Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[CH3:23][CH:24]([N:26]=[C:27]=[O:28])[CH3:25]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.ClCCl>[CH3:23][CH:24]([NH:26][C:27](=[O:1])[OH:28])[CH3:25].[CH3:23][CH:24]([NH:26][C:27](=[O:1])[OH:28])[CH3:25].[OH:1][CH2:2][C:3]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([CH3:16])[C:4]=1[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1
Reactant: CC(C)N=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: Cn1c(-c2ccccc2)c(CO)c(CO)c1-c1ccncc1
Solvent: ClCCl
Product: CC(C)NC(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a similar manner a mixture of the 3,4-Bis(Hydroxymethyl)-1-methyl-5-phenyl-2-(4-pyridinyl)pyrrole, as prepared in Example VIII, 2-propylisocyanate and dibutyltin diacetate (2 drops) in anhydrous dichloromethane are stirred at room temperature under an argon atmosphere for 15 hours. The mixture is concentrated in vacuo and the residue is subjected to flash chromatography to give the 3,4-bis(hydroxymethyl)-1-methyl-5-phenyl-2(4-pyridinyl)pyrrole Bis[N-(2-propyl)carbamate]. Reacting the carbamate with iodomethyl propionate in accord with Example III will provide the iodide salt.
Reaction SMILES: O=C(CC)C(O)=O.O=C(CCC)C(O)=O.CC(C)CC(=O)C(O)=O.O[CH:26]([C:32]([OH:34])=[O:33])[C@@H:27]([C:29]([OH:31])=[O:30])[NH2:28]>>[NH2:28][C@H:27]([C:29]([OH:31])=[O:30])[CH2:26][C:32]([OH:34])=[O:33]
Reactant: N[C@H](C(=O)O)C(O)C(=O)O
Agent: CC(C)CC(=O)C(=O)O
Agent: CCC(=O)C(=O)O
Agent: CCCC(=O)C(=O)O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
β-hydroxy, aspartic acid derviatives 12b-d were prepared from copperglycinate and 2-oxobutanoic acid, 2-oxopentanoic acid and 4-methyl,2-oxopentanoic acid, respectively, according to the procedure described by L. Benoiton et al. (J. Am. Chem. Soc, 81, 1726-1729, 1959). β-Hydroxyaspartic acid was obtained from Sigma Chem. Comp.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.B1C2CCCC1CCC2.C1C[O:24]CC1>>[O:9]1[C:5]2([CH2:10][CH2:11][CH:2]([CH2:1][OH:24])[CH2:3][CH2:4]2)[O:6][CH2:7][CH2:8]1
Reactant: C1CCOC1
Reactant: C=C1CCC2(CC1)OCCO2
Agent: B1C2CCCC1CCC2
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of 8-methyene-1,4-dioxa-spiro[4.5]decane (2.0 g, 13 mmol, 1.0 eq.) in THF (10 mL) at 0° C. was added dropwise 9-BBN (0.5 M in THF, 104 mL, 4.0 eq.) and the resulting mixture was stirred for 15 min and then warmed to room temperature and stirred overnight. Then NaBO4.4H2O (32 g, 16 eq.) was introduced at 0 portionwise and the resulting mixture was warmed to room temperature and stirred overnight, diluted with hexanes (30 mL) and the separated aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc-hexanes) to give (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.5 g, 67%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(CN)O.O>C(OCCO)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: O
Solvent: CCOCCO
Solvent: NCCO
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 114 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) in mixture of 2-ethoxyethanol (13.0 g) and ethanolamine (1.3 g, 21.3 mmol, 1.65 equiv) and is heated at 110 to 114° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at 15 to 25° C. in a mixture of ethanolamine (9.6 g, 157.2 mol, 12.2 equiv) and 2-ethoxyethanol (0.8 g) and the solution is added in portions to the thebaine mixture over 1 hour 10 minutes while maintaining the batch temperature in the range 110 to 118° C. The reaction mixture is held at 110 to 114° C. for 1.5 h then cooled to 19° C. and water (24 g) added in two portions while maintaining the batch temperature at ≦30° C. The resulting slurry (pH 10.9) is stirred and further cooled to 0 to 5° C. and then filtered. The product washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.64 g, 90.3% yield; 98.5 area % purity by HPLC).
Reaction SMILES: ClC1C=CC(CC2C(=O)OC(C)(C)OC2=O)=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl.[Cl:40][C:41]1[CH:42]=[C:43]([CH:55]=[CH:56][CH:57]=1)[CH2:44][CH:45]1[C:50](=[O:51])[O:49]C(C)(C)[O:47][C:46]1=[O:54]>>[Cl:40][C:41]1[CH:42]=[C:43]([CH:55]=[CH:56][CH:57]=1)[CH2:44][CH:45]([C:46]([OH:54])=[O:47])[C:50]([OH:51])=[O:49]
Reactant: CC1(C)OC(=O)C(Cc2cccc(Cl)c2)C(=O)O1
Agent: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: O=C(O)C(Cc1cccc(Cl)c1)C(=O)O

Procedure:
The title compound was prepared by substituting 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a) with 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 5: step a) then following the procedure described for the preparation of 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([CH3:20])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>O1CCOCC1>[CH2:2]([O:4][C:5]([C:7]1([CH3:20])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of hydrochloric acid (12N, 12.5 mL) in dioxane (25 mL) is added to 4-methyl piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (7.5 g, 0.028 mol) and stirred at room temperature for 1 hr. The reaction mixture is concentrated under reduced pressure and the residue is treated with aqueous solution of sodium bicarbonate to adjust the pH to 8-9. It is again concentrated under reduced pressure and the residue is treated with dichloromethane. After drying over sodium sulfate solvent is removed to get the crude residue which is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane:ammonium hydroxide 14:85:1) to get 4-methylpiperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC2N=NN(OS(C3C=CC(Cl)=CC=3)(=O)=O)C=2C=1.[CH2:46](O)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][C:19]([O:21][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH3:46])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)O)C(N)=O
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)CC[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(N)=O
Yield: 36.8 %

Procedure:
t-Butyloxycarbonyl-L-valyl-D-isoglutamine (1.73 g, 5 mmol) and 6-chloro-1-p-chlorobenzenesulfonyloxybenzotriazole (2.06 g, 6 mmol) were reacted in DMF (5 ml) in the presence of TEA (0.84 ml) in a similar manner to that in Example 6 (II). Then stearyl alcohol (4.05 g, 15 mmol) and TEA (0.7 ml) were added and the mixture was reacted at room temperature for 20 hours. The usual work-up as described in Example 6 (II) gave stearyl t-butyloxycarbonyl-L-valyl-D-isoglutaminate (1.10 g). m.p. 88°-89° C. [α]D23 +4.0° (C 0.5, DMF). Rf2 =0.68, Rf3 =0.34
Reaction SMILES: C(OC(=O)C)C.Cl.C(OC(=O)[NH:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[CH:32]2)[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(C)(C)C.CO.N>C(OCC)(=O)C>[NH2:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[CH:32]2)[CH2:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1
Reactant: Cn1c(=O)ccc2cc(OCCCN(CCNC(=O)OC(C)(C)C)Cc3ccncc3)ccc21
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1c(=O)ccc2cc(OCCCN(CCN)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A 4N-hydrogen chloride ethyl acetate solution (0.22 ml) was added to an ethyl acetate solution (3 ml) of (2-{[3-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (137 mg), and the mixture was stirred at room temperature overnight. 5N-Ammonia methanol solution (1 ml) was added to the reaction mixture, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (85.7 mg) as an colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:33])[C:21]1[CH:26]=[C:25]([F:27])[C:24](F)=[C:23]([N+:29]([O-:31])=[O:30])[C:22]=1[F:32].[C-:34]#[N:35].[Na+]>CN(C)C=O>[C:34]([C:24]1[C:25]([F:27])=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:15])([F:16])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=2[CH3:18])=[O:33])=[C:22]([F:32])[C:23]=1[N+:29]([O-:31])=[O:30])#[N:35]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(F)c([N+](=O)[O-])c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(C#N)c([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-2,4,5-trifluoro-benzamide (6.77 g, 13.75 mmol) (Example I15) in N,N-dimethylformamide (137 ml) at 0° C. was added sodium cyanide (740 mg, 15.13 mmol). The reaction mixture was stirred at 0° C. for one hour and then at ambient temperature for 16 hours. The reaction mixture was concentrated and the residue partitioned between water and dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 8:2) to give 4-cyano-2,5-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (3.2 g, 46.6% yield). 1H-NMR (400 MHz, CDCl3): 2.35 (6H, s), 7.38 (2H, s), 7.83 (1H, d), 8.29 (1H, m) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([C:15]#N)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:28].[Na+].[K+]>ClCCl>[Cl:1][C:2]1[C:3]([C:12]2([CH:15]=[O:28])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: N#CC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Product: O=CC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: -78 °C

Procedure:
3.50 g of 1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropanecarbonitrile (step 1) was dissolved in 70 ml of dichloromethane and the solution was cooled to −78° C. At this temperature 14.9 ml of diisobutylaluminium hydride (1M solution in tetrahydrofuran) was added dropwise under stirring. The mixture was left to warm to ambient temperature and stirred for 6 days. Then the reaction mixture was poured into 100 ml of a saturated aqueous solution of potassium sodium tartrate and stirred for one hour. The aqueous phase was extracted three times with 100 ml portions of dichloromethane, the organic phase dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel with cyclohexane/ethyl acetate (95:5) as eluent. Thus, 0.72 g of 1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropanecarbaldehyde was obtained as a yellow oil. 1H-NMR (CDCl3): 9.07 ppm (s, 1H), 8.73 ppm (s, 1H), 7.98 ppm (s, 1H), 1.78 ppm (m, 2H), 1.69 ppm (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:28]=5)=[CH:23][CH:22]=4)=[C:14]3[N:13]=2)[C:5]1=[O:40].C(N(C(C)C)C(C)C)C.C[C:51]1[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>ClCCl.N1C=CC=CC=1>[C:54]1([S:57]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]3[CH:17]=[CH:16][N:15]4[N:18]=[CH:19][C:20]([C:21]5[CH:22]=[CH:23][C:24]([C:27]6[N:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[N:28]=6)=[CH:25][CH:26]=5)=[C:14]4[N:13]=3)[C:5]2=[O:40])(=[O:59])=[O:58])[CH:55]=[CH:56][CH:51]=[CH:52][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1CN(CCOS(=O)(=O)c2ccccc2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-1-(2-hydroxyethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (Example 25, step 6; 0.080 g, 0.142 mmol) in dichloromethane/pyridine (1:1, 10 mL total) was added N-ethyl-N-isopropylpropan-2-amine (0.0520 mL, 0.284 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.136 g, 0.711 mmol). The reaction was stirred overnight at ambient temperature to provide (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl benzenesulfonate. The crude material was directly in the next reaction (0.102 g, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([O:19]CC)=[O:18])[C:6]=2[CH:22]=1.O[Li].O>O1CCOCC1.O>[Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([OH:19])=[O:18])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1Br
Temperature: 100 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
To a solution of ethyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (53 g, 0.23 mol) in dioxane/H2O (5/1, 600 mL) was added LiOH.H2O (25 g, 1.17 mol), and the mixture was stirred at 100° C. for 3 hours. After concentrated, the resulting residue was dissolved in H2O, 1 N HCl was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was removed to provide the product of 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (48 g, yield: 96%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.49 (s, 1H), 9.67 (s, 1H), 8.30 (s, 1H), 8.12˜8.17 (m, 2H), 7.87 (s, 1H), 7.45˜7.50 (m, 2H), 3.16 (s, 3H). MS (M+H)+: 428/430.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][C:17]([OH:19])=O)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.Cl.[CH3:25][O:26][CH2:27][NH2:28].CCN(C(C)C)C(C)C.Cl>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:25][O:26][CH2:27][NH:28][C:17](=[O:19])[CH2:16][N:11]([CH2:12][C:13]([OH:15])=[O:14])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: COCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCNC(=O)CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-N-(carboxymethyl)glycine (28.45 g, 106.46 mmol) in DMF (163 mL) was added EDC (24.08 g, 125.62 mmol). The solution was cooled to 0° C. and treated with a mixture of N-methoxymethylamine hydrochloride (12.25 g, 125.62 mmol) and Hunig's base (21.88 mL, 125.62 mmol) in DMF (55 mL). The reaction was stirred at room temperature overnight and poured over a mixture of ice and aqueous 10% HCl solution. The mixture was extracted twice with EtOAc. The combined organics were washed twice with aqueous 10% HCl solution and once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a crude oil which was suspended in saturated aqueous NaHCO3 solution. The mixture was washed with EtOAc, adjusted to pH 2 with aqueous 1N HCl, and extracted three times with EtOAc. The final three organic extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a golden oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Li]CC1N2C=NC=C2C=CC=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32](OCC)([O:36]CC)[O:33][CH2:34][CH3:35]>O1CCCC1.CCCCCC>[CH2:34]([O:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)=[O:36])[CH3:35]
Reactant: Cc1cccc2cncn12
Reactant: CCOC(CCCCBr)(OCC)OCC
Agent: [Li]CCCC
Agent: [Li]Cc1cccc2cncn12
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CCCCCc1cccc2cncn12

Procedure:
To a solution of 50 g of 5-methylimidazo[1,5-a]pyridine [J. Org. Chem. 40, 1210 (1975)] in 625 ml of tetrahydrofuran precooled to -75° is added under nitrogen atmosphere 175 ml of 2.4N n-butyllithium in hexane while maintaining temperature below -53°. The solution of 5-(lithiomethyl)imidazo[1,5-a]pyridine, is cooled back to -75° and a solution of 121.8 g of 5-bromo-1,1,1-triethoxypentane in 125 ml of tetrahydrofuran is added rapidly at which time the temperature rises to -60°. The reaction mixture is allowed to warm to -4° over a 45 minute period and evaporated practically to dryness. The residue is partitioned between 500 ml of ethyl ether and 240 ml of 3N hydrochloric acid. The ether solution is further extracted twice with 60 ml of 3N hydrochloric acid; the combined aqueous extract is basified with 100 ml of concentrated ammonia hydroxide and reextracted twice with 200 ml of ethyl ether. The ether extract is dried over magnesium sulfate and evaporated to dryness to give an oil which is distilled under high vacuum to give 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine boiling at 180°-5°/0.12 mm Hg.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:15][C:16]#[N:17])[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:18]([O:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH3:19].C(O)(=O)C>C(O)C.O>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][CH2:23][CH:15]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:3]([Cl:2])[CH:4]=1)[C:16]#[N:17])[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: N#CCc1ccc(C2CCCCC2)c(Cl)c1
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCC(C#N)c1ccc(C2CCCCC2)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 2.5 g of sodium in 50 ml of ethanol there is added dropwise a mixture of 23.4 g of 3-chloro-4-cyclohexyl-phenylacetonitrile and 10 g of acrylic acid ethyl ester. The solution is boiled overnight and then poured into a mixture of 10 ml of glacial acetic acid and 150 ml of water. The ethanol is evaporated and the residue distilled in a high vacuum to obtain 4-(3-chloro-4-cyclohexylphenyl)-4-cyano-butyric acid ethyl ester boiling at 200°-203°C under a pressure of 0.35 mm of Hg.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[F:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C:26]([CH2:25][C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:34][CH:33]=3)([OH:32])[CH2:31][CH2:30]2)=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Product: OC1(Cc2ccc(F)cc2)CCN(CCCOc2ccc(OCc3ccccc3)cc2)CC1

Procedure:
The title compound, MS: m/e=450.5 (M+H+), was prepared from 1-(3-bromopropoxy)-4-(benzyloxy)-benzene and 4-(4-fluor-benzyl)-piperidin-4-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH2:13][C:14]([OH:18])=[O:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(c1ccc(Cl)cc1)c1cc(CCO)on1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 8.8 g of 2-[3-(4-chlorobenzoyl)isoxazol-5-yl)ethanol, 850 ml of CH2Cl2, a few crystals of tetra-n-butylammonium hydrogen sulfate and 130 ml of 9M H2SO4 was added 10.3 g of pulverized K2Cr2O7. The resulting mixture was stirred at room temperature for 2 hours. After allowing the mixture to settle, it was decanted from the unreacted dichromate. The aqueous phase was extracted with CH2Cl2, and the organics were washed with water and brine, and dried over MgSO4. Concentration gave 5.1 g of a solid. Recrystallization from toluene gave 3.0 g (32%) of needles, m.p. 126°-128°.
Reaction SMILES: [CH2:1]([NH:7][CH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C=O.[BH3-][C:30]#N.[Na+]>>[CH2:1]([N:7]([CH3:30])[CH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [BH3-]C#N
Reactant: CCCCCCNC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Agent: C=O
Agent: [Na+]
Product: CCCCCCN(C)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Yield: 73.6 %

Procedure:
Using a method similar to Example 13, using 6-(1-hexylamino-indan-5-yloxy)-nicotinamide (example 12, 490 mg, 1.38 mmol), paraformaldehyde (443 mg), and NaBH3CN (261 mg, 4.16 mmol) gives the title compound (373 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=368 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.38 (d, 1H), 6.98-6.93 (m, 3H), 5.89 (br. s, 2H), 4.42 (t, 1H), 2.97-2.78 (m, 2H), 2.40 (m, 2H), 2.22 (s, 3H), 2.08 (m, 2H), 1.51 (m, 2H), 1.36-1.22 (m, 6H), 0.88 (t, 3H).