Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)=[CH:3][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[C:13]([CH3:19])([CH3:18])[CH2:12][CH2:11][C:10]2([CH3:21])[CH3:20])(=[O:6])=[O:5].C([Li])CCC.CCCCCC>C1COCC1>[C:3]([S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[C:13]([CH3:19])([CH3:18])[CH2:12][CH2:11][C:10]2([CH3:21])[CH3:20])(=[O:6])=[O:5])#[CH:2]
Reactant: Cc1cc2c(cc1S(=O)(=O)C=C(Cl)Cl)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 5(b), by reaction at −78° C. of 6-(2,2-dichlorovinylsulphonyl)-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (8 g, 24.3 mmol) in 200 ml of THF with 2.5 M n-butyllithium/hexane (21.4 ml, 53.5 mmol), 2.08 g (33%) of the expected alkyne are obtained in the form of a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:26](=[O:28])[CH3:27])[CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.CO.[OH-].[Na+]>C1COCC1.C(Cl)Cl.O>[C:26]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:29])=[O:2])[CH:6]=1)[CH3:25])(=[O:28])[CH3:27]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C)C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C)C(C)=O

Procedure:
{2′-[(Acetyl-methyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester (0.038 g, 0.09 mmol) was dissolved in THF (0.38 mL), MeOH (0.3 mL), and aqueous 1N NaOH (0.2 mL), and the mixture was stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was diluted with CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC. The desired fractions were combined, concentrated, and the isolated material was diluted with CH2Cl2 and neutralized with saturated aqueous NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated to give the title compound. The aqueous layer was acidified and extracted with EtOAc, and the organic layer was concentrated to give additional product.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[O:5][C:6]2[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12]=2F)[N:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[O:5][C:6]2[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12]=2[N:36]2[CH2:37][CH2:38][C@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]2)[N:8]=1)[CH3:2]
Reactant: CCN(CC)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 150 °C
Reaction time: 60 h
Yield: 65.9 %

Procedure:
2-(Diethylamino)-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-133) (78 mg, 0.24 mmol) was dissolved in dimethyl sulfoxide (2 ml) in a sealed tube, then triethylamine (67 μl, 0.48 mmol) and (3S)-3-(dimethylamino)pyrrolidine (61 μl, 0.48 mmol) were added. The reaction system was heated at 150° C. for 4.5 hours and then at 100° C. for 60 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, and this was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=92:8) to obtain the entitled compound (66 mg, 65%) as a brown solid.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[C@H:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[NH:23][CH:22]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[C@H:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:2]3[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=3)[CH:28]=2)[NH:23][CH:22]=1)[CH3:20]
Reactant: Cc1ncc(Br)n1C
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnc(C)n3C)cc12
Temperature: 100 °C

Procedure:
A solution of 5-bromo-1,2-dimethyl-1H-imidazole (0.0183 g, 0.104 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxy-phenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.030 g, 0.070 mmol), potassium carbonate (0.0289 g, 0.209 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (2.84 mg, 0.00348 mmol) in previously degassed 4:1 dioxane:water (1.50 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. The reaction mixture was purified by Gilson HPLC resulting in the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.1 Hz, 3H), 2.58 (s, 3H), 3.47 (s, 3H), 3.67 (s, 3H), 5.12 (q, J=7.1 Hz, 1H), 6.90 (dd, J=4.3, 9.1 Hz, 1H), 7.08 (dd, J=9.0, 9.0 Hz, 1H), 7.22 (s, 1H), 7.46 (d, J=1.0 Hz, 1H), 7.56 (s, 1H), 8.18 (d, J=1.8 Hz, 1H). MS (ES+): m/z 399.12, 401.11 (76/24) [MH+]. HPLC: tR=2.77 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[N:13]=[CH:14][C:15]([C:18]2[CH:19]=[C:20]([C:25]3[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[O:27][N:26]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[N:16][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[N:16][C:15]([C:18]2[CH:19]=[C:20]([C:25]3[C:29](=[O:30])[C:28]([CH3:31])([CH3:32])[O:27][N:26]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[CH:14][N:13]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(N)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(NC(=O)c2ccccc2Cl)cn1
Temperature: 0 °C
Yield: 33.8 %

Procedure:
To a 0° C. cooled and stirred, solution of 2-chlorobenzoyl chloride (43 μL, 0.34 mmol, 1.0 eq) in DCM (2 mL) was added drop wise a solution of Intermediate 1b, (100 mg, 0.34 mmol, 1.0 eq) in DCM (5 mL) followed by pyridine (47 μL, 0.44 mmol, 1.3 eq). The resulting mixture was stirred at room temperature for 15 h. The reaction was diluted with DCM (10 mL), and washed with 10% hydrochloric acid (5 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane as eluent) to afford 50 mg of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 8.80 (s, 1H, D2O exchangeable), 8.39 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.09 (dd, J=8.0, 2.0 Hz, 1H), 7.84 (dd, J=7.0, 1.5 Hz, 1H), 7.52-7.40 (m, 4H), 2.47 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 435, 437 [(MH)+, Cl35,37].
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH2:9]P(OCC)(=O)OCC)[O:6][N:5]=1.COC([O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O)C>CS(C)=O>[CH3:3][C:4]1[CH:8]=[C:7]([CH:9]=[CH:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[OH:22])[O:6][N:5]=1
Reactant: COC(C)Oc1ccccc1C=O
Reactant: CCOP(=O)(Cc1cc(C)no1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C=Cc2ccccc2O)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.8 g (0.2 mole) of a 55% strength suspension of sodium hydride in paraffin oil are introduced into 100 ml of absolute dimethylsulfoxide. 47 g (0.2 mole) of diethyl (3-methyl-isoxazol-5-yl)-methanephosphonate are added dropwise at room temperature. The mixture is then stirred for 30 minutes, after which 36 g (0.2 mole) of o-(1-methoxyethoxy)-benzaldehyde are added dropwise, with continued stirring. The reaction mixture is then stirred for 24 hours at room temperature and is poured onto 1 liter of ice water, and the batch is extracted 3 times with 80 ml of methylene chloride at a time. The combined organic phases are dried with sodium sulfate and evaporated down on a rotary evaporator. The oily residue is dissolved in 80 ml of methanol and 10 ml of water, 2 ml of 5 N HCl are added, and the mixture is stirred for 10 minutes. Excess water is then added slowly until a precipitate forms. This is filtered off, washed with water and recrystallized from ethanol. 19 g (47% of theory) of colorless crystals, of melting point 236°-238° C., are obtained.
Reaction SMILES: ClC1C=C(C2C(OC)=CC=C([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)=[O:17])C=2F)C=CC=1.C(NC1C=CC(C(O)=O)=CC=1)(=O)C.O=S(Cl)[Cl:44]>C1COCC1.CN(C=O)C>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([Cl:44])=[O:17])=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: COc1ccc(C(=O)c2ccc(NC(C)=O)cc2)c(F)c1-c1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Agent: CC(=O)Nc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Synthesis of N-[4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide (I-19, R1═CH3, R2═Cl, Y═F, R3=4-acetylaminophenyl): To a stirred suspension of 4-acetylaminobenzoic acid (Aldrich, 1.32 g, 5.58 mmol) in anhydrous THF (20 mL) was added SOCl2 (1.19 g, 10.04 mmol) and DMF (4 drops). The reaction mixture was stirred at room temperature for 3 h, concentrated under vacuum to afford 4-acetylaminobenzoyl chloride (I-18, R3=4-acetylaminophenyl) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=[O:5].C1COCC1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([N:1]2[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:21])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(Br)cc1C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1cc(Br)ccc1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a vial charged with 2-amino-5-bromobenzaldehyde (commercially available from Matrix Scientific, Columbia, S.C.) (0.500 g, 2.500 mmol) were added THF (4.17 mL), toluene (4.17 mL), TEA (0.871 mL, 6.25 mmol) and phthalic anhydride (0.849 mL, 8.75 mmol). The mixture was heated at 100° C. overnight. LC-MS indicated that the product was present as a component of a complex mixture. The resulting mixture was passed through a 10 g SCX-2 column with much solid sticking to the top of the column and some product eluting through indicating a solubility issue in MeOH. The solid and filtrate were dissolved in DCM:MeOH and the crude residue was adsorbed onto silica gel with drying under reduced pressure. The adsorbed material was purified with a 50 g SNAP column ramping EtOAc in heptane from 0-45%, then isocratic at 45% to elute 5-bromo-2-(1,3-dioxoisoindolin-2-yl)benzaldehyde (0.290 g, 0.878 mmol, 35.1% yield) as a yellow solid. m/z (ESI) 330.0/332.0 (M+H)+.
Reaction SMILES: CN(C=O)C.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].Br[C:13]1[C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[S:15][C:14]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[N+:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:13]([C:11]#[C:10][Si:7]([CH3:9])([CH3:8])[CH3:6])=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:15][C:16]=2[CH:21]=1)([O-:24])=[O:23]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1Br
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
DMF (20 ml), (trimethylsilyl)acetylene (5 ml), triethylamine (10 ml) and bis(triphenylphosphine)palladium (II) dichloride (420 mg, 0.6 mmol) were added to ethyl 3-bromo-6-nitro-1-benzothiophene-2-carboxylate obtained in Example (183b) (794 mg, 2.41 mmol) and copper (I) iodide (12 mg, 0.63 mmol), and the mixture was stirred at 80° C. for one hour. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with dilute hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10) and recrystallized from an ethyl acetate/hexane solvent, to obtain 110 mg of the title compound as crystals.
Reaction SMILES: [N+]([O-])([O-])=O.[Ag+:5].[C:6](=[O:9])([O-:8])[O-:7].[Sr+2:10]>[N+]([O-])([O-])=O.[Ag+]>[C:6](=[O:7])([O-:9])[O-:8].[Ag+2:5].[C:6](=[O:7])([O-:9])[O-:8].[Sr+2:10]
Reactant: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Sr+2]
Product: [Ag+2]
Reaction time: 3 h

Procedure:
100 g of an aqueous silver nitrate solution containing 10 g of silver nitrate was added dropwise to 245.0 g of a slurry solution containing 23.5 g of strontium carbonate having a surface area of 6.7 m2/g and an alkaline metal content of 20 ppm or less (manufactured by SAKAI CHEMICAL INDUSTRY CO., LTD., under the trade name of SW-K) as alkaline earth metal carbonate at 20° C. to 25° C., followed by stirring for 3 hours. The solid was collected by filtration, washed with 200 mL of ion exchanged water four times to obtain 193 g of a silver carbonate/strontium carbonate mixture. Then, a sliver catalyst was prepared by filling the resulting silver carbonate/strontium carbonate mixture in a calcinations glass tube, followed by subjecting to calcination at 350° C. for 3 hours under an air flow of 100 mL/min.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][C:6]([C:10](OC)=[O:11])=[N:7][C:8]=1[CH3:9].[BH4-].[Na+]>O>[CH3:2][C:3]1[N:4]=[CH:5][C:6]([CH2:10][OH:11])=[N:7][C:8]=1[CH3:9]
Reactant: COC(=O)c1cnc(C)c(C)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1ncc(CO)nc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
To a solution of methyl 5,6-dimethylpyrazine-2-carboxylate hydrochloride (340 mg, 1.68 mmol) in water (10 mL) was added sodium borohydride (320 mg, 8.4 mmol) in 5 portions at 0° C. Then the mixture was allowed to warm to room temperature and stirred for 16 h. The solvent was then removed under reduced pressure, chloroform (30 mL) was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give an off yellow solid (125 mg). MS (ESI): m/z 139.1 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][CH2:8][N:9]([CH:14]1[CH2:19][CH2:18][CH:17]([N:20](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][CH2:15]1)[S:10]([CH3:13])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]>CCO.CO.[OH-].[OH-].[Pd+2]>[C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][CH2:8][N:9]([CH:14]1[CH2:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH2:19]1)[S:10]([CH3:13])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1)S(C)(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCN(C1CCC(N)CC1)S(C)(=O)=O
Yield: 98 %

Procedure:
N-[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-N-(4-dibenzylamino-cyclohexyl)-methanesulfonamide (3.282 g, 6.18 mmol) and Pd(OH)2 (0.40 g) were combined in EtOH/MeOH under Ar, and treated with H2 (45 psi) at RT for 1 day. The reaction mixture was then filtered, the solid washed with EtOH, the filtrates combined, and solvent removed in vacuo to yield N-[2-(t-butyl-dimethyl-silanyloxy)-ethyl]-N-(4-amino-cyclohexyl)-methanesulfonamide (2.123 g).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[CH:11]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:28][CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[CH:11]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)Cc1sc(S)nc1-2
Product: O=C(O)COc1ccc2c(c1)Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 42 %

Procedure:
Using ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-6-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 42%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]2[N:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[OH:17][CH2:16][C@:11]([CH3:15])([CH2:10][C@H:9]([NH:18][C:19]([C:21]1[N:22]=[N:23][NH:24][CH:25]=1)=[O:20])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[CH:3][CH:4]=1)[C:12]([OH:14])=[O:13]
Reactant: Cc1ccccc1B(O)O
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1ccc(C[C@H](C[C@@](C)(CO)C(=O)O)NC(=O)c2c[nH]nn2)cc1
Temperature: 90 °C
Yield: 34.2 %

Procedure:
(2S,4R)-5-(4-bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid (38 mg, 92 μmol) was combined with 2-methylphenylboronic acid (25.1 mg, 185 μmol), sodium carbonate (29.4 mg, 277 μmol), water (0.2 mL) and dioxane (1.5 mL). The reaction vessel was sealed, air was removed by vacuum, and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18 μmol) was quickly added and air was removed by vacuum. The mixture was heated at 90° C. for 45 minutes. The mixture was acidified to pH ˜3 and filtered, and the solvate was concentrated. The residue was dissolved in AcOH (0.7 mL) and purified by preparative HPLC to yield the title compound (13.3 mg). MS m/z [M+H]+ calc'd for C23H26N4O4, 423.20. found 423.2.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 40.9 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.4 mg) was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:11])[CH3:10]>CN(C=O)C.C(Cl)Cl>[C:9]([C:12]1[C:13]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:16]([Br:1])[CH:17]=1)(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1ccc(C(C)=O)c(OCc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
N-Bromosuccinimide (0.756 g, 4.27 mmol) was added portionwise to a solution of N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (1.2 g, 4.24 mmol) in DMF (24 ml) and the reaction stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with water and dried over MgSO4 to afford a white solid (1.03 g, 67%). LC/MS: RT=2.609 min. 362/364 (MH+).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]#[C:3][C:4]([O:6][CH3:7])=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:12]1([NH:11]/[C:3](=[CH:2]/[C:1]([O:9][CH3:10])=[O:8])/[C:4]([O:6][CH3:7])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)/C=C(/Nc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl but-2-ynedioate (1.452 mL) in methanol (20 mL) was added aniline (0.98 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was purified by column chromatography on silica gel (20-50% ethyl acetate in hexane) to obtain the title compound (1.73 g) having the following physical data.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:17]#[N:18])[C:10]=2[N:9]=[CH:8]1
Reactant: CN1CCCC1=O
Reactant: Brc1cccc2c1ncn2C1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1ncn2C1CCCCO1
Temperature: 85 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
A mixture of 54 (1.30 g, 4.62 mmol), Zn(CN)2 (1.08 g, 9.24 mmol), Pd(PPh3)4 (0.53 g, 0.46 mmol) and NMP (15 mL) was stirred under nitrogen at 85° C. for 14 h. The mixture was filtered and the filtrate was purified by reverse phase chromatography eluting with 35% MeCN/H2O (containing 0.5% ammonia) to afford 0.75 g (70%) 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-4-carbonitrile (56) as brown solid: MS (ESI) m/z=228.3 [M+l]+.