Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11](C(N)=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].BrBr.[OH2:28]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([NH:8][C:6]([O:5][CH3:1])=[O:28])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(C(N)=O)c2C1
Agent: BrBr
Agent: [Na]
Solvent: CO
Product: COC(=O)Nc1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 84 %

Procedure:
2-t-Butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine-10-carboxamide (0.5 g, 1.53 mmol) was added to a solution of sodium (0.078 g, 3.37 mmol) in methanol (31 ml), and bromine (0.245 g, 1.53 mmol) was added dropwise thereto while maintaining the temperature at 25° C. or lower. After completion of the dropwise addition, the resulting mixture was heated under reflux for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by a silica gel chromatography (hexane-ethyl acetate=1 : 1) to obtain the desired compound (0.46 g, 1.28 mmol, 84%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][CH:7]=[N:8][CH:9]=1)=[O:4].Br[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([CH2:11][N:6]2[C:5]([C:3]([OH:2])=[O:4])=[CH:9][N:8]=[CH:7]2)=[O:13])=[N:16][CH:17]=1
Reactant: COC(=O)c1cnc[nH]1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cncc1C(=O)O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 200 mg 3H-Imidazole-4-carboxylic acid methyl ester, 396 mg), 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide and 220 mg K2CO3 in 2 ml DMF was stirred for 16 h at RT. The solvent was removed under reduced pressure and the precipitate dissolved in 5 ml THF/water 2:1. Then, 1.5 ml KOH 10% was added at RT and the reaction mixture was stirred for 16 h. Finally, 3 ml of halfconcentrated hydrochloric acid was added to precipitate the acid as a white solid. Yield: 260 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]([CH:16]=O)=[C:14]([Br:18])[N:13]=[C:12]2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]([F:23])[C:5]=1[F:24].N1C=CC=CC=1.[OH2:32].[NH2:33]O.Cl>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]([CH:16]=[N:33][OH:32])=[C:14]([Br:18])[N:13]=[C:12]2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]([F:23])[C:5]=1[F:24]
Reactant: CCCCc1nc(Br)c(C=O)n1Cc1ccc(C(=O)OC)c(F)c1F
Reactant: NO
Reactant: O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1nc(Br)c(C=NO)n1Cc1ccc(C(=O)OC)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
Intermediate (8a) (4.1 g, 10 mmol) was dissolved in pyridine (20 mL, 200 mmol), and water (10 mL, 600 mmol). NH2OH.HCl (898 mg, 12.9 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (20 mL) and the mixture stirred for 20 minutes. The resulting solid was filtered and dried to yield 3.6 g of intermediate (8b) as a light yellow solid. MS m/z: [M+H+] calcd for C17H18BrF2N3O3, 431.24. found 432.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#N>>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:39]=[CH:38][C:37]([C:21]5[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=5)=[CH:36][CH:35]=4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(-c5cnn(C)c5)cc4)cc3)[C@H]2C1

Procedure:
The title compound was prepared according to the procedure described in Example 7D, substituting the product of Example 41A for the product of Example 7C and substituting 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 4-cyanophenylboronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 7.78 (s, 1H) 7.62 (s, 1H) 7.45-7.60 (m, 6H) 6.65 (d, J=8.82 Hz, 2H) 4.11-4.21 (m, 1H) 3.95 (s, 3H) 3.50-3.61 (m, 1H) 3.23-3.35 (m, 1H) 2.90-3.05 (m, 1H) 2.69-2.77 (m, 1H) 2.50-2.69 (m, 3H) 2.33 (s, 3H) 2.11-2.26 (m, 1H) 1.88-2.02 (m, 1H). MS: (M+H)+=359.
Reaction SMILES: CN(C)C=O.C(N(CC)CC)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:23][CH3:24])[CH2:21][OH:22])=[CH:16][CH:15]=1.[I-].C[S+]=[C:28]1[S:32][CH2:31][CH2:30][S:29]1>C(OCC)C>[S:29]1[CH2:30][CH2:31][S:32][C:28]1=[N:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:23][CH3:24])[CH2:21][OH:22])=[CH:18][CH:19]=1
Reactant: CCC(CO)c1ccc(N)cc1
Reactant: C[S+]=C1SCCS1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CO)c1ccc(N=C2SCCS2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 450 ml of dimethylformamide containing 23.8 ml of triethylamine was added 11.4 g of 2-(4-aminophenyl)-butanol and to the resulting solution was added, in portions over 45 minutes, 21 g of methyl(1,3-dithiolan-2-ylidene)sulfonium iodide. The resulting hazy-yellow solution was stirred for 2 hours and then poured into ice water. The aqueous mixture was extracted 5 times with diethyl ether and the combined organic extracts were washed 7 times with 0.2 N hydrochloric acid, twice with water and once with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and the resulting crude residue was purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. The purified light-yellow oil obtained was immediately dissolved in warm diethyl ether and allowed to crystallize. The solid which formed was separated by filtration and dried to give 2-[4-(1,3-dithiolan-2-ylideneamino)phenyl]butanol as white spars melting at about 98.5°-100.5° C. This compound has the following structural formula ##STR3##
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14]Br)([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:17]=[N+:18]=[N-:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1ccccc1CN=[N+]=[N-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of crude 2-bromomethylphenylacetic acid t-butyl ester (0.349 mol) in 600 mL DMF was added 34.1 g (0.524 mol) sodium azide and the mixture stirred at 65° C. for 3 h. After cooling to ambient temperature, the mixture was diluted with 1.2 L ethyl acetate. The organic layer was washed with water (3×800 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the titled compound as a yellow oil. This material was used without further purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([OH:12])[C:6]#[C:7][C:8]#[C:9][CH2:10][OH:11].[CH2:13]([OH:22])[CH2:14][C:15]#[C:16][CH2:17][C:18]#[C:19][CH2:20][OH:21]>>[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH3:1][NH:2][C:3]([O:21][CH2:20][CH3:19])=[O:4].[CH2:5]([OH:12])[C:6]#[C:7][C:8]#[C:9][CH2:10][OH:11].[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH2:13]([OH:22])[CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][OH:21]
Reactant: OCC#CCC#CCCO
Reactant: CN=C=O
Agent: OCC#CC#CCO
Product: CCOC(=O)NC
Product: OCCC#CC#CCCO

Procedure:
The limitation in this process is that the total number of diols and isocyanates or diols and organic sulfonic acid agents is at least three, thereby resulting in a co-crystallized composition directly recoverable from the reaction mixture. For example, methylisocyanate can be reacted with a mixture of 2,4-hexadiyn-1,6-diol and 3,6-octadiyne-1,8-diol to yield a co-crystallized composition of (1) 2,4-hexadiyn-1,6-diol bis(methylurethane) and (2) 3,5-octadiyn-1,8-diol bis(methylurethane). Similarly, methylisocyanate and ethylisocyanate can be reacted with 2,4-hexadiyn-1,6-diol to yield a co-crystallized composition of (1) 2,4-hexadiyn-1,6-diol bis(methylurethane), (2) 2,4-hexadiyn-1,6-diol bis(ethylurethane) and (3) 2,4-hexadiyn-1-ol-methylurethane-6-ol-ethylurethane.
Reaction SMILES: C(CCCCC[C:8]1[N:9]=[CH:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)#N.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[Li+].[Cl-].[NH4+:24]>CN(C)C=O>[NH:17]1[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:16]2[N:11]3[CH:10]=[N:9][CH:8]=[C:12]3[CH:13]=[CH:14][CH:15]=2)=[N:24][N:19]=[N:18]1
Reactant: [N-]=[N+]=[N-]
Reactant: [NH4+]
Reactant: N#CCCCCCc1ncn2ccccc12
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(CCCCCc2nnn[nH]2)n2cncc2c1

Procedure:
A solution of 5-(5-cyanopentyl-imidazo[1,5-a]pyridine (5.26 g) in 16 ml of dry dimethylformamide is heated at 120° for 15 hours with sodium azide (2.15 g), lithium chloride (0.2 g) and ammonium chloride (1.80 g). After cooling and filtering, the solvent is evaporated and the residue is dissolved in 50 ml of water, extracted with 25 ml of ethyl acetate and brought to pH=5 with concentrated sulfuric acid. The precipitated solid is filtered, washed with water and dried to yield 5-[5-(5-tetrazolyl)pentyl]imidazo[1,5-a]pyridine, m.p. 149°-150°. The mono-hydrochloride salt has m.p. 188°-190°.
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[N:25][C:24]([C:27](OCC)=[O:28])=[CH:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[NH3:39]>>[NH2:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[N:25][C:24]([C:27]([NH2:39])=[O:28])=[CH:23][N:22]4[C:32]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: N
Reactant: CCOC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2cn1
Product: NC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-a]pyrazine-6-carboxylate [Int-5] (70 mg, 0.14 mmol, 1.0 eq) in 2.0 mL ammonia (7M solution in methanol, ˜100 eq) was heated to 130° C. for 5 h in a single mode microwave oven. The volatile components were removed by the use of a rotary evaporator. The crude amide detected by UPLC was directly forwarded to the deprotection step. Therefore, the raw material was dissolved in 1.3 mL DCM/methanol (5/3) and 0.61 mL of 4 M hydrogenchloride in dioxane were added. The solution was stirred overnight at room temperature. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine and dried with sodium sulphate. The solvent was using a rotary evaporator and the crude material was purified via MPLC (Biotage Isolera, 25 g Snap-cartridge; eluent: hexane/ethyl acetate (1/1)→ethyl acetate) to deliver 20 mg (40%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:15][S:16]([O:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C@H:22]([C:38]([OH:40])=O)[CH2:21]1)(=[O:18])=[O:17].[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>O1CCCC1>[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:38]([C@@H:22]2[CH2:21][C@H:20]([O:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:24][N:23]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:40])[CH2:46][CH2:45]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h

Procedure:
0.21 ml of triethylamine, followed by 0.19 ml of pivaloyl chloride, were added dropwise at -20° C. to a solution of 0.5 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 5 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 5 minutes. A solution of 0.25 of 1-(2-hydroxyethyl)piperazine in 3 ml of dry tetrahydrofuran was then added, and the reaction mixture was stirred at the same temperature for 30 minutes, after which the solvent was removed by distillation under reduced pressure. The resulting residue was worked up and purified in a similar manner to that described in step 54(a)(ii), to give 0.42 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound obtained as described in step 54(a)(ii) above.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(O)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=23)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Nc1ccc(F)cc1
Temperature: 80 °C
Yield: 116.7 %

Procedure:
Intermediate 1 (0.051 g) and 4-fluoroaniline (0.024 g) were suspended in ethanol (2 ml) and triethylamine (0.14 ml) was added. The mixture was stirred under nitrogen and heated at 80° C. for 16 h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM and water. The organic layer was loaded directly onto an SPE cartridge (silica, 5 g) and eluted sequentially with; (i) DCM, (ii) DCM: Et2O (2:1), (iii) DCM:Et2O (1:1), (iv) Et2O, (v) EtOAc, (vi) MeOH. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 6 (0.077 g). LCMS showed MH+=328; TRET=3.36 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]3[N:22]4[CH2:23][CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C:21]4=[N:20][C:15]=3[CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCl.C(OCC)C>O1CCOCC1>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]3[N:22]4[CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:21]4=[N:20][C:15]=3[CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1ccc(COc2ccc3c(c2)ncc2nc4n(c23)CCCNC4)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (25 mL of a 4 N solution in 1,4-dioxane) was added to a solution of tert-butyl 3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate in a 1:1 mixture of dichloromethane and diethyl ether (50 mL). The reaction was stirred overnight at ambient temperature; a precipitate formed. The precipitate was harvested via filtration and dried under reduce pressure to provide 9.66 g of 3-benzyloxy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCNCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCNCCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}-β-alaninate (D85) (186 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (40 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated to about 5 mL and then HCl aquous solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL) and water (5 mL). The mixture was acidified with HCl aquous solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}-β-alanine (E62) (130 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.70 (2H, t), 3.12-3.29 (4H, m), 3.33 (2H, m), 4.88-4.94 (1H, m), 7.27 (1H, t), 7.41 (1H, d), 7.47 (1H, d), 7.90 (1H, d), 7.99 (1H, dd), 8.22 (1H, dd), 8.39 (1H, d), 8.71 (1H, br), 11.03 (1H, br s), 12.70 (1H, br s). MS (ES): C24H26ClN4O4 requires 468; found 469.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[C:9]2[C:15](=[O:16])[NH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:25][C:26]([O:29][C:30]([N:32]([CH3:37])[CH2:33][C:34](O)=[O:35])=[O:31])([CH3:28])[CH3:27].O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:37][N:32]([CH2:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[C:9]2[C:15](=[O:16])[NH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:35])[C:30](=[O:31])[O:29][C:26]([CH3:28])([CH3:25])[CH3:27]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1cccc(Nc2nc(NCCCN)nc3cc[nH]c(=O)c23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1cccc(Nc2nc(NCCCNC(=O)CN(C)C(=O)OC(C)(C)C)nc3cc[nH]c(=O)c23)c1
Reaction time: 2.5 h
Yield: 58.4 %

Procedure:
To a solution of 2-[(3-aminopropyl)amino]-4-[(3-methylphenyl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one (50 mg, 0.114 mmol) in N,N-Dimethylformamide (DMF) (1.5 mL) were added N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-methylglycine (25.9 mg, 0.137 mmol), 1H-1,2,3-benzotriazol-1-ol hydrate (34.9 mg, 0.228 mmol), 4-methylmorpholine (57.7 mg, 0.570 mmol), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (28.4 mg, 0.148 mmol), and the reaction mixture was stirred for 2.5 h. It was then concentrated and the residue was subjected to reverse-phase HPLC purification to give 33 mg of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[C:25]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([F:49])[C:39]([C:42]4[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=4)=[C:40]([F:41])[C:35]=3[N:34]=[C:33]2[O:50][CH:51]2[CH2:56][CH2:55][CH:54]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:53][CH2:52]2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[C:25]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:26]=[CH:27][C:28]([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([F:49])[C:39]([C:42]4[CH:43]=[CH:44][C:45]([C:13]5[CH:12]=[CH:11][C:10]([C:8]([N:5]6[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]6)=[O:9])=[CH:15][CH:14]=5)=[CH:46][CH:47]=4)=[C:40]([F:41])[C:35]=3[N:34]=[C:33]2[O:50][CH:51]2[CH2:52][CH2:53][CH:54]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:55][CH2:56]2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(O)CC3)cc2)OC1(C)C
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(Br)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
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: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccc(C(=O)N6CCC(O)CC6)cc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 120 °C

Procedure:
To a yellow solution of (4-hydroxypiperidin-1-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone (0.147 g, 0.443 mmol), ethyl 4-{[1-(biphenyl-4-ylmethyl)-5-(4-bromophenyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexane-carboxylate (0.260 g, 0.403 mmol), and Pd(PPh3)4 (0.028 g, 0.024 mmol) was added 1 M K2CO3 (1.20 mL, 1.20 mmol) dropwise via syringe. The mixture was heated at 120° C. for 45 min, and then diluted with EtOAc and H2O. The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (100% EtOAc) afforded the desired compound as a ˜2:1 mixture of trans/cis isomers. The cis/trans isomers were separated via reverse phase Gilson™ HPLC (60-100% MeCN/H2O) to afford a faster eluting isomer A and a slower eluting isomer B as white solids.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][O:23][CH2:24]Cl.C(N(C(C)C)CC)(C)C>ClCCl.C(Cl)(Cl)Cl>[CH3:22][O:23][CH2:24][O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCCCCCCCCCCCCCCO
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCCCCCCOCOC
Reaction time: 8 h

Procedure:
To a solution of 5.44 g of ethyl 16-hydroxyhexadecanoate in 80 ml of dichloromethane was added under ice-cooling 1.63 ml of methoxymethyl chloride, 4.1 ml of diisopropylethylamine was added dropwise and then the mixture was stirred overnight. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was chromatographed over a silica gel column to afford the title compound as a colorless oily substance.