Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C[O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].BrCCC[CH2:17][C:18]([O:20][CH3:21])=[O:19].BrCC(OC)=O.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>CO>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:11]=1)([OH:3])=[O:5].[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:35]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])[C:36]([O:38][CH3:39])=[O:37])=[CH:10][CH:11]=1)([OH:3])=[O:5]
Reactant: COC(=O)CCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COC(=O)CCCCBr
Agent: COC(=O)CBr
Agent: [Na]
Solvent: CO
Product: CCCCCCC(Oc1ccc(C(=O)O)cc1)C(=O)OC
Product: COC(=O)COc1ccc(C(=O)O)cc1
Yield: 75 %
Yield: 85 %

Procedure:
Freshly cut sodium metal (5.98 g, 0.26 mole) was gradually introduced into 150 ml of dry methanol in a 1000 ml flask equipped with a stirrer, and a reflux condenser with a drying tube. Upon complete solution of the sodium, first, 39.56 g (0.26 mole) of methyl p-hydroxybenzoate in 100 ml of methanol and later 50.0 g (0.26 mole) of methyl 5-bromovalerate were added rapidly. The reaction was allowed to reflux for 78 hours. After 78 hours of refluxing precipitated material was removed by filtration. The diester was precipitated upon pouring the solution into an ice water mixture. A clear powdery white precipitate was obtained, and filtered from the remaining solution. The precipitate was dried overnight, and weighed to obtain 58.35 g (84% yield). Methyl p-carboxyphenoxyacetate (CPA), (85% yield), and methyl p-carboxyphenoxyoctanoate (CPO) (75% yield) were prepared similarly using methyl bromoacetate, and methyl 8-bromooctanoate, respectively. The data analysis of the esters is described in Table 1. The methyl esters were then hydrolyzed to the corresponding diacids as follows:
Reaction SMILES: O.NN.[C:4]([C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:54]=[CH:55][CH:56]=2)[C:18]([NH:20][C:21]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][S:44]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[CH:38]=[CH:37][C:22]=2[O:23][CH2:24][CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)=[O:19])[S:11][CH:12]=1)([CH3:7])([CH3:6])[CH3:5].C(O)C>O1CCCC1>[C:4]([C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:54]=[CH:55][CH:56]=2)[C:18]([NH:20][C:21]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][S:44]([C:47]3[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=3)(=[O:45])=[O:46])[CH:38]=[CH:37][C:22]=2[O:23][CH2:24][CH2:25][NH2:26])=[O:19])[S:11][CH:12]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCCN3C(=O)c4ccccc4C3=O)c2)n1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCCN)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, hydrazine monohydrate (190 μl, 3.8 mmol) was added to a mixture of N-[2-[2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy]ethyl]phthalimide (1.5 g, 1.9 mmol), ethanol (5 ml) and tetrahydrofuran (20 ml), and the resulting mixture was stirred overnight at room temperature and then heated under reflux for 3 hours. Ice-water was added to the reaction solution, and then the product formed was extracted with chloroform. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and distilled water in that order, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was purified by silica gel column chromatography (eluent=chloroform:acetone=2:1), made into hydrochloride by adding 4 N hydrochloric acid/ethyl acetate, and then crystallized from diethyl ether to give 3-[(4-tert-butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)-propyl]-2'-(2-aminoethoxy)benzanilide 1.4 hydrochloride.0.7 hydrate (160 mg, 0.23 mmol, 12%) as white crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].CO.[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:20]1=2)[CH3:18].[BH4-].[Na+]>O>[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:27])([CH3:28])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH2:35][NH:1][CH2:2][CH2:3][N:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:14])[CH:33]=[CH:34][C:20]1=2)[CH3:18]
Reactant: NCCn1ccc2ccccc2c1=O
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCn3ccc4ccccc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
2-(2-Aminoethyl)-2H-isoquinolin-1-one (1.0 g) was added to a methanol solution (15 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (1.46 g). The mixture was stirred for 0.5 hours at room temperature. Sodium borohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=9:1→8:2). The purified product was condensed under reduced pressure to give the title compound(1.92 g) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH:7]([C:9]([CH3:11])=O)=[CH2:8].C(N(CC)CC)C.C([OH:21])C>>[CH3:1][C:2](=[O:21])[CH2:3][CH2:4][C:5](=[O:6])[CH2:8][CH2:7][CH2:9][CH3:11]
Reactant: C=CC(C)=O
Reactant: CCO
Reactant: CCCCC=O
Solvent: CCN(CC)CC
Product: CCCCC(=O)CCC(C)=O

Procedure:
Following the procedure described in Example 1, 13.5 g (0.05 mol) of Cat. 1, 43.1 g (0.5 mol) of n-valeraldehyde, 35.1 g (0.5 mol) of methyl vinyl ketone, 500 ml of ethanol and 20.2 g (0.2 mol) of triethylamine are heated for 12 hours under nitrogen at the reflux temperature. For working up, the solvent is distilled, the cooled residue is taken up in chloroform, the chloroform phase is washed with dilute sulphuric acid and subsequently with water, the chloroform is removed and the liquid residue is distilled in a waterpump vacuum. Nonane-2,5-dione is obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.CCOC(C)=O>[C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:34]=[N+:35]=[N-:36])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@H](OCCOCCOCCCl)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@H](OCCOCCOCCN=[N+]=[N-])[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution of 36 (2.9 g, 5.8 mmol), sodium azide (1.89 g, 29.1 mmol) and nBu4NI (4.3 g, 11.6 mmol) in anhydrous DMF (20 mL) was stirred at 90° C. for 24 h. The solution was cooled to rt then diluted with EtOAc (300 mL). The organic layer was washed with water (3×200 mL), dried (Na2SO4), filtered and evaporated. The oily residue was purified by flash silica gel column chromatography (PE then PE/EtOAc 1:1) to afford 37 (2.54 g, 86%) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz): δ 1.96, 2.02, 2.08, 2.13 (4s, 4×3H, 4×CH3CO), 3.37 (t, 2H, J=5.0 Hz, CH2N3), 3.60-3.72 (m, 9H, OCH2CH2O), 3.74-3.84 (m, 1H, OCH2), 4.00-4.15 (m, 2H, H-5, H-6), 4.27 (dd, 1H, J6′,5=5.1 Hz, J6′,6=12.4 Hz, H-6′), 4.85 (d, 1H, J1,2=1.5 Hz, H-1), 5.20-5.37 (m, 3H, H-2, H-3, H-4). 13C NMR (CDCl3, 75 MHz): δ 20.62, 20.63, 20.7, 20.8 (4s, 4×CH3CO), 50.6 (CH2N3), 62.3 (C-6), 66.0, 68.3, 69.0, 69.5 (4s, C-2 to C-5), 67.2, 69.97, 70.02, 70.6, 70.7 (5s, 5×CH2O), 97.6 (C-1), 169.6, 169.8, 170.0, 170.6 (4s, 4×CH3CO). [α]D=+34 (c=1/CH2Cl2). ESIMS (positive mode) m/z: 528 [M+Na]+. HRESIMS (positive mode) m/z: calcd for C20H31N3O12Na1 [M+Na]+528.1805, found 528.1801.
Reaction SMILES: C([Si]([S:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])(C(C)C)C(C)C)(C)C.[H-].[Na+].[C:24]([C:26]1([CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH2:31][CH2:30][C:29](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:28][CH2:27]1)#[N:25]>O1CCCC1.C1(C)C=CC=CC=1>[CH:50]1([CH2:49][C:26]2([C:24]#[N:25])[CH2:31][CH2:30][C:29]([S:11][Si:12]([CH:13]([CH3:14])[CH3:15])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:20])[CH3:21])=[CH:28][CH2:27]2)[CH2:52][CH2:51]1
Reactant: CC(C)[Si](S[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Reactant: N#CC1(CC2CC2)CC=C(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[Si](SC1=CCC(C#N)(CC2CC2)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a degassed, cooled (0° C.) solution of triisopropylsilylsulfide (11.1 g, 58.6 mmol) in tetrahydrofuran (60 ml) was added portionwise over 10 minutes sodium hydride (2.34 g, 60% dispersion in oil) and the mixture stirred until a clear solution formed. 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic acid 4-cyano-4-cyclopropylmethylcyclohex-1-enyl ester (26.9 g, 58.6 mmol) was dissolved in anhydrous toluene (170 ml) and degassed for 30 minutes before addition of TIPS sodium sulfide solution and tetrakis triphenylphosphine palladium (0) (3.38 g, 2.93 mmol). On complete addition the mixture was plunged into an oil bath preheated to 90° C. After 15 min the mixture becomes dark brown in colour. After a further 15 min the mixture was allowed to cool to ambient temperature. The mixture was poured on to ice (200 g) and extracted with diethyl ether (2×200 ml). The combined organic layer was washed with water (200 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by dry flash column chromatography on silica eluting with isohexane on a gradient of dichloromethane (5-30%). Collecting appropriate fractions followed by evaporation gave a brown oil (20.5 g, 100%). 1H NMR δ (ppm) (CDCl3): 5.92 (1H, s), 2.61-2.54 (2H, m), 2.38-2.28 (1H, m), 2.21-2.10 (3H, m), 1.67-1.44 (2H, m), 1.33-1.23 (3H, m), 1.14 (18H, d, J=7.2 Hz), 0.95-0.85 (1H, m), 0.58-0.55 (2H, m), 0.20-0.18 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[Br:11][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1nccn2ccnc12
Solvent: ClCCl
Product: Clc1nccn2c(Br)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 8-chloro-imidazo[1,2-a]pyrazine (1.53 g, 0.01 mol) in DCM (30 mL) is added N-bromosuccinimide (1.78 g, 0.01 mol) and the reaction is stirred at room temperature for 2 h. After this time the solution is washed with saturated aqueous solution of Na2CO3 (2×20 mL), dried (MgSO4), filtered and concentrated in vacuo to give 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (2.11 g, 96%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:23][CH2:24][OH:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:35].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:23][C:24]([OH:35])=[O:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CCO)c1ccccc1F
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)O)c1ccccc1F
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 290 mg of 8-(cyclohexylmethoxy)-N-[(1S)-1-(2-fluorophenyl)-3-hydroxypropyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in dichloromethane was added 300 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, followed by stirring overnight. To the reaction mixture were added saturated aqueous sodium bicarbonate, an aqueous sodium thiosulfate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue and 230 μl of 2-methyl-2-butene in 6.5 ml of dioxane was added 1.7 ml of an aqueous solution of 93 mg of sodium chlorite and 315 mg of sodium dihydrogen phosphate in a water bath, followed by stirring for 30 minutes in a water bath. To the reaction mixture were added water, 1 M hydrochloric acid, and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained purified product was added diisopropyl ether, and the resulting solid was filtered and dried to obtain 80 mg of (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-(2-fluorophenyl)propanoic acid.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3C)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 2-methylphenylboronic acid (136 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (68 mg, yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:19]=[C:18](C(F)(F)F)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:16]=3)[N:11]=2)[CH2:6]1)=[O:4].[Br:35]C1C2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=C(C=O)C=1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:19]=[C:18]([Br:35])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:16]=3)[N:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2cc(C(F)(F)F)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)cc(Br)c3c2)CC1
Product: COC(=O)C1CN(Cc2cc(Br)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester using 4-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinoline-2-carbaldehyde as starting material. ESI-MS (M+H+): 489.20/491.20.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[S:32][C:33]([C:36]#[N:37])=[CH:34][N:35]=2)[CH2:4]1)[CH3:2].O1CCOCC1.CCO.C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[S:32][C:33]([C:36]#[N:37])=[CH:34][N:35]=2)[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](Nc2ncc(C#N)s2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: CC[C@@H]1C[C@H](Nc2ncc(C#N)s2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 50 °C
Yield: 61 %

Procedure:
A mixture of 2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile (0.21 g, 0.39 mmol), 1,4-dioxane (4.5 mL), EtOH (3.5 mL) and Na2CO3 (2 N aqueous, 5.8 mL, 15.7 mmol) was heated at about 50° C. for about 12 h. The reaction mixture was neutralized to pH 7 by the addition of AcOH (0.3 mL), washed with water (2×5 mL) and extracted with DCM (3×5 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give 2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-thiazole-5-carbonitrile (0.09 g, 60%): LC/MS (Table 1, Method c) Rt=1.95 min; MS m/z: 379 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH:18][CH:19]([C:36]2[C:41]([Cl:42])=[N:40][CH:39]=[CH:38][N:37]=2)[C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27]3)=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.O=P(Cl)(Cl)Cl>CC#N>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:37]3[CH:38]=[CH:39][N:40]=[C:41]([Cl:42])[C:36]3=[C:19]([C:20]3[CH:29]=[C:28]4[C:23]([CH:24]=[CH:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[N:27]4)=[CH:22][CH:21]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)CC1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
4-{[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-piperidine-1-carboxylic acid benzyl ester (2.1 g, 3.6 mmol) was dissolved in CH3CN (126.0 mL) and DMF (0.4 mL) in a round bottom flask equipped with a condenser. The reaction was charged with POCl3 (1.7 mL, 17.9 mmol) and stirred at 55° C. for 3 h. The reaction mixture was concentrated in vacuo, redissolved in DCM, cooled to 0° C., and charged with 2M NH3 in isopropanol to basic pH. Hydromatrix was added, the mixture was concentrated in vacuo, and the resulting residue was purified by silica gel chromatography (Jones Flashmaster, 20 g/70 mL cartridge, eluting with 100% CH2Cl2 to 2% CH3CN/CH2Cl2) to afford 4-[8-chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-piperidine-1-carboxylic acid benzyl ester as a yellow solid; MS (ES+): m/z 574 (100) [MH+]; HPLC: tR=4.2 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C@@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH:25][C@@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)=[CH:3][CH:2]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
[1,1′-Biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>>[ClH:1].[OH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]=[C:2]2[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]
Reactant: NCC(O)CO
Reactant: Oc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Product: Cl
Product: OCC(O)CNc1cc(-c2ccccc2)nc2ccc(O)cc12

Procedure:
The title compound, m.p. 303-304° C., and MS: m/e=310 (M+), was prepared from 4-chloro-2-phenyl-quinolin-6-ol and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][CH2:11][CH3:12])#N.[N:14]1C=CC=C[CH:15]=1.[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:24](Cl)=[O:25]>CCOCC>[C:15]([C:4]1[CH:3]=[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:13][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[C:21]([Br:20])[CH:22]=1)#[N:14]
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1Br
Reactant: CCCCc1ccc(O)cc1C#N
Reactant: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CCCC)cc2C#N)cc1Br
Yield: 87.6 %

Procedure:
4.2 g (0.024 mol) of the 3-cyano-4-n-butylphenol prepared in Step V was dissolved in 50 ml ether, and 6 ml pyridine was added as a catalyst. 9.7 g (0.029 mol) of the 3-bromo-4-n-heptyloxybenzoyl chloride solution prepared in Step III and 30 ml of ether was slowly added to the reaction solution with violently shaking in a water bath having floating ice cubes. After the addition, the reaction solution was allowed to stand at room temperature for a while and was refluxed for two hours. After completion of the reaction, the reaction mixture was filtered to remove inorganic salt. An organic layer was cleaned and dehydrated and the solvent was distilled off. The residue was recrystallized in hexane to yield 9.9 g of (2'-cyano-4'-n-butylphenyl)-3-bromo-4-n-heptyloxybenzoate. The calculated yield was 87.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:31])([F:30])[CH:27]1[O:29][CH2:28]1>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:28][CH:27]([OH:29])[C:26]([F:31])([F:30])[F:25])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)C1CO1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CC(O)C(F)(F)F)c2ccccc2-c2ccccc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
((S)-6-Oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester (108 mg, 0.33 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (762 mg, 6.7 mmol) were dissolved in DMF (2 ml) and heated to 90° C. for 4 h in a sealed tube. After addition of another 500 mg of 1,1,1-trifluoro-2,3-epoxypropane, heating was continued for 18 h. The mixture was diluted with ethyl acetate and water (10 ml each), separated and the aqueous phase extracted twice with each 10 ml ethyl acetate. The combine organic phases are dried over magnesium sulfate and evaporated to dryness. Chromatography (silica, eluent heptanes/ethyl acetate gradient from 1 to 30%) afforded the title compound as white solid (76%). MS: m/e=437(M+H+).