Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.N1C=CC=CC=1.[Cl:29][CH2:30][CH2:31][C:32](Cl)=[O:33].[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CN(C)C=O>[Cl:29][CH2:30][CH2:31][C:32]([NH:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)=[O:33]
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1N
Reactant: O=C(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1NC(=O)CCCl
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.7 %

Procedure:
To a solution of 3-amino-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine (0.6 g) and pyridine (0.2 g) in toluene (10 ml) was added 3-chloropropionyl chloride (0.32 g) at 0° C. The mixture was stirred at the same temperature for 30 minutes and further at ambient temperature for 6 hours. After the mixture was allowed to stand at ambient temperature for 3 days, N,N-dimethylformamide (10 ml) was added thereto to dissolve the precipitates. The mixture was stirred at ambient temperature for 5 hours, diluted with ice-cold water (50 ml) and ethyl acetate (50 ml), and adjusted to pH 10 with 5N sodium hydroxide. The separated organic layer was washed with brine, dried and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 3-(3-chloropropionylamino)-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine (0.48 g).
Reaction SMILES: Cl[C:2](=[CH2:7])[C:3]([O:5][CH3:6])=[O:4].[Cl-].C([N+](CC)(CC)CCCC)C.C([O-])([O-])=O.[K+].[K+].[CH:26]1([C:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41]([O:43][CH3:44])=[O:42])=[CH:38][CH:39]=3)[NH:34][C:33]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CC#N>[CH:26]1([C:32]2[C:40]3[CH:39]=[CH:38][C:37]([C:41]([O:43][CH3:44])=[O:42])=[CH:36][C:35]=3[N:34]3[C:33]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:51][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:7]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Reactant: C=C(Cl)C(=O)OC
Agent: CCCC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Oc1ccccc1-3
Temperature: 60 °C
Yield: 81 %

Procedure:
Methyl chloroacrylate (1.7 eq.), triethylbutyl ammonium chloride (0.2 eq.) and K2CO3 (6 eq.) were added to a solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in International patent application publication W02006/046030, Example 9) in anhydrous MeCN (0.02 M). The mixture was heated at 60° C. overnight and then allowed to cool to RT. Volatiles were removed in vacuo, diluted with EtOAc, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by FC (EtOAc/PE 10:90) to afford the product as a solid (81%). (ES+) m/z 434 (M+H)+.
Reaction SMILES: COCCOC.Br[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
Reactant: CCOC(=O)c1ncccc1Br
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: ClCCl
Solvent: COCCOC
Product: CCOC(=O)c1ncccc1-c1ccccc1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
150 ml of 1,2-dimethoxyethane were aerated with argon, and 874 mg (0.75 mmol) of Pd(PPh3)4 and 3.45 g (15 mmol) ethyl 3-bromopyridine-2-carboxylate were added. After 10 min, 5.53 g (22.5 mmol) of 2-(tert-butoxycarbonylaminomethyl)phenylboronic acid and finally 15 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux for 18 h under argon, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 3.4 g (66%) of a viscous oil were obtained. MS (ES+): m/z=357 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:25][CH2:26][CH2:27][CH2:28]I.O>O1CCCC1.CCOCC>[Cl:25][CH2:26][CH2:27][CH2:28][CH:13]1[C:12](=[O:16])[C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][O:9][C:10]=2[CH2:15][CH2:14]1
Reactant: ClCCCI
Reactant: O=C1CCCc2onc(-c3ccccc3)c21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In 478 ml anhydrous tetrahydrofuran (THF) was dissolved 10.2 g 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 47.8 ml lithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise. The resulting solution was stiffed for 10 minutes at -78° C. and 7.7 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and ether. The layers were separated and the aqueous phase was extracted twice with dichloromethane and twice with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (10% ethyl acetate/hexane) gave 6.2 g of 5-(3-chloropropyl) -6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH:46]1[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:48]=[N:47]1>>[CH2:54]([O:53][C:51]([C:49]1[CH:50]=[N:46][N:47]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:48]=1)=[O:52])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 65.3 %

Procedure:
By a procedure analogous to that of Example 32 Step A, t-butyl 4-hydroxypiperidine-1-carboxylate (0.79 g, 3.6 mmol) was reacted with triphenylphosphine (1.26 g, 4.8 mmol), diethyl azodicarboxylate (0.76 mL, 4.8 mmol) and ethyl 1H-pyrazole-4-carboxylate (0.50 g, 3.6 mmol) to afford the title compound (0.76 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:29]([N:30]2[CH2:41][CH2:40][N:39]3[C:32](=[CH:33][C:34]4[CH2:35][C:36]([CH3:43])([CH3:42])[CH2:37][C:38]=43)[C:31]2=[O:44])=[CH:28][C:27]([F:45])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1)(=[O:21])[CH3:20].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.C(OCC)C.O.C(OCC)(=O)C>[CH2:17]([N:13]1[C:14]([CH3:16])=[CH:15][C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:25]3[C:24]([CH2:23][O:22][C:19](=[O:21])[CH3:20])=[C:29]([N:30]4[CH2:41][CH2:40][N:39]5[C:32](=[CH:33][C:34]6[CH2:35][C:36]([CH3:42])([CH3:43])[CH2:37][C:38]=65)[C:31]4=[O:44])[CH:28]=[C:27]([F:45])[CH:26]=3)[CH:3]=2)=[N:12]1)[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CCn1nc(Nc2cc(Br)cn(C)c2=O)cc1C
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: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1nc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)cc1C
Temperature: 130 °C
Yield: 63.3 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 302a (170 mg, 0.5 mmol), 230a (350 mg, 0.7 mmol), 1,2-dimethoxyethane (4 mL) and 1M aqueous sodium carbonate (1.6 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (31 mg, 0.03 mmol) was added. The mixture was heated in microwave to 130° C. for 15 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of methylene chloride-60:35:5 methylene chloride:diethyl ether:methanol to afford a 60% yield (190 mg) of 302b.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([CH2:6][NH:7][C:8]2[C:9](=O)[C:10](=[O:15])[C:11]=2[O:12]CC)=[C:4]([CH3:20])[CH:3]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([CH2:6][NH:7][C:8]2[C:11](=[O:12])[C:10](=[O:15])[C:9]=2[NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:17]([CH3:19])[CH:18]=1
Reactant: CC(C)(C)N
Reactant: CCOc1c(NCc2c(C)cc(Br)cc2C)c(=O)c1=O
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1CNc1c(NC(C)(C)C)c(=O)c1=O
Reaction time: 18 h

Procedure:
A solution of 3-(4-bromo-2,6-dimethyl-benzylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione (0.49 g, 1.45 mmol), t-butylamine (26 mL) and dichloromethane (8 mL) was allowed to stand at room temperature for 18 hours, then refluxed for 8 hours. The resulting solid was filtered, rinsed with acetonitrile, and dried (0.4 mm, 40° C.). This gave 0.33 g (62%) of the title compound as an off-white solid: mp 267°-271° C. (dec); 1H NMR (DMSO-d6) δ7.40 (br s, 1H), 7.32 (s, 2H), 7.30 (br t, 1H), 4.76 (d, 2H), 2.34 (s, 6H), 1.34 (s, 9H) ppm. IR (KBr): 3200, 2980, 1790, 1650 cm-1 ; MS (m/z) 364/366 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].CN(C)CCN(C)C.C([Li])CCC.[CH2:32]1[O:34][CH2:33]1.B(F)(F)F.CCOCC>O1CCCC1>[OH:34][CH2:33][CH2:32][C:5]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]=1[O:13][CH3:14]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: C1CO1
Agent: CN(C)CCN(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1cc(OC)c(OCOC)c(CCO)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
10 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 500 ml of tetrahydrofuran, then to this solution was added 7.01 ml (46.44 mM) of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C. in a dry ice-acetone bath. To this cooled mixture was added dropwise 29.1 ml of n-butyllithium (1.6M-hexane solution), then stirred for 30 minutes. Next, 26.4 ml (2.091M solution) of tetrahydrofuran solution of ethylene oxide and 0.5 ml of boron trifluoride-diethyl ether (BF3 ·Et2O were added to the reaction mixture. 10 Minutes after, the dry ice-acetone bath was removed from the reaction equipment, then 2 hours later, the reaction mixture was concentrated to obtain the residue and 500 ml of diethyl ether was added thereto, and washed 4 times with 200 ml of water, further washed 4 times with 200 ml of a saturated sodium chloride aqueous solution, next dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was treated by a silica gel column chromatography [diameter 6 cm×length 30 cm, eluent: ethyl acetate:n-hexane=(2:3), "Wakogel C-200"] to yield 8.5 g of 1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene. Colorless needless crystals. Melting point: 121°-123° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([OH:9])=O)[N:4]([CH3:10])[C:3]1=[O:11].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:43][C:44]1[C:45]([CH3:52])=[C:46]([CH2:50][NH2:51])[CH:47]=[CH:48][CH:49]=1>ClCCl>[Cl:43][C:44]1[C:45]([CH3:52])=[C:46]([CH2:50][NH:51][C:7]([CH:5]2[CH2:6][N:2]([CH3:1])[C:3](=[O:11])[N:4]2[CH3:10])=[O:9])[CH:47]=[CH:48][CH:49]=1
Reactant: Cc1c(Cl)cccc1CN
Reactant: CN1CC(C(=O)O)N(C)C1=O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1c(Cl)cccc1CNC(=O)C1CN(C)C(=O)N1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
To 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylic acid (6.000 ml, 0.600 mmol) (0.1M solution in dichloromethane) was added the N-ethylmorpholine (0.380 ml, 3.00 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 0.720 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.720 mmol), and the reaction stirred at RT under argon for 10 minutes. [(3-Chloro-2-methylphenyl)methyl]amine (103 mg, 0.660 mmol) was then added and the reaction left to stir at RT under argon overnight. The reaction mixture was diluted with dichloromethane (15 ml) and then the solution was washed with saturated sodium hydrogen carbonate solution (20 ml), water (20 ml), 3N citric acid solution (20 ml), brine (20 ml) and then dried over magnesium sulphate. The solvent was evaporated in vacuo. The residue was purified by mass-directed automated HPLC. Fractions containing product were combined and solvent evaporated in vacuo, co-evaporated with diethyl ether to give the N-[(3-chloro-2-methylphenyl)methyl]-1,3-dimethyl-2-oxo-4-imidazolidinecarboxamide as a white solid (50 mg, 26.8% yield). LC/MS [M+H]+=296, retention time=1.96 minutes
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:19]=[C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:18])[C:12]2=[N:11]1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:19]=[C:13]2[CH:14]=[N+:15]([O-:28])[CH:16]=[C:17]([F:18])[C:12]2=[N:11]1
Reactant: Fc1cc(Cl)c(-n2cc3cncc(F)c3n2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(F)cc3Cl)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichloro-4-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (3.37 g, 11.2 mmol) in DCM (50 mL) under nitrogen, was added mCPBA (2.9 g, 16.8 mmol). The reaction mixture was stirred at 0° C. for 2 hours, warmed to room temperature, and stirred for a further 5 hours. The reaction was washed with sodium thiosulfate (sat. aq.), sodium hydrogen carbonate (sat. aq.), and brine. The organic layer was then dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to afford the title compound as an off-white solid (2.98 g, 84% yield). LCMS (Method D): RT=2.48 min, m/z: 316 [M+H+].
Reaction SMILES: C(OC([NH:8][C:9]([CH3:32])([CH3:31])[CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23]CC)=[O:22])[CH:19]=2)[CH:14]=[C:13]1[C:26]([O:28]CC)=[O:27])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)(=O)C.O>[NH2:8][C:9]([CH3:32])([CH3:31])[CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=2)[CH:14]=[C:13]1[C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CCC(C)(C)NC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(N)CCn1c(C(=O)O)cc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of the crude diethyl 1-{3-[(tert-butoxycarbonyl)amino-]-3-methylbutyl}-1H-indole-2,6-dicarboxylate from the preceding step in CH2Cl2 (3 mL) is added TFA (1.5 mL). The mixture is stirred at room temperature for 2 h. The solvent is evaporated and the residue dried in vacuo. To a solution of the residue in ethanol (8 mL). is added triethylamine (0.13 mL, 0.90 mmol) and K2CO3 (124 mg, 0.90 mmol). The mixture is heated at 80° C. for 2 h and at 100° C. for 64 h. Water (20 mL) and acetic acid (1 mL) are added and the mixture is extracted with EtOAc. The organic layers are dried (Na2SO2) and concentrated to afford the title compound which is used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:55]=[CH:54][C:16]([C:17]([N:19]([CH2:46][C:47]([O:49]C(C)(C)C)=[O:48])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][NH:30][C:31]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)=[CH:35][CH:34]=4)=[O:32])=O)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:56]([F:59])([F:58])[F:57])[CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]([CH2:46][C:47]([OH:49])=[O:48])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[O:32][C:31]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=6)=[CH:35][CH:34]=5)=[N:30][N:29]=4)=[CH:25][CH:26]=3)=[O:18])=[CH:54][CH:55]=2)=[O:11])=[C:5]([C:56]([F:58])([F:57])[F:59])[CH:4]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)NNC(=O)c4ccc(-c5ccc(C)cc5)cc4)cc3)cc2)c(C(F)(F)F)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4nnc(-c5ccc(-c6ccc(C)cc6)cc5)o4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
To a stirring solution of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4′-methyl-[1,1′-biphenyl]-4-carbonyl)hydrazine carbonyl)benzyl)benzamido)acetate INT-51 (138 mg, 0.17 mmol) and triethylamine (37 μL, 0.26 mmol) in DCM (4 mL) was added 2-chloro-1,3-dimethylimidazolinium chloride (32.0 mg, 0.19 mmol). After stirring at room temperature for 16 h, the reaction mixture was warmed to 40° C. After 1 h, additional triethylamine (37.0 μL, 0.26 mmol) was added. After a further 2 h, the reaction mixture was allowed to cool to room temperature then washed with NaHCO3 (10 mL), split through a hydrophobic frit and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was diluted with DCM (2 mL), treated with TFA (2 mL) and allowed to stir for 1 h at room temperature. The solvents were concentrated and the residue purified by preparative HPLC to afford 10 mg (8%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)benzyl)benzamido)acetic acid 367 as a white solid. LCMS-ESI (m/z) calculated for C41H33F3N4O6: 734; found 735 [M+H]+, tR=8.40 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 10.36 (s, 1H), 8.26-8.09 (m, 4H), 7.99-7.87 (m, 2H), 7.77-7.50 (m, 6H), 7.47-7.31 (m, 5H), 7.26-7.14 (m, 2H), 4.76 (s, 1H), 4.69 (s, 1H), 4.04 (s, 1H), 3.96 (m, 1H), 3.88-3.77 (m, 5H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([O:5]S(C(F)(F)F)(=O)=O)([CH3:4])[CH3:3].[CH2:13]([C:15]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[C:41][C:42]2(O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[C:36]([CH3:50])[CH:35]=1)([C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[C:20]([CH3:33])[CH:19]=1)[CH2:16][CH3:17])[CH3:14].N1C=CC=CC=1.[Cl-].[NH4+]>ClCCl>[CH2:13]([C:15]([C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:25][C:26]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:30])[O:28]2)=[C:20]([CH3:33])[CH:19]=1)([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[C:41][C:42]2([O:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[C:36]([CH3:50])[CH:35]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 1.5 h
Yield: 30.3 %

Procedure:
Trifluoromethanesulfonic acid trimethylsilyl ester (0.37 mL, 2.04 mmol) was added to a solution of the mixture containing 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-cycloheptanol (529 mg) and pyridine (0.42 mL, 5.19 mmol) in dichloromethane (4.0 mL) at 0° C., and the mixture was stirred at the same temperature for 90 minutes. An ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 80:20) to give the target compound as a colorless oil (183 mg, 28% in three steps).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[O:11]C(=O)OC(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]3[CH:33]=[CH:32][NH:31][C:28]3=[N:29][CH:30]=2)[CH:20]=1.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:33]2[C:27]3[C:28](=[N:29][CH:30]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[CH:26]=3)[NH:31][CH:32]=2)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C=O)c1F
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To carbonic acid tert-butyl ester 2,4-difluoro-3-formyl-phenyl ester (39, 0.405 g, 15.7 mmol) in methanol (36 mL), under an atmosphere of nitrogen, was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 288.0 mg, 14.8 mmol, prepared as described in Example 17) and potassium hydroxide (145.0 mg, 25.9 mmol). The reaction was stirred at room temperature overnight. Then, the reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The mixture was purified by silica gel column chromatography eluting with 4% methanol in methylene chloride to provide two separate compounds, a colorless oil (P-0009, 0.23 g, 44.1%, MS (ESI) [M+H+]+=354.1), and a colorless oil (P-0042, 0.050 g, 9.2%, MS (ESI) [M+H+]+=367.1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[C@H:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][NH:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[C@H:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][N:10]([CH3:11])[S:28]([CH3:27])(=[O:30])=[O:29])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H](Cc1cccs1)N(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
N-Methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester (1.72 g, 6.05 mmol) was dissolved in dichloromethane (30 ml). Triethylamine (0.84 ml, 6.05 mmol) was added. The solution was cooled to -78° C. Methanesulfonyl chloride (0.47 ml, 6.05 mmol) was added dropwise. The reaction mixture was warmed to room temperature over a period of 3.5 h. It was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (100 ml). It was washed with 10% aqueous sodium hydrogen sulfate solution (200 ml). The aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetate/heptane 1:1 as eluent, to give 1.94 g of N-methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester.