (7.55 g). To a solution of the obtained amide compound in DMA (100 ml) was added potassium tert-butoxide (4.09 g), and the mixture was stirred for 30 min. To the reaction mixture was added [4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methylbromide (18.6 g), and the mixture was stirred at 50° C. for 3 hrs. The reaction mixture was added to ethyl acetate-water and, after partitioning and extraction, the extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with hexane-ethyl acetate:3-2 v/v) to give the object compound (20.6 g, yield 93.6%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:33][CH3:34])(=[O:10])=[O:9])=[C:4]([Cl:35])[CH:3]=1.[CH3:36][C:37]1[CH:38]=[C:39](B(O)O)[S:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(OCC)(=O)C>[Cl:35][C:4]1[CH:3]=[C:2]([C:39]2[S:40][CH:41]=[C:37]([CH3:36])[CH:38]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:33][CH3:34])(=[O:10])=[O:9]
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: Cc1csc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1Cl

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-{[(4-bromo-2-chlorophenyl)sulfonyl]amino}-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D13) (0.15 g, 0.254 mmol), 4-methylthiophene-2-boronic acid (0.054 g, 0.382 mmol), (1,1′-Bis(diphenylphosphino)ferrocene)palladium(II) chloride, DCM complex (9.2 mg, 0.0127 mmol), sodium carbonate (0.053 g, 0.508 mmol) were heated in DME (2 mL) and water (1 mL) at 120° C. in the microwave for 20 minutes. The reaction was then diluted with ethyl acetate (50 mL) and washed with saturated sodium hydrogen carbonate (2×30 mL) and brine (30 mL). The organic layer was dried (MgSO4) and evaporated to give a dark brown oil which was purified by chromatography [silica gel, eluting with 0 to 50% Ethyl acetate/pentane]. Product fractions evaporated to give a pale yellow foam (D14) (0.127 g) MS (ES+) m/e 607/609 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].C(O)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1.[CH:20](Cl)(Cl)Cl>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([C:13]3[CH:12]=[CH:17][CH:16]=[CH:15][N:14]=3)[S:10][C:3]=2[CH:4]=1
Reactant: O=C(O)c1cccnc1
Reactant: COc1ccc(N)c(S)c1
Reactant: ClC(Cl)Cl
Product: COc1ccc2nc(-c3ccccn3)sc2c1

Procedure:
A mixture of 2-amino-5-methoxy-benzenethiol, 25 g (0.16 mole) and nicotinic acid, 24.6 g (0.2 mole) is dissolved in 250 cc of CHCl3 containing 160 g of PPE. The mixture is refluxed overnight. The mixture is concentrated to dryness and the residue poured on ice and the pH of the solution is adjusted to 10 using 50% NaOH solution. The precipitate is filtered, washed with water and dried to yield 34.5 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:26]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:26]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:30]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-c3cn(C)nn3)cc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-c3cn(C)nn3)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-vinylbenzoate (0.42 g) in a mixed solvent of acetone (10.0 mL)-acetonitrile (10.0 mL)-water (10.0 mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodium periodate (1.24 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.26 g) as a crude product.
Reaction SMILES: C(OC([NH:8][C:9]1([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:30]>C(Cl)Cl.C(OCC)C>[Cl-:30].[CH2:28]([O:27][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:9]2([NH3+:8])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:15])=[CH:18][CH:19]=1)[CH3:29]
Reactant: Cl
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCCC2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2([NH3+])CCCC2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl (2E)-3-{4-[({1-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]phenyl}acrylate (from Step 1) was dissolved in CH2Cl2 (0.5 M) and an excess of hydrogen chloride in diethyl ether (2.0 M) was added. The solution was left stirring overnight at RT. The precipitate formed was filtered off and dried in vacuo. A colourless solid was obtained (99%), which was used without further characterisation.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23](B(O)O)=[CH:24][CH:25]=[CH:26][CH:27]=1.[C:37]1([CH2:43][CH2:44][SH:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=[C:10]2[CH2:12][S:45][CH2:44][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: SCCc1ccccc1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)C=C(CSCCc2ccccc2)c2cc(-c3ccccc3-c3ccccc3)ccc2N1

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 2-biphenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 57 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:16]2[S:17][CH:18]=[C:19]([Br:21])[CH:20]=2)[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([NH:30][C:31]([NH:1][C:2]1([C:16]2[S:17][CH:18]=[C:19]([Br:21])[CH:20]=2)[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2cc(Br)cs2)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cc(Br)cs2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-amino-3-(4-bromo-2-thienyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (8.5 g, 22.5 mmol) in tetrahydrofuran (100 mL) at 0° C. is added benzoyl isothiocyanate (3.24 mL, 24 mmol). The resulting solution is warmed to room temperature, and stirred under nitrogen at room temperature for 2 hours. The solution is concentrated and the residue is purified by silica gel flash chromatography eluting with hexanes/ethyl acetate (gradient from 100:0 to 0:100 over 30 min) to give the title compound. ES/MS (m/e): (79Br/81Br) 538/540 (M+H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[CH2:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].N1CCCC1>C1(C)C=CC=CC=1>[CH2:21]([C:20]1([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[CH2:13][C:11](=[O:12])[C:8]2[CH:7]=[CH:6][C:5]([OH:14])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=2[O:10]1)[CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: C=CCCCC(=O)CCCC=C
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: C=CCCCC1(CCCC=C)CC(=O)c2ccc(O)c(CCC)c2O1
Yield: 84.6 %

Procedure:
A mixture of 3.93 g (20.2 mmol) of 2,4-dihydroxy-3-propylacetophenone, 3.36 g (20.2 mmol) of the title product of Example 68, 1.44 g (20.2 mmol) of pyrrolidine, and 23.5 ml of toluene was stirred at reflux under a water separator containing 3A molecular sieves for 5 hours. The mixture was then permitted to cool, and the solvent was removed under reduced pressure. Chromatography of the residue over silica gel using 25% ethyl acetate/hexane as eluant gave the title compound (5.85 g) as a dark red oil.