Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:36]4[C:32]([CH3:31])=[N:33][NH:34][CH:35]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3c[nH]nc3C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 15 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (59.6 mg, 0.286 mmol), bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol) and potassium carbonate (79 mg, 0.573 mmol). Water (1 mL) was added and the mixture heated at 100° C. in a microwave for 15 min (×2). The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase re-extracted with ethyl acetate (2×20 mL). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (15 mg). LCMS (A) m/z: 525 [M+1]+, Rt 1.23 min (acidic).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:5]1[CH2:10][CH:9](O)[C:8]2[S:12][CH:13]=[CH:14][C:7]=2[CH2:6]1.I[Si](C)(C)C.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(#N)C>[CH3:1][O:2][C:3]([C@@H:4]([N:5]1[CH2:6][C:7]2[CH:14]=[CH:13][S:12][C:8]=2[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:22]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate (9) (59.79 g, 177.0 mmol) in toluene and acetonitrile is added to a solution of iodotrimethylsilane in acetonitrile at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 2 hours. Water is then added to the mixture at 0–5° C. The mixture is then warmed again to room temperature and stirred for an additional 4 hours. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oil product (55.8 g). The product obtained was found to be identical to the product obtained in Example 1 by 1H-NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]=[C:34]=[S:35])[CH2:27][CH2:26]1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:34]([NH:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:16]2[N:15]([CH2:14][C:10]3[O:9][CH:13]=[CH:12][CH:11]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:26][CH2:27]1)=[S:35]
Reactant: Nc1ccncc1N
Reactant: S=C=NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Solvent: C1CCOC1
Product: Nc1ccncc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Yield: 87 %

Procedure:
A mixture of 5.4 parts of 3,4-pyridinediamine, 16 parts of 1-(2-furanylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18 parts (87%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea (intermediate 133).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:4][CH:3]=1.[C:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:21][CH:22]=2)=[O:32])=[CH:29][CH:28]=1)(=[O:25])[CH3:24]
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(O)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
In pyridine was dissolved 5 g of dodecyl p-hydroxybenzoate, and a solution of 5 g of p-acetoxybenzoic acid chloride in chloroform was added dropwise to the solution and the mixture was stirred at room temperature for 4 hours. Water was added to the thus-obtained solution, the mixture was extracted with chloroform, and the extract was washed with a 0.5N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride in succession, dehydrated on anhydrous magnesium sulfate and concentrated. The concentrate was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 3.18 g dodecyl 4-(4-acetoxybenzoyloxy)benzoate. The obtained ester was dissolved in a mixed solvent of tetrahydrofuran and methanol at a volume ratio of 10/1, 7 ml of a 1N aqueous solution of lithium hydroxide was added to the solution, and the obtained mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Then, the liquid was dried on anhydrous magnesium sulfate and concentrated, and the concentrate was recrystallized from a liquid mixture of n-hexane and ethyl acetate to obtain 2.22 g of dodecyl 4-(4-hydroxybenzoyloxy)benzoate.
Reaction SMILES: [C:1]1([CH3:54])[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:32](OS(C(F)(F)F)(=O)=O)[CH3:33])[C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:42])[C@H:12]2[NH:43][C:44](=[O:53])[CH2:45][O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C>O1CCCC1>[C:1]1([CH3:54])[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:32]=[CH2:33])[C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:42])[C@H:12]2[NH:43][C:44](=[O:53])[CH2:45][O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: CC(OS(=O)(=O)C(F)(F)F)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Yield: 103.9 %

Procedure:
Embodiment a: A solution of diphenylmethyl 2-[(3R,4R)-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-trifluoromethanesulfonyloxy-2-butenoate (XVa, 0.300 g, 0.00036 mole) in dry tetrahydrofuran (3 mL) was treated with triethylamine (0.077 mL, 0.00036 mole) for 1 h at room temperature. Reverse-phase chromatography (C-18 column, eluting with 65% acetonitrile - 35% of 0.01M phosphate pH 6.5 buffer) showed complete consumption of the starting material after 45 min with formation of a single, faster-eluting product. 0.05M sulfuric acid and ethyl acetate was added to the reaction mixture, followed by separating the two phases The organic phase was dried with sodium sulfate and evaporated to give 0.245g of diphenylmethyl 2-[(3R,4R)-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-2,3-butadienoate (Ia) as a colorless foam (quantitative yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]([CH2:16][NH:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:11]([C:13](O)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]3[CH2:16][N:17]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[C:13](=[O:14])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1CNC1CCCC1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1c2nc(-c3ccc(Cl)cc3)n(-c3ccccc3F)c2CN1C1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.3 %

Procedure:
A mixture of 2-(4-chloro-phenyl-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid I-5k (1.2 g, 2.59 mmol), EDC (994 mg, 5.18 mmol), HOAt (704 mg, 5.18 mmol), and triethylamine (1.1 ml, 7.76 mmol) in CH2Cl2 (200 ml) was stirred for 17 hours at room temperature. The reaction mixture was washed with sat'd aq NaHCO3 and sat'd aq. NaCl, dried and concentrated in vacuo. The crude residue was purified on SiO2-gel using a solvent gradient of 30% EtOAc/hexanes to 60% EtOAc/hexanes to give 4A-1 as a white solid (752 mg, 73%): +APCI MS (M+1) 396.2; 1H NMR (CDCl3): δ 7.61-7.59 (m, 2H), 7.42-7.37 (m, 6H), 4.60 (m, 1H), 4.50 (s, 2H), 2.0 (m, 2H), 1.8-1.65 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:19]([C:21]1[CH:22]=[C:23]([CH:39]([CH3:41])[CH3:40])[C:24]2[O:28][C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:38]=1)#[N:20]>>[C:19]([C:21]1[CH:22]=[C:23]([CH:39]([CH3:41])[CH3:40])[C:24]2[O:28][C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH:1][CH2:2][C:3]4([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH2:4]4)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:38]=1)#[N:20]
Reactant: CC(C)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C(C)C)CCN(C(=O)OC(C)(C)C)CC4)cc3)oc12

Procedure:
To a solution of tert-butyl 4-cyano-4-isopropylpiperidine-1-carboxylate (90 mg, 0.357 mmol) in ammonium hydroxide (2 ml) and ethanol (4 ml) was added Raney nickel (100 mg, 1.167 mmol). The mixture was flushed with nitrogen, then flushed with hydrogen and stirred overnight under a hydrogen balloon, at which point LC/MS analysis showed the desired product. The mixture was filtered through a plug of Celite, washing liberally with methanol, and then concentrated to a small volume and partitioned between 20 ml of 1 N sodium hydroxide and 25 ml of ethyl acetate. The aqueous phase was extracted with 2×20 ml of ethyl acetate, and then the combined organics were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 50% methanol in dichloromethane over 10 column volumes to provide tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg). The title compound was then prepared from tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg) and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (57 mg, INTERMEDIATE 2) as described in EXAMPLE 35. Mass spectrum (ESI) 545.3 (M+1). 1H NMR (500 MHz, CDCl3): 8.33 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 6.14 (br t, J=6.0 Hz, 1H), 3.63 (m, 4H), 3.47 (septet, J=7.0 Hz, 1H), 3.33 (br t, J=10.5 Hz, 2H), 1.83 (septet, J=7.0 Hz, 1H), 1.54-1.66 (m, 4H), 1.46 (d, J=7.0 Hz, 6H), 1.45 (s, 9H), 0.99 (d, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([C:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[CH:5]([CH:11]=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[C:21]([O:20][C:18]([C:4]1([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[C:1](=[O:3])[CH:2]=[CH:11][CH:5]1[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(C=O)CC(=O)OC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC

Procedure:
A 790 mg quantity of the compound (3) obtained above is dissolved in 50 ml of benzene containing 1 ml of acetic acid and 1 ml of piperidine, and the solution is refluxed for 4 hours. On completion of the reaction, the solvent is removed, and the residue dissolved in ethyl acetate. The solution is washed with water and an aqueous solution of sodium bicarbonate and thereafter dried. The residue is distilled in a vacuum, giving 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (1-a), R1 =t-Bu, R2 =CH3) in a yield of 78%, b.p. 82°-86° C./0.006 mm Hg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].CCN(CC)CC.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C(Cl)Cl>[C:21]1([CH3:22])[CH:23]=[CH:24][C:18]([S:15]([N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[CH:6]=[O:7])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccnc2C=O)cc1
Yield: 58.2 %

Procedure:
To a suspension of 2-imidazolecarboxaldehyde (1.01 g, 10.51 mmol) in CH2Cl2 (25 mL) was added Et3N (2.9 mL, 21.02 mmol) and tosyl chloride (3.01 g, 15.77 mmol) and the reaction mixture was heated to reflux overnight. Then the mixture was cooled and washed with saturated NH4Cl (4×30 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a dark brown oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded 1-(toluene-4-sulfonyl)-1H-imidazole-2-carbaldehyde as a yellow oil (1.53 g, 58%). 1H NMR (CDCl3) δ 2.45 (s, 3H), 7.31 (s, 1H), 7.49 (d, 2H, J=6.0 Hz), 7.83 (s, 1H), 8.00 (d, 2H, J=7.5 hz), 9.78 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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.COCCOC.CCO>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:19][CH2:20]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
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: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3Cl)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.11 g, 0.327 mmol), 2-chlorophenylboronic acid (51 mg, 329 μmol), 5 mL DME/EtOH (4:1), 0.5 mL 2M K2CO3 and tetrakis(triphenylphosphine)palladium (20mg) was stirred at 90° C. for 1 h. The reaction mixture was cooled to RT. The crude product was purified via flash chromatography (silica gel) with 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the crude compound (120 mg) as a yellow solid. The compound was further purified by HPLC by dissolving the crude product in methanol (˜20 mg/mL) and injecting at a rate of about 0.500 mL per injection onto the Gilson preparatory HPLC. Pure product fractions were collected, combined, basefied with sodium bicarbonate (saturated, aqueous), extracted with CH2Cl2, separated, dried over sodium sulfate, and concentrated via rotary evaporation to give pure title compound (28.8 mg) as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:45])=[C:39]([S:41]([O-:44])(=[O:43])=[O:42])[CH:40]=1.[Na+]>C(Cl)Cl.C1COCC1>[OH:45][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])=[CH:40][C:39]=1[S:41]([OH:44])(=[O:42])=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ccc(O)c(S(=O)(=O)[O-])c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@@H](CCC(=O)Nc1ccc(O)c(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) was dissolved in methylene chloride (1 ml) and THF (1 ml), and CDI (65 mg, 1.1 mmol) was added to the solution. The mixture was stirred for 30 minutes at room temperature. Sodium 5-amino-2-hydroxybenzenesulfonate (77 mg, 0.33 mmol) was added to the mixture and stirred overnight at room temperature. After the solvent was removed by distillation, the mixture was purified in accordance with the purification step A. The resulting intermediate was dissolved in 2 ml of TFA. After stirring for 3 hours at room temperature, the solvent was distilled off. The mixture was purified according to the purification step A to give the title compound.
Reaction SMILES: CCN=C=[N:5][CH2:6][CH2:7][CH2:8]N(C)C.Cl.[C:13]1([CH2:19][C:20]([OH:22])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N)CC.C1C=CC2N(O)N=NC=2C=1>CC#N.CCOC(C)=O>[C:13]1([CH2:19][C:20]([NH:5][CH2:6][CH2:7][CH3:8])=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCN
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCNC(=O)Cc1ccccc1
Reaction time: 72 h

Procedure:
EDAC.HCl (959 mg, 5 mmol) was added to a mixture of phenylacetic acid (681 mg, 5 mmol), propylamine (411 μL, 5 mmol) and HOBT (676 mg, 5 mmol) in 5 mL of CH3CN. The reaction was stirred for 72 hours. After this time, the mixture was diluted with AcOEt. The organic layer was washed three times with HCl 2N, three times with NaOH 2N, dried over MgSO4 and concentrated. A with solid was obtained (576 mg, 65%). NMR 1H (ppm, CDCl3): 7.39-7.24 (m, 5H), 5.38 (br. s., 1H), 3.57 (s, 2H), 3.20-3.13 (m, 2H), 1.45 (sex. J3=7.19 Hz, 2H), 0.83 (t, J3=7.40 Hz, 3H).
Reaction SMILES: [CH:1]1([N:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11](Br)=[C:10]([CH3:15])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:35])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>N1C(C)=CC(C)=CC=1C>[CH:17]1([N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11]([O:35][C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)=[C:10]([CH3:15])[CH:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1Br
Reactant: COc1cc(O)cc(OC)c1OC
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Oc2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2C)cc(OC)c1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using 4-bromo-3-methyl benzoic acid N-cyclopentyl-N-cyclohexyl amide (983 mg, 2.7 mmol), 3,4,5-trimethoxy phenol (983 mg, 2.7 mmol) and cuprous oxide (200 mg, 1.3 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 181-182° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CO
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
5 g of 4-fluoro-3-trifluoromethylbenzoic acid and 9 ml SOCl2 were stirred in 50 ml of MeOH at 60° C. for 8 h. The volatile constituents were then removed in vacuo to result in 5.1 g of a colorless oil, which was employed further without purification.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)OC1(c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 72, 80.0 mg, 0.23 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 48.0 mg (56%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:24](O)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([N:13]1[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[CH2:10][CH:11]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:12]1)=[O:29]
Reactant: CC(C)(C)C(=O)O
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C(C)(C)C)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 22 mg (0.22 mmol, 1.1 eq.) of pivalic acid were reacted according to General Method 1. Yield: 37 mg (34% of theory)
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(N(CC)CC)C.[C:33]([NH:36][C:37](=[O:40])[CH2:38]Cl)(=[O:35])[CH3:34]>O>[C:33]([NH:36][C:37](=[O:40])[CH2:38][S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:35])[CH3:34]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)NC(=O)CCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a suspension of 100.4 g. (0.40 mole) of triphenylmethylmercaptan in 500 ml. of dry dimethylformamide was added 40.4 g. (0.40 mole) of dry triethylamine. The reaction mixture was cooled in ice and stirred as portions of 54.2 g. (0.40 mole) of the product of Step A above were added over 10 minutes. The reaction mixture was stirred an additional hour with ice cooling and then overnight at room temperature. Water was then added carefully to the reaction mixture until just before the cloud point, when the mixture was seeded and crystallization began. Yield of product was 98.5 g. with an m.p. of 147°-149° C.