Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH2:43]Cl)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH2:43][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]2)[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2O)c1
Reactant: ClCc1cc(OCc2ccccc2)c2ccccc2c1
Product: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OCc3ccccc3)c3ccccc3c2)c1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(3-methoxycarbonyl-phenyl)-piperidine-1-carboxylate with 1-benzyloxy-3-chloromethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-methoxycarbonyl-phenyl)-piperidine-1-carboxylate as a pale yellow amorphous powder; MS: 582 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][NH2:20]>C1(C)C=CC=CC=1>[CH3:18][N:19]1[N:20]=[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:12]
Reactant: CNN
Reactant: O=C(O)c1ccccc1C(=O)c1ccncc1
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccncc2)c2ccccc2c1=O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a suspension of 2-(isonicotinoyl)benzoic acid (10.0 g, 44.1 mmol) in toluene (50 mL) was added methyl hydrazine (2.59 mL, 48.6 mmol). The mixture was heated to reflux while collecting water in a Dean-Stark trap for 6 hours. Additional methylhydrazine (2.59 mL) was added and the mixture was heated to reflux for another 5 hours. The reaction mixture was cooled to room temperature and the product was collected by filtration. The product was recrystallized from hot methanol to afford 8.5 g (81%) of 2-methyl-4-(4-pyridyl)-1-(2H)-phthalazinone, m.p. 173°-174° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][S:5][C:6]=1[NH2:7].C(N(CC)CC)C.[CH2:16]1[CH:23]2[C:19]3([C:25](Cl)=[O:26])[CH2:20][CH:21]([CH2:24][CH:17]1[CH2:18]3)[CH2:22]2>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][S:5][C:6]=1[NH:7][C:25]([C:19]12[CH2:20][CH:21]3[CH2:24][CH:17]([CH2:16][CH:23]1[CH2:22]3)[CH2:18]2)=[O:26]
Reactant: Cc1nsc(N)c1Br
Reactant: O=C(Cl)C12CC3CC(CC1C3)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nsc(NC(=O)C23CC4CC(CC2C4)C3)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of 4-bromo-3-methylisothiazol-5-amine (prepared as described in J. Chem. Soc. 1963, p 2032) (1.93 g, 10.1 mmol) in tetrahydrofuran (25 mL) with triethylamine (1.7 mL, 12.2 mmol) at 0° C. was added slowly a solution of Example 4A (1.9 g, 10.3 mmol) in tetrahydrofuran (15 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was evaporated to dryness, partitioned between H2O/ethyl acetate and the aqueous extracted again (2×) with ethyl acetate. The organics were combined, dried (MgSO4), filtered and solvent evaporated. Flash chromatography over silica gel eluting with 15% ethyl acetate/hexane provided 0.3 g of the title compound plus 1.8 g of diacylated compound. The latter was heated to reflux in methanol for 3 h, cooled, solvent evaporated and flash chromatographed over silica gel eluting with 20% ethyl acetate/hexane to provide an additional 0.99 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 1.63-1.76 (m, 4H), 1.87-1.98 (m, 4H), 2.10-2.15 (m, 2H), 2.45 (s, 3H), 2.81 (t, 1H), 8.23 (br s, 1H).
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:8]2[CH:7]3[C:16]4=[C:3]([O:2][N:1]=[C:15]4[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=4)[CH2:4][CH2:5][CH2:6]3)=[CH:20][CH:19]=1
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CN2c3ccccc3-c3noc4c3C2CCC4)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 40 ml dry DMF were combined 3.00 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 8.8 ml 4-fluorobenzylbromide and 3 g milled K2CO3. The mixture was stirred mechanically under nitrogen at ambient temperature for 2 days during which the reaction was complete. The reaction mixture was poured into excess water and extracted with DCM. The DCM layer was concentrated to a residue and the residue was triturated with 1:1 methanol/water and recrystallized from 1:1 DCM/hexanes to yield after drying 2.21 g needles, m.p. 214° C. (dec.).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26](F)[CH:27]=1)[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>O>[C:23]([C:22]1[CH:25]=[C:26]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)[CH:27]=[C:20]([F:19])[CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)cc(C#N)c2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 3,5-difluorobenzonitrile (348 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was purified via flash chromatography using 1:1 hexanes/EtoAc as the mobile phase. Isolated 677 mg (2.12 mmol, 85% yield).
Reaction SMILES: Cl.C[O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]C)=[O:15])[CH:9]=1)[NH2:6].[CH:19]1([N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]2[CH:41]=[CH:40][O:39][CH:38]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:4]([CH:5]([NH:6][C:34]([C:32]1[CH:31]=[CH:30][C:29]2[N:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:26]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)=[N:27][C:28]=2[CH:33]=1)=[O:35])[CH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:14]([OH:16])=[O:15])([OH:3])=[O:18]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: COC(=O)c1cccc(C[C@H](N)C(=O)OC)c1
Agent: Cl
Product: O=C(O)c1cccc(CC(NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)c1

Procedure:
Racemic 3-(carbomethoxy)phenylalanine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the title compound of example 1234.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[C@@:8]3([CH3:40])[C@@H:15]([O:16][C:17]([CH3:19])=[O:18])[C@@H:14]([O:20][C:21]([CH3:23])=[O:22])[C@@H:13]4[C@@:24]5([CH3:39])[C@@H:29]([O:30][C:31]([CH3:33])=[O:32])[C@H:28]6[O:34][C@H:27]6[CH2:26][C@@H:25]5[C:35]([C@H:37]([OH:38])[C@H:12]4[C@@H:9]3[C@@H:10]([OH:11])[C@H:6]2[C@@:5]2([CH3:47])[C@@:41]([OH:46])([CH3:45])[C:42]([O:44][C:4]2=[CH:3]1)=[O:43])=[O:36].N1C=CC=CC=1.[C:54](OC(=O)C)(=[O:56])[CH3:55]>>[CH3:1][C@H:2]1[C@@H:7]2[C@@:8]3([CH3:40])[C@@H:15]([O:16][C:17]([CH3:19])=[O:18])[C@@H:14]([O:20][C:21]([CH3:23])=[O:22])[C@@H:13]4[C@@:24]5([CH3:39])[C@@H:29]([O:30][C:31]([CH3:33])=[O:32])[C@H:28]6[O:34][C@H:27]6[CH2:26][C@@H:25]5[C:35]([C@H:37]([OH:38])[C@H:12]4[C@@H:9]3[C@@H:10]([O:11][C:54]([CH3:55])=[O:56])[C@H:6]2[C@@:5]2([CH3:47])[C@@:41]([OH:46])([CH3:45])[C:42]([O:44][C:4]2=[CH:3]1)=[O:43])=[O:36]
Reactant: CC(=O)O[C@H]1[C@H]2[C@H]([C@@H]3[C@@H](O)[C@@H]4[C@H]([C@H](C)C=C5OC(=O)[C@@](C)(O)[C@@]54C)[C@@]3(C)[C@H]1OC(C)=O)[C@@H](O)C(=O)[C@H]1C[C@@H]3O[C@@H]3[C@H](OC(C)=O)[C@]21C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H]2[C@H]3[C@H]([C@H](OC(C)=O)[C@H](OC(C)=O)[C@]2(C)[C@@H]2[C@@H]1[C@]1(C)C(=C[C@H]2C)OC(=O)[C@@]1(C)O)[C@]1(C)[C@H](C[C@@H]2O[C@@H]2[C@@H]1OC(C)=O)C(=O)[C@@H]3O
Reaction time: 48 h

Procedure:
Taccalonolide B (3 mg) was dissolved in 0.3 mL of acetic anhydride. To this solution, 0.3 mL of anhydrous pyridine was added and was kept at room temperature for 48 h. The reaction solution was dried in miVac and separated using C18 HPLC to yield taccalonolide A and TB-Ac-16.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=1>>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=3)[CH2:2][CH2:3]2)=[CH:18][CH:17]=1)#[N:16]
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1
Reactant: N#Cc1ccc(OCCCBr)cc1F
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)c(F)c3)CC2)cc1
Yield: 48.3 %

Procedure:
As described in Reference Example 7, 0.12 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile and 0.15 g of 4-(3-bromopropoxy)-2-fluorobenzonitrile were used to provide 0.10 g of 4-(3-{4-[3-(4-cyanophenoxy)propyl]-1-piperidinyl}propoxy)-2-fluorobenzonitrile as white solid form.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:13][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][OH:16])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:27]([CH3:29])=[CH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:21]([O:20][C:18]([N:17]1[C@@H:14]([CH2:13][C:10]2([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)[CH2:15][O:16][C:27]1([CH3:29])[CH3:28])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1(COCc2ccccc2)CC1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(COCc3ccccc3)CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 31.4 g of 1-benzyloxymethyl-1-[2(S)-tert-butoxycarbonylamino-3-hydroxy-propan-1-yl]cyclopropane, 80 ml of 2-methoxypropene and 0.5 g of p-toluenesulfonic acid hydrate in 170 ml of methylene chloride is stirred at room temperature for 16 h. The mixture is concentrated and the residue is purified by means of FC over 900 g of silica gel (mobile phase G): Rf (G)=0.23.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6](=[S:24])[CH:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2].[CH2:25](N(C(C)C)C(C)C)[CH3:26].BrCC>O1CCOCC1>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([S:24][CH2:25][CH3:26])=[C:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Reactant: CCN(C(C)C)C(C)C
Solvent: CCBr
Solvent: C1COCCO1
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(CC)C2S1

Procedure:
To a solution of 0.5 g of 4-nitrobenzyl 6-ethyl-7-oxo-3-thioxo-4-thia-1-azabicyclo[3,2,0]heptane 2-carboxylate in 2 ml of dioxane was added, in one batch, 0.57 ml of N-ethyldiisopropylamine, then 0.10 ml of bromoethane. When the reaction was complete, the solution was evaporated in vacuo and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the title product. (Yield 0.300 g)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C-:11]#[N:12].[K+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:9][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Br)cc(CC#N)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
The crude 1-bromo-3-(bromomethyl)-5-methylbenzene obtained from step 5 (188 g, ˜0.71 M) was dissolved in ethanol (470 mL) by warming in an oil bath (50-60° C.). Potassium cyanide (69.57 g, 1.068 M) was added, then distilled water (235 mL). The mixture was heated to reflux and stirred for 3 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was dissolved in dichloromethane and ethyl acetate-hexane (1:20) and loaded onto a silica gel column and eluted with ethyl acetate-hexane (from 1:20 to 1:6) to afford 85 g (53% for 2 steps) of 3-bromo-5-methylbenzyl cyanide (5) as a pale brown oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O.C(C1C=CC=CC=1C(O)=O)=O.[C:29]([O:33][C:34](=[O:52])[CH2:35][C@H:36]([NH2:51])[CH:37]([OH:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:52])[CH2:35][C@H:36]([NH:51][C:13](=[O:15])[C@@H:12]([N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]1=[O:1])[CH2:16][CH3:17])[C:37](=[O:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC[C@@H](C(=O)O)n1ccc2ccccc2c1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Agent: O=Cc1ccccc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2ccccc2c1=O

Procedure:
This compound was prepared using (S)-2-(1-oxo-1H-isoquinolin-2-yl)-butyric acid (prepared from 2-formylbenzoic acid using procedures similar to those described in methods A-E) and (3S)-3-Amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods H-J) using procedures similar to those described in methods F-G. This compound was isolated as a white solid This compound was prepared using methods similar to A-G and was isolated as a white solid 1H NMR (400 MHz CDCl3) δ 0.98 (3H, t), 1.30 (9H, s), 1.98-2.02 (1H, m), 2.26-2.32 (1H, m), 2.68 (1H, dd), 2.90 (1H, dd), 4.83-4.88 (1H, m), 5.06 (1H, d), 5.15 (1H, d), 5.50 (1H, t), 6.60 (1H, d), 6.75-6.82 (1H, m), 7.23 (1H, d), 7.33 (1H, d), 7.49-7.55 (1H, m), 7.68 (1H, t), 8.41 (1H, d); 19F NMR (376 MHz, CDCl3) (proton decoupled) δ −139.94, −139.97, −140.0, −140.02. −157/06, −157.09, −157.12, −157.14; ES(+) 565.3, ES(−) 563.3.
Reaction SMILES: C([N:3]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11][CH2:10][N:9]([CH:23]([CH:30]([N:37]2[CH2:48][CH2:47][N:46]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[CH2:45][CH2:44][N:43](C=O)[CH2:42][CH2:41][N:40]([CH2:59][C:60]([O:62]C(C)(C)C)=[O:61])[CH2:39][CH2:38]2)[C:31]([O:33]C(C)C)=[O:32])[C:24]([O:26]C(C)C)=[O:25])[CH2:8][CH2:7][N:6]([CH2:67][C:68]([O:70]C(C)(C)C)=[O:69])[CH2:5][CH2:4]1)=O.O.[Li+].[OH-].Cl>C(O)C>[C:16]([CH2:15][N:12]1[CH2:13][CH2:14][NH:3][CH2:4][CH2:5][N:6]([CH2:67][C:68]([OH:70])=[O:69])[CH2:7][CH2:8][N:9]([CH:23]([CH:30]([N:37]2[CH2:38][CH2:39][N:40]([CH2:59][C:60]([OH:62])=[O:61])[CH2:41][CH2:42][NH:43][CH2:44][CH2:45][N:46]([CH2:49][C:50]([OH:52])=[O:51])[CH2:47][CH2:48]2)[C:31]([OH:33])=[O:32])[C:24]([OH:26])=[O:25])[CH2:10][CH2:11]1)([OH:18])=[O:17]
Reactant: CC(C)OC(=O)C(C(C(=O)OC(C)C)N1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1)N1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCN(C(C(=O)O)C(C(=O)O)N2CCN(CC(=O)O)CCNCCN(CC(=O)O)CC2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In a 250 mL RB flask, the compound of Example 13 (1.0 g, 1.5 mmol) is dissolved in ethanol (30 mL) and water is added until the solution turns slightly turbid. The reaction mixture is heated at 100° C. and 1N LiOH (12 mL) is added. After maintaining the mixture at 100° C. for 8 hours, the solution is adjusted to pH 0.5 with 5N HCl (aq), and the mixture is refluxed for 1.5 hours and stirred at ambient temperature for an additional 18 hours. The cooled reaction material is desalted by ion exchange chromatography using an AG5OW-X8 [80 mL, (H+ form)] strongly cation exchange resin. The product is eluted with 1.0N NH4OH. The fractions containing product are combined and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH3:27].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: COc1ccc(C2CCCNC2)c2c1NC(=O)C2
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCCC(c2ccc(OC)c3c2CC(=O)N3)C1
Reaction time: 1.5 h

Procedure:
A mixture of 2 g of the product of Example 1 in 40 ml of dimethylformamide, 3.39 g of potassium carbonate and 1.6 ml of propyl iodide was stirred under inert atmosphere for 90 minutes. After adding water, extracting with methylene chloride, washing with water, drying, evaporating to dryness under reduced pressure and purifying the residue by chromatography over silica (eluent: methylene chloride--methanol 9-1), 1.6 g of 1,3-dihydro-7-methoxy-4-(1-propyl-3-piperidinyl)-2H-indol-2-one melting at ≈120° C. were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:52][CH3:53])[C@H:42]([N:46]1[CH2:50][CH2:49][NH:48][C:47]1=[O:51])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][CH2:49][NH:48][C:47]1=[O:51])[C@@H:41]([CH3:40])[CH2:52][CH3:53])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCNC1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCNC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
A solution of the product of Example 1H (0.020 g, 0.038 mmol) in tetrahydrofuran (0.40 mL) was treated with the product from Example 161B (0.0075 g, 0.038 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 12 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 50% acetone in dichloromethane to give the title compound (0.019 g, 71% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.6 Hz, 3 H), 0.75 (t, J=7.4 Hz, 3 H), 0.80 (s, 9 H), 0.85-0.96 (m, 1H), 1.24-1.35 (m, 2H), 1.48-1.56 (m, 1 H), 1.70-1.79 (m, 1 H), 2.54-2.72 (m, 3 H), 2.79-2.85 (m, 2H), 2.98-3.14 (m, 3H), 3.50-5.58 (m, 4 H), 3.77-3.91 (m, 3 H), 4.11-4.23 (m, 1H), 4.54 (d, J=7.4 Hz, 1 H), 6.31 (s, 1 H), 6.90 (d, J=9.6 Hz, 1 H), 7.09-7.26 (m, 8 H), 7.30-7.34 (m, 1 H), 7.80-7.97 (m, 5 H), 8.64 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:12][CH2:13][C@@H:14]1[C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[N:34]=[CH:33][CH:32]=[N:31]1)=[O:22])=[N:7]2.C([O-])=O.[NH4+]>O1CCOCC1.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>[CH3:20][C@@H:19]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[N:30]2[N:31]=[CH:32][CH:33]=[N:34]2)=[O:22])[C@@H:14]1[CH2:13][NH:12][C:6]1[N:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=2)[N:7]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3c(Br)cccc3n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3ccccc3n2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(((5-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.057 g, 0.111 mmol), HCOONH4 (0.14 g, 0.222 mmol) and Pd(PPh3)4 (0.026 g, 0.022 mmol) in dioxane and water (4:1, 2 mL) was heated for 2 h at 100° C. The mixture was cooled to rt and filtered through diatomaceous earth. The solvent was removed and the crude residue was purified via silica gel chromatography to obtain the title compound. ESI-MS (m/z): 442 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][C@@H:5]1[CH2:11][OH:12].[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCCC.C1COCC1>[C:13]1([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:12][CH2:11][C@H:5]3[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][N:4]3[CH3:3])=[O:26])[CH2:23][CH2:24]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN1CCN(C)[C@@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CN1CCN(C)[C@@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
Sodium hydride (1.14 g, 60% dispersion in mineral oil, 28.6 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of 1,4-dimethyl-(R)-2-hydroxymethyl piperazine (Intermediate 4; 1.38 g, 9.5 mmol) in THF (20 mL) was added drop-wise, followed by a solution of the 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 4.06 g, 12.4 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature, stirred for 16 hours, the reaction mixture was cooled to 0° C. then quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with sat aq NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was suspended in water:formic acid solution [1:1] (20 mL), filtered and the filtrate was purified by reverse phase column chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-15%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate (1.93 g, 61%) as a pale yellow solid.