Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[N:11]12[CH2:18][CH2:17][C:14]([C:19]([O:21]CC)=O)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C1COCC1>[N:11]12[CH2:12][CH2:13][C:14]([C:19]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=3)([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[OH:21])([CH2:15][CH2:16]1)[CH2:17][CH2:18]2
Reactant: COc1cccc([Mg]Br)c1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: COc1cccc(C(O)(c2cccc(OC)c2)C23CCN(CC2)CC3)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A solution of 3-(methyloxy)phenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1608 g, 0.877 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.2881 g, 92.9%). EI-MS m/z 354(M+H+) Rt (1.46 min).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([C:21]=2[C:23]([O:25][C:26]2[C:31]([Br:32])=[CH:30][C:29]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:28][C:27]=2[Br:38])=[O:24])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH:19]1[C:20]2[C:15](=[N:14][C:13]3[C:22]([C:21]=2[C:23]([O:25][C:26]2[C:27]([Br:38])=[CH:28][C:29]([CH2:33][CH2:34][C:35]([O:1][N:2]4[C:6](=[O:7])[CH2:5][CH2:4][C:3]4=[O:8])=[O:36])=[CH:30][C:31]=2[Br:32])=[O:24])=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CCc1cc(Br)c(OC(=O)c2c3ccccc3nc3ccccc23)c(Br)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CCc1cc(Br)c(OC(=O)c2c3ccccc3nc3ccccc23)c(Br)c1)ON1C(=O)CCC1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
N-Hydroxysuccinimide (12 mg, 0.10 mmol) and 2,6-dibromo-4-(2-carboxyethyl)phenyl acridine-9-carboxylate (50 mg, 0.090 mmol) were dissolved in anhydrous DMF (3 ml) and cooled to −20° C. Dicyclohexylcarbodiimide (DCC, 22 mg, 0.11 mmol) was added and the mixture was stirred at −20° C. for 2 h. The solution was stirred overnight at room temperature, and then evaporated to dryness. The residue was extracted with dichloromethane (50 ml) and the filtrate was evaporated to obtain the crude product (100 mg). Further purification was carried out by chromatotron, eluted with chloroform. The solvent was evaporated from the appropriate combined fractions to give the desired product as a light-brown solid (40 mg, 64%), mp 175–6° C. FAB-MS m/z 627 [(M+1)+, 20%], 225 [100], 206 [18], 179 [10], 143 [8].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)[N:3]=1.[H-].[Na+].I[CH3:33]>C1COCC1>[CH3:33][N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)[C:27](=[O:29])[CH3:28]
Reactant: CI
Reactant: CC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide (50 mg) was dissolved in THF (2.5 mL) and sodium hydride (60% w/w oil dispersion, 0.005 g, 1 eq.) was added at 0° C. After 5 minutes iodomethane was added (5 uL, 1.0 eq.) and the mixture was warmed to room temperature. After 10 h the solution was partitioned between water (3 mL) and ethyl acetate (3×5 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude was purified by flash chromatography on silica gel, eluting with a gradient from dichloromethane to dichloromethane-methanol (98:2) affording the title compound in 61% yield (0.02 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)cc2N1
Yield: 34 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 34% of theory; LC (method 4): tR=1.88 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH3:22])=CC=1.CCCCCCC>C(O)C.[Pd]>[CH3:22][C:10]1[C:11]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: COc1ccc(COc2cccc(Oc3ccccc3)c2C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCCC
Product: Cc1c(O)cccc1Oc1ccccc1
Reaction time: 72 h
Yield: 32.8 %

Procedure:
1-(4-Methoxybenzyloxy)-2-methyl-3-phenoxybenzene (205 mg, 0.64 mmol) was dissolved in ethanol (5 mL) and palladium on charcoal 10% wt (60 mg) was added. The reaction mixture was agitated under an atmosphere of hydrogen (1 atm) for 72 h. The crude reaction mixture was filtered over dicalite and the solvents removed in vacuo. The crude product was taken up in DCM (4 mL) and 1N NaOH (aq) (4 mL) and the aqueous layer was separated, then acidified to pH 1 with 5N HCI (aq). The aqueous layer was extracted with DCM (10 mL) and the combined organics were concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 5:95 ethyl acetate:heptane afforded 2-methyl-3-phenoxyphenol (43 mg, 0.21 mmol, 34%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])/[CH:9]=[C:10](\Cl)/[CH3:11])(=[O:3])[CH3:2].[CH3:17][O-:18].[Na+]>CO>[C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[O:18][CH3:17])/[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)/C=C(/C)Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CO/C(C)=C\C(=O)Nc1cccc(C(C)=O)c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A mixture of 400 ml of methanol, 41 g of m-acetyl-3-chlorocrotonanilide and 9.4 g of sodium methylate was stirred at 20° C for 72 hours and the mixture was vacuum filtered to recover the sodium chloride formed and the desired product. The solid was dissolved in refluxing acetone and the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure. The waste waters were evaporated to dryness and the residue was taken up in 200 ml of a 7-3 benzene-ethyl acetate mixture. The mixture was vacuum filtered and the solid was dissolved in refluxing acetone. The solution was filtered and the filtrate was evaporated to dryness for a total yield of 19.5 g of m-acetyl-3-methoxy-crotonanilide melting at 168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([NH:7][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1ccccc1
Yield: 60 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-chloro-2-(1H-tetrazol-5-yl)aniline (3.6 mmol) and benzoyl chloride to yield the desired product (647 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.75 (d, 1H), 8.08-8.05 (m, 3H), 7.69-7.62 (m, 3H), 7.49 (dd, 1H); MS (EI) for C14H10ClN5O: m/z 300 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:10][CH:9]=1>C1COCC1.C(OCC)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:18])[CH2:15][OH:16])=[CH:12][CH:13]=1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CO)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Lithium aluminium hydride (29.8 ml of a 1.0M solution in THF, 29.8 mmol) was added dropwise to a stirred solution of 4-fluoro-α-methylphenyl acetic acid (5.0 g, 29.8 mmol), in diethyl ether (100 ml), which had been cooled to -10° C. The mixture was warmed to +25° C. and stirred for 1 h before quenching with methanol (20 ml) and 4M NaOH (20 ml). The mixture was filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane to give 2-(4-fluorophenyl)propyl alcohol (3.65 g, 79%). To a solution of the preceding alcohol (3.65 g, 23.7 mmol) and carbon tetrabromide (9.82, 29.62 mmol), in dichloromethane (75 ml), was added triphenylphosphine (9.31 g, 35.5 mmol), portionwise. The mixture was stirred for 1 h at room temperature and diethyl ether (50 ml) then added. The precipitated triphenylphosphine oxide was filtered off and the solvents removed in vacuo. The residue was chromatographed through silica gel eluting with ethyl acetate/hexane (1:2) to afford the desired bromide (3.05 g, 60%), δ(250 MHz, CDCl3) 1.40 (3H, d, J=6.8 Hz, Me), 3.06-3.20 (1H, m, CH), 3.42-3.61 (2H, m, CH2), 6.97-7.26 (4H, m, Ar--H).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([C:29](=O)[CH2:30][CH2:31][CH2:32][CH3:33])[C:25](OC)=[O:26])=[C:19]([F:35])[CH:18]=1)#[N:10].O>CO>[CH2:30]([C:29]1[N:4]=[C:2]([CH3:3])[NH:5][C:25](=[O:26])[C:24]=1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][C:19]=1[F:35])[CH2:31][CH2:32][CH3:33]
Reactant: CC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Yield: 68.9 %

Procedure:
To a suspension of acetamidine hydrochloride (6.7 g) in methanol (50 mL) were added sodium methoxide (28% methanol solution, 20.5 mL) and then methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (13.0 g), and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was triturated with diisopropyl ether to give the title compound (9.15 g, 69%) as pale-yellow crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH2:5][CH3:6].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C=O)C>[CH2:3]([C:7]1[N:11]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:9]=2[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2cccc(C)c2[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a slurry of NaH (60%, 0.21 g. 5.3 mmol) in DMF was added with stirring a solution of 2-butyl-4-methyl-benzimidazole (1 g. 5.3 mmol) in DMF (20 mL under nitrogen atmosphere. After the gas evolution was complete, the reaction mixture was cooled in ice and a solution of 4-nitrobenzyl bromide (1.5 g, 5.3 mmol) in DMF (5 mL) was added with stirring. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 16 hours. DMF was distilled under reduced pressure and the residue was taken up in EtOAc, and the solution was washed with water. It was dried over MgSO4 and evaporated to give a solid which was chromatographed (CH2Cl2 /EtOAc 4/1-EtOAc) to give 1.5 g of a solid, MP 115°-116° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1CCCC1=O>Cl>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[CH:3][CH:4]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: CN1CCCC1=O
Agent: Cl
Product: N#Cc1ccc(CCCO)cc1

Procedure:
A mixture of 4-bromobenzenepropanol (9.0 g), cuprous cyanide (4.5 g), cuprous iodide (20 mg), and N-methyl-2-pyrrolidone (20 ml) was heated at 180°-190° for 4 h and poured into a solution of ferric chloride hexahydrate (4.5 g) in hydrochloric acid (2 M; 30 ml). The mixture was heated at 70°-80° for 15 min and extracted with EA (3×100 ml). The extract was washed with hydrochloric acid (2 M; 50 ml), water (50 ml), and aqueous sodium hydroxide (2 M; 50 ml), dried and evaporated. The residue was purified by [C] eluting with cyclohexane-ER (1:1) to give the title compound (3.5 g). T.l.c. (cyclohexane-ER 1:1) Rf 0.15
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20](OCC1C=CC=CC=1)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:31]#CBr.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pd].CCOCC>[C:1]([O:5][C:6](=[O:30])[C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20]#[N:31])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC#N)C(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 0.75 h
Yield: 66.9 %

Procedure:
To a solution of 6.1 g (14.4 mmol) N5-((Benzyloxy)carbonyl)-N2-(tert-butoxycarbonyl)-L-ornithine tert-butyl ester in 100 mL ethyl acetate was added 1.0 g 10% palladium on carbon. The suspension was shaken at 22° C. under 50 psi H2 for 45 minutes in a 500 mL Parr bottle. The catalyst was removed by filtration through celite. The resulting solution was concentrated to yield a crude oil. The oil was dissolved into 50 mL of diethyl ether and added dropwise to a 0° C. stirred solution of 1.52 g (14.3 mmol) of cyanogen bromide in 30 mL ether. The solution was stirred for 2 h, poured into aqueous sodium bicarbonate, and extracted with ether. The ether solution was dried (magnesium sulfate), concentrated, and purified by silica gel chromatography (100 g, 130-400 mesh silica gel). Elution with a gradient of ethyl acetate in hexanes (30%-60%) gave 3.0 g (67% yield) N2-(tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][OH:25])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCC(CCO)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of 0.174 g of methyl 8-(p-chlorophenylsulfonamido)-4-(2-hydroxyethyl)octanoate in 2 ml methylene chloride is cooled to 0° and 0.1 ml of triethylamine is added followed by 0.042 ml of methylsulfonyl chloride. After 1 h, the reaction mixture is washed with saturated sodium bicarbonate and the organic layer is dried, filtered and evaporated to yield methyl 8-(p-chlorophenylsulfonamido)-4-(2-methylsulfonyloxyethyl)-octanoate as an oil.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[N:19]([C:31]3[C:32]4[C@H:39]([CH2:40][CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:18]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[CH2:40]([C@H:39]1[C:32]2[C:31]([N:19]3[C:20]4[C:25](=[C:24]([CH2:26][NH:27][CH:28]([CH3:29])[CH3:30])[CH:23]=[CH:22][CH:21]=4)[C:15]4([CH2:16][CH2:17][NH:12][CH2:13][CH2:14]4)[CH2:18]3)=[N:36][CH:35]=[N:34][C:33]=2[CH2:37][CH2:38]1)[CH3:41]
Reactant: CC[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(C)C)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CNC(C)C)cccc43)c21
Reaction time: 2 h

Procedure:
Ammonium formate (21.5 mg, 0.341 mmol) was added to a mixture of (R)—N-((1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (16.9 mg, 0.0341 mmol) and 10% Pd/C (10 mg) in methanol (1 mL) and refluxed. LCMS suggested debenzylation was complete after 2 hours. The reaction was concentrated and partitioned between DCM and saturated NaHCO3 solution. The aqueous portion was extracted a second time, and the combined organics were dried over Na2SO4. The DCM solution was decanted and concentrated under vacuum to provide the free-base product, (R)—N-((1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine. 1H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 7.31 (d, 1H), 7.14 (t, 1H), 6.93 (d, 1H), 3.85-4.01 (m, 4H), 3.29 (m, 1H), 3.08 (dd, 2H), 2.90-2.97 (m, 4H), 2.58 (m, 1H), 2.01-2.26 (m, 4H), 1.85 (m, 1H), 1.68 (dd, 2H), 1.46 (m, 2H), 1.03-1.11 (m, 7H), 0.78 (t, 3H). The product was dissolved in THF (1 mL) and converted to the hydrochloride salt by treatment with a 1M HCl solution in Et2O (1 mL). The reaction was sonicated, and the solvent was removed under vacuum providing (R)—N-((1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride (11 mg, 0.021 mmol, 62% yield) as a powder. MS (APCI+) [M+H]: 406.3.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]=4[C:35]([OH:37])=O)[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(CC)CC>CN(C=O)C>[C:29]1([C:26]2[C:25]([C:35](=[O:37])[NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[C:24]([C:22]3[O:21][N:20]=[C:19]([C:16]4[CH:17]=[CH:18][C:13]([CH2:12][N:10]5[CH2:11][CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]5)=[CH:14][CH:15]=4)[N:23]=3)[O:28][N:27]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(=O)O)n3)cc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(=O)NCC(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-phenylisoxazole-4-carboxylic acid (30 mg, 0.060 mmol), 2,2,2-trifluoroethylamine (7.15 μL, 0.090 mmol), BOP-Cl (18.24 mg, 0.072 mmol) and Et3N (0.025 mL, 0.179 mmol) in DMF (0.5 mL) was stirred at rt over the weekend. The reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to a colorless solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-70% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(3-phenyl-4-(2,2,2-trifluoroethylcarbamoyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (18 mg, 0.031 mmol, 51.7% yield) as a white solid. This material was deemed suitable to use in the next step without further purification. HPLC retention time=1.71 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=584.10.
Reaction SMILES: [CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[C:13](OC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncoc1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ncoc1Cc1ccccc1

Procedure:
Methyl 5-benzyl-4-oxazolecarboxylate is reduced with lithium aluminium hydride in tetrahydrofuran to give 5-benzyl-4-hydroxymethyloxazole, which on reaction with thionyl chloride is converted to 5-benzyl-4-chloromethyloxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 46.4 %

Procedure:
Example 22 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.028 g) and (4-methoxyphenyl)acetic acid (0.018 g) to give the title compound (0.02 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[NH:4][C:5]2[CH:6]=[C:7]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:8]=[C:9]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])[C:10]=2[CH:11]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O>[CH:16]1([NH:15][S:12]([C:9]2[C:10]3[CH:11]=[C:2]([C:31]4[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=4)[C:3](=[O:28])[NH:4][C:5]=3[CH:6]=[C:7]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:8]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(Br)c(=O)[nH]c2c1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(-c3cccnc3)c(=O)[nH]c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide (45 mg, 0.1 mmol), 3-pyridine boronic acid (25 mg, 0.2 mmol), cesium carbonate (100 mg, 0.3 mmol), Peppsi-iPr (4 mg, 5 mol %), dimethoxyethane (2 mL) and water (1 mL) was stirred at 100° C. for 2 hours. The reaction mixture was concentrated before being purified by preparative HPLC to give N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-(pyridin-3-yl)-1,2-dihydroquinoline-5-sulfonamide as a yellow powder.