Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[CH2:12][CH2:13][C:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([N:35]=[C:36]=[O:37])[CH3:34])=[C:29]([CH3:38])[CH:28]=1.C(O)(=O)C>O1CCCC1.O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([N:35]2[CH2:12][CH2:13][C@:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:19][C:36]2=[O:37])[CH3:34])=[C:29]([CH3:38])[CH:28]=1
Reactant: Cc1cc(Br)ccc1[C@H](C)N=C=O
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2C)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium hexamethyldisilazide (1 mol/L in tetrahydrofuran, 18.7 mL) was added dropwise (at such a rate that the solution temperature maintains below 25° C.) to a solution of 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (3.82 g) and (S)-4-bromo-1-(1-isocyanato-ethyl)-2-methyl-benzene (4.49 g) in tetrahydrofuran (140 mL) chilled in an ice bath. The solution was stirred in the cooling bath for 30 min and at room temperature for another 60 min. Then acetic acid (1.9 mL) in water (40 mL) was slowly added to the reaction mixture. The resulting mixture was concentrated under reduced pressure and the residue was taken up in tert-butyl methyl ether. The resulting solution was washed with water, dried (MgSO4), and concentrated. The residue was submitted to chromatography on silica gel (cyclohexane/ethyl acetate 90:10→40:60) to afford the title compound as a colorless solid. Besides the title compound a diastereomer thereof, 3-[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-6-(S)-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one, was isolated as an oil {1.55 g, Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+}. Yield: 1.34 g (18% of theory); Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+; 1H NMR (400 MHz, DMSO-d6) 1.40 (d, J=6.8 Hz, 3H), 1.53 (s, 3H), 1.71 (s, 3H), 1.81-190 (m, 1H), 1.98-2.08 (m, 1H), 2.43-ca. 2.51 (m, 3H), 2.86-2.94 (m, 1H), 4.58 (hardly resolved m, 1H), 4.77 (hardly resolved m, 1H), 5.30 (q, J=6.8 Hz, 1H), 7.15-7.19 (m, 2H), 7.24-7.35 (m, 6H). The assignment of the stereogenic centers of the title compound is based on the comparison of the 1H NMR data with the data of the known analog 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one.
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32](Cl)(=[O:34])[CH3:33]>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[C:32](=[O:34])[CH3:33])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Reactant: CC(=O)Cl
Product: CCCCCCCCC#Cc1ccc(CN(C(C)=O)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure E using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and acetyl chloride. HPLC, Rt: 5.8 min (purity: 99.9%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[N:16]=[C:15]([C:17]3[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[N:13][C:12]=1[CH:43]=[CH2:44])[NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+]>Cl.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[N:16]=[C:15]([C:17]5[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]6[O:24][C:23]([C:25]7[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=7)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=6[CH:36]=5)[CH:14]=[N:13][C:12]=4[CH2:43][CH2:44][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C=Cc1ncc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
A solution of 5-(6-(4-fluoro-1H-indol-2-yl)-5-vinylpyrazin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.08 mmol) in HCl/1,4-dioxane (1 mL) was stirred at 80° C. for 1 h under nitrogen atmosphere. The reaction mixture was concentrated; then the residue was used to the next step reaction without purification. To the residue in DMF, Cs2CO3 was added (53 mg, 0.16 mmol), the reaction mixture was stirred at 80° C. for 1 h under nitrogen atmosphere, concentrated and purified by prep-TLC (PE:EA=1:2) to give the desired product (10 mg, yield: 20%). 1H-NMR (CDCl3, 400 MHz) δ 8.56 (s, 1H), 8.03 (s, 1H), 7.90 (dd, J=9.2 Hz, 5.2 Hz, 2H), 7.64 (s, 1H), 7.29 (s, 1H), 7.09˜7.17 (m, 4H), 6.74˜6.78 (m, 1H), 5.85 (br s, 1H), 4.41 (t, J=6.8 Hz, 2H), 3.47 (t, J=6.8 Hz, 2H), 3.34 (s, 3H), 2.94 (d, J=4.8 Hz, 3H), 2.73 (s, 3H). MS (M+H)+: 614.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:39]2[CH:40]=[N:41][C:42]([CH3:46])=[CH:43][C:44]=2[CH3:45])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31]CC2C=CC=CC=2)=[O:23])[C:11]1=[O:47]>C(O)C.[Pd]>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:39]2[CH:40]=[N:41][C:42]([CH3:46])=[CH:43][C:44]=2[CH3:45])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])=[O:23])[C:11]1=[O:47]
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1OCc1ccccc1)c1cnc(C)cc1C
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1cnc(C)cc1C
Yield: 85.9 %

Procedure:
2-{(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(4,6-dimethyl-3-pyridinyl)-N-{2-[(phenylmethyl)oxy]phenyl}acetamide (intermediate 3) (3.30 g) was dissolved in ethanol (75 ml) and hydrogenated over palladium on charcoal (wet 10% Pd, 0.50 g) for 20 hours. The catalyst was removed by filtration and washed with dichloromethane. The combined filtrate and washings were evaporated in vacuo. The residue was applied to a 90 g Biotage column and eluted with ethyl acetate. The required fractions were combined and evaporated in vacuo to give 2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(4,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)acetamide (2.43 g, 87%) as a pale yellow solid.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([O:9][CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5]1)=[N+:2]=[N-:3]>C1(C)C=CC=CC=1>[F:19][C:15]1[CH:14]=[C:13]([C:12]2[N:3]=[N:2][N:1]3[C:11]=2[CH2:10][O:9][C@H:8]2[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5][C@H:4]32)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](OCC#Cc2cccc(F)c2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2OCc3c(-c4cccc(F)c4)nnn3[C@H]2C1
Yield: 88.2 %

Procedure:
Example 56 can be prepared in the same manner as example 53 from (3S,4S)-tert-butyl 3-azido-4-(3-(3-fluorophenyl)prop-2-ynyloxy)pyrrolidine-1-carboxylate (143 mg, 0.39 mmol) and toluene (12 ml), afforded the titled compound (124 mg, 86%) as white solid. M.p. 249-250° C.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([O:24][C@@H:25]([CH3:31])[C:26]([O:28]CC)=O)[CH:5]=1)(=[O:3])[NH2:2].CO.[NH3:34]>>[NH2:34][C:26](=[O:28])[C@@H:25]([O:24][C:6]1[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=1)[CH3:31]
Reactant: N
Reactant: CCOC(=O)[C@H](C)Oc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: CO
Product: C[C@H](Oc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Yield: 31 %

Procedure:
A solution of (S)-ethyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)oxy)propanoate (0.762 g, 1.79 mmol) in 7M ammonia in methanol (10 mL, 70 mmol) was heated in a sealed tube overnight at 50° C. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 25-100% acetone in hexanes. The product fractions were evaporated in vacuo and the residue triturated with 5 mL MeOH. The solid was filtered and rinsed again with 2 mL MeOH. The MeOH filtrate and washings were evaporated in vacuo and triturated with 2 mL MeOH, filtered, and rinsed again with 1 mL MeOH. The first and second batches of solid were combined and dried under vacuum at 40° C. to give (S)-6-((1-amino-1-oxopropan-2-yl)oxy)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a white powder (0.220 g, 0.555 mmol, 31% yield). 1H NMR (400 MHz, DMSO-d6): 8.59 (2H, d, J=8.8 Hz), 8.50 (1H, s), 7.96 (1H, s), 7.69 (1H, s), 7.33-7.25 (2H, m), 7.24 (1H, s), 7.23-7.15 (3H, m), 7.06 (2H, d, J=8.8 Hz), 5.36 (1H, q, J=6.8 Hz), 1.52 (3H, d, J=7.0 Hz). LC/MS: m/z=397.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([N:22]([CH2:31][CH2:32][CH2:33][N:34]1C(=O)C2C(=CC=CC=2)C1=O)[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O>CCO>[NH2:34][CH2:33][CH2:32][CH2:31][N:22]([CH:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:19]([CH3:21])[CH3:20])[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)C(c1cc2cc(Cl)ccc2n1Cc1ccccc1)N(CCCN1C(=O)c2ccccc2C1=O)C(=O)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)C(c1cc2cc(Cl)ccc2n1Cc1ccccc1)N(CCCN)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of product of step 10 (50 mg) in 1 mL of EtOH was added hydrazine (0.1 mL). The mixture was stirred at room temperature for 2 h. The solution was poured into water, and extracted with EtOAc (×3). The organic layers were combined, washed with 10% NaOH aq., H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified preparatory HPLC to give N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]benzamide.
Reaction SMILES: C(O)(=O)C.C[Si]([N:9]=[N+:10]=[N-:11])(C)C.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1.C(N(CC)CC)C>ClCCl>[N:9]([CH:14]1[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]1)=[N+:10]=[N-:11]
Reactant: O=C1C=CCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC1CCC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
To a solution of acetic acid (20 g, 0.33 mol) in dichloromethane (375 mL) was added trimethylsilyl azide (38 g, 0.33 mol), and the mixture was stirred at room temperature for 20 minutes. Then cyclopent-2-enone (9 g, 0.11 mol) was added to the reaction mixture followed by triethylamine (2.22 g, 0.022 mol), and the mixture was stirred at room temperature for 48 hours. The resulting mixture was quenched with aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine three times and purified by column chromatography (Hexanes/ethyl acetate=1:3) to give 7.2 g of 3-Azido-cyclopentanone as a colorless liquid (TLC showed two spots), which was used for next step directly. 1H NMR (400 MHz, CDCl3): δ: 4.31-4.26 (m, 1H), 2.46-2.08 (m, 6H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.B(O)(O)[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:18][CH:19]=1)#[CH:24]
Reactant: C#Cc1ccc(B(O)O)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: C#Cc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(dihydroxyborophenyl)acetylene according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H12N4, 285. Found, 285.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])([O:12][CH3:13])=[O:11]>C(#N)C>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:10]([O:12][CH3:13])=[O:11])(=[O:22])=[O:21])=[O:25])[N:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(N)cc(Cl)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a warmed mixture containing 1.4 g (0.01 mole) 2,4-diamino-6-chloropyrimidine in 50 ml acetonitrile is added 2.4 g (0.01 mole) 2-carbomethoxybenzenesulfonylisocyanate. The reaction mixture was stirred at room temperature for four days. The reaction mixture was filtered and the precipitate washed with ether. The filtered solid was air dried and purified in the following manner. To an aqueous suspension of the reaction mixture was added n-propylamine and the aqueous mixture filtered. The resultant clear solution was carefully acidified with concentrated HCl to pH=1-2. The mixture was filtered, washed with ether and air dried to yield a white solid, m.p. 170°-172° C. The infrared spectrums showed characteristic absorption bands at 1740, 1700 cm-1. The NMR and mass spectral data are consistent for the desired product.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[NH:21][C:20](=[O:27])/[C:19]/2=[CH:28]\[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][NH:29]/[CH:28]=[C:19]2\[C:20](=[O:27])[NH:21][C:22](=[O:26])[C:23]3[C:18]\2=[CH:17][C:16]([Br:15])=[CH:25][CH:24]=3)=[CH:32][C:33]=1[OH:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Yield: 17.7 %

Procedure:
To a solution of benzyl bromide (33.0 μl, 0.28 mmol) and tetrabutylammonium iodide (104 mg, 0.283 mmol) in anhydrous N,N-dimethylformamide (2 ML) is added of potassium carbonate (207 mg, 1.5 mmol). The mixture stirred at room temperature and (4Z)-6-bromo-4-{[(3,4-dihydroxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (100 mg, 0.26 mmol) is added. After the mixture is stirred at 65° C. for 30 min, the resulting mixture is concentrated and the residue is then partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer is then dried and purified by high performance liquid chromatography to give 22 mg of a white solid. MS (ESI) m/z 478.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([O:27]CC)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+].Cl>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylate (810 mg, 2.07 mmol) and lithium hydroxide hydrate (434 mg, 10.3 mmol) in methanol (30 ml) and water (5 ml) was stirred for 18 hours at 25° C. The mixture was adjusted to pH=7 using hydrochloric acid (2 molar, 5.15 ml) and then evaporated to dryness under reduced pressure. 1-Methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (1.38 g) as light brown solid was used without further purification. MS: m/z=364.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:21][CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:19]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:18]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[C:9](OC)=[O:10].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.Cl>C1COCC1>[OH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([NH:13][C:14]([CH:16]2[CH2:21][CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:19]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:18]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:17]2)=[O:15])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2ccc(C(=O)OC)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2ccc(CO)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 5 h
Yield: 100 %

Procedure:
N-(3-Methoxy-4-methoxycarbonylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (70 mg, 0.06 mmol) was dissolved in dehydrated THF (1 ml), 1M DIBAL/toluene (0.2 ml, 0.012 mmol) was added dropwise, and the mixture was stirred for 5 hr. After completion of the reaction, 1N hydrochloric acid was added to quench the reaction, and the mixture was extracted with chloroform (5 ml) and washed with 1N hydrochloric acid (3 ml). The solvent was evaporated and the residue was precipitated with methanol (10 ml) and slurry-washed with acetonitrile (5 ml) and 1N hydrochloric acid (5 ml) to give N-(4-hydroxymethyl-3-methoxyphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (60 mg, 0.06 mmol, yield 100%).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:37]=[C:38]=[O:39])[CH2:35][CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:38]([NH:37][CH2:34][CH2:35][CH3:36])=[O:39])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCN=C=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 18.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, propyl isocyanate (0.24 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 100:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(propylamino)carboxamide (0.13 g, 20%) as a white solid: mp 160-162° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.86-7.69 (m, 3H), 6.44 (t, J=5.9 Hz, 1H), 6.16 (t, J=1H), 5.18-5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 2H), 2.99-2.83 (m, 3H), 2.64-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.42-1.32 (m, 2H), 0.83 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) δ 172.78, 169.84, 167.59, 167.05, 158.03, 141.16, 134.62, 133.34, 131.51, 126.96, 121.63, 48.82, 41.18, 30.94, 23.15, 21.99, 11.33; Anal. Calcd. For C18H20N4O5: C, 58.06; H, 5.41; N, 15.05. Found: C, 57.94; H, 5.31; N, 14.90.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:38]=1>>[F:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:39]=1[O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49]
Reactant: COCCCOc1cc(CCl)ccc1F
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1F

Procedure:
Analogously to Method D, 0.213 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.114 g of 4-chloromethyl-1-fluoro-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rt=6.28.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a 0° C. solution of 2.5 ml (22 mmol) 4-aminobenzylamine in 100 mL CH2Cl2 was added 3 mL (22 mmol) triethylamine and 2.7 mL (22 mmol) pivaloyl chloride slowly by syringe over 5 min. and the reaction mixture was warmed to room temperature and stirred 1 hour. Additional portions of. triethylamine (0.4 ml )and pivaloyl chloride (0.4 ml) were added and the reaction mixture was allowed to stir 16 hours. The reaction mixture was then diluted with 400 mL EtOAc, washed with 400 mL each of, saturated aqueous NaHCO3, water, and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by washing with 100 mL EtOAc, and extracting this wash with 2×100 mL 1N HCl. The combined aqueous extracts were brought to pH>10 with 6M NaOH and extracted 3×100 mL EtOAc. The combined EtOAc extracts were then dried over Na2SO4, filtered and concentrated to give 2.5 g N-(4-amino-benzyl)-2,2-dimethyl-propionamide as a off-white solid. 1H NMR (300 mHz, CDCl3) δ 7.15 (d, 2H); 6.65 (d, 2H); 5.75 (b s, 1H); 4.30 (d, 2H); 3.65 (b s, 2H); 1.20 (s, 9H).