Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:13]2[NH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10][C:9]=2[CH:8]=[C:7]([N+:18]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([C:5]1[C:13]2[NH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[N:10][C:9]=2[CH:8]=[C:7]([NH2:18])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2nc(C(F)(F)F)[nH]c12
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)c1cc(N)cc2nc(C(F)(F)F)[nH]c12
Yield: 160 %

Procedure:
4-tert-Butyl-6-nitro-2-trifluoromethylbenzimidazole (6.0 grams of crude) was dissolved in 100 milliliters of ethanol and a small amount of platinum oxide was added. The reaction mixture was then placed in a pressure container and hydrogenated until hydrogen uptake ceased. The reaction mixture was filtered and solvent removed to yield 8.6 grams of crude 4-tert-butyl-6-amino-2-trifluoromethylbenzimidazole, as a brown oil.
Reaction SMILES: N1(C2CC[N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)[CH2:7]C2)CCC1.[N:28]1([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])[CH2:33]CN[CH2:30][CH2:29]1>>[Cl:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:19]2[N:20]=[C:12]([CH2:11][N:8]3[CH2:30][CH2:29][N:28]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])[CH2:33][CH2:7]3)[S:13][C:14]=2[N:15]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using 2-piperazin-1-ylisobutyramide in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (70 mg, 46%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>CCOCC>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:8][CH:6]([CH3:7])[CH2:5][CH2:4][CH2:3][C:2]#[CH:1]
Reactant: C#CCCCC(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C#CCCCC(C)OC1CCCCO1
Reaction time: 18 h
Yield: 96 %

Procedure:
Alcohol 5 (7.7 g, 68.75 mmol) was dissolved in 75 mL dry ether and cooled to 0°. A few crystals of p-toluenesulphonic acid were added, followed by dropwise addition of 6.35 g (75.6 mmol) of dihydropyran. The solution was warmed to 20°, stirred for 18 hr, and then extracted with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The solution was dried (MgSO4), concentrated in vacuo, and distilled, yielding 12.96 g of 6 (96% yield).
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].Cl[CH2:59][CH2:60][CH3:61]>CN(C)C=O>[CH3:59][C:60]([O:14][C:15]([C:17]12[C:28]3([CH:30]=[O:31])[CH2:29][CH:20]([C:21]1([CH2:33][O:34][C:35]14[CH:44]([O:45][Si:46]([C:49]([CH3:50])([CH3:52])[CH3:51])([CH3:47])[CH3:48])[CH:41]5[CH:42]([O:43][CH2:22][CH2:21][CH3:33])[CH:37]([CH:38]([O:40]5)[O:39]1)[O:36]4)[CH2:22][CH:23]1[CH:27]3[CH2:26][CH2:25][CH:24]1[CH3:32])[CH:19]=[C:18]2[CH:53]([CH3:55])[CH3:54])=[O:16])([CH3:61])[C:17]1[CH:28]=[CH:29][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCl
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(C)(C)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg of compound (6) was dissolved in 1.0 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 4 mg of sodium hydride under cooling with ice. After 30 minutes, 56.3 μl of 1-chloropropane was added, and the reaction solution was stirred at room temperature for 3 hours. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with n-hexane-ethyl acetate (4:1). The fraction containing the desired product was concentrated to dryness to give 21.6 mg of compound (30).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (53.3, 0.219 mole and benzenesulfonyl chloride (44 g, 0.25 mole) in 500 ml of pyridine was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was extracted with dilute sulfuric acid and then was dried over magnesium sulfate. The volume was reduced to 400 ml, hexane was added and 39.2 g (50.6%) of the title compound was collected as a white, crystalline solid, mp 156.5°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:46])[CH2:14][N:15]2[C:24](=[O:25])[C:23]3[N:22]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:21]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH:37]C(OC(C)(C)C)=O)[CH2:32]4)=[N:20][C:19]=3[N:18]([CH3:45])[C:16]2=[O:17])[CH:10]=[CH:11][CH:12]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:46])[CH2:14][N:15]2[C:24](=[O:25])[C:23]3[N:22]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:21]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH2:37])[CH2:32]4)=[N:20][C:19]=3[N:18]([CH3:45])[C:16]2=[O:17])[CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: COC(=O)COc1cccc(C(=O)Cn2c(=O)c3c(nc(N4CCCC(NC(=O)OC(C)(C)C)C4)n3CC=C(C)C)n(C)c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)COc1cccc(C(=O)Cn2c(=O)c3c(nc(N4CCCC(N)C4)n3CC=C(C)C)n(C)c2=O)c1

Procedure:
Prepared by treating 1-(2-{3-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with trifluoroacetic acid in methylene chloride at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][O:61][C:62]1[CH:63]=[C:64]([CH2:68][NH2:69])[CH:65]=[CH:66][CH:67]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:69][CH2:68][C:64]3[CH:65]=[CH:66][CH:67]=[C:62]([O:61][CH3:60])[CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: COc1cccc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. 1-[3-(Methyloxy)phenyl]methanamine (65.6 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (186 mg) as a light yellow solid. LC-MS (ES) m/z=475 [M+H]+.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[S:24][C:23]([O:25]C)=[N:22][CH:21]=2)=[O:19])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[S:24][C:23](=[O:25])[NH:22][CH:21]=2)=[O:19])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(OC)s1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]c(=O)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxythiazole-5-carboxamido)-2-methylpentanoate, intermediate 19, (171 mg, 0.38 mmol) in dioxane (6 mL) is added 4 M HCl in dioxane (0.25 mL, 1.00 mmol). The crude is stirred at room temperature for 5 hrs. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(2-oxo-2,3-dihydrothiazole-5-carboxamido)pentanoate (57 mg). HPLC retention time=1.80 minutes (condition A), MS 439.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J=7.1 Hz, 3 H), 1.23 (t, J=7.2 Hz, 3 H), 1.67 (ddd, J=14.0, 10.0, 3.5 Hz, 1 H), 1.85-2.03 (m, 1 H), 2.51-2.69 (m, 1 H), 2.77-2.91 (m, 1 H), 2.93-3.05 (m, 1 H), 4.13 (q, J=7.1 Hz, 2 H), 4.26-4.42 (m, 1 H), 5.97 (d, J=8.1 Hz, 1 H), 7.17-7.29 (m, 2 H) 7.29-7.37 (m, 1 H) 7.42 (t, J=7.6 Hz, 2 H) 7.53 (d, J=7.8 Hz, 2 H) 7.57 (d, J=8.1 Hz, 2 H) 9.46 (br. s., 1 H).
Reaction SMILES: O([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)C1C=CC=CC=1.[NH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]([OH:29])=[O:28]>CO>[NH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]([OH:29])=[O:28].[CH:18]1[C:19]2[C:14](=[N:13][C:12]3[C:21]([C:20]=2[NH:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(Oc2cccc3nc4ccccc4cc23)cc1
Agent: NCCNCC(=O)O
Solvent: CO
Product: O=C(O)CNCCNc1c2ccccc2nc2ccccc12

Procedure:
2-((2-Aminoethyl)glycine (4-3) was synthesized following the method reported by Gilon. 2-((2-(Acridin-9-ylamino)ethyl)glycine was synthesized as follows. A mixture of phenoxyacridine (1.35 g, 0.005 mol) and 4-3 (0.65 g, 0.0055 mol) in 20 mL of dry MeOH was refluxed for 36 h. The yellow solid that precipitated during the reaction was collected by filtration, and washed with ethanol and ether, then dried in a vacuum, affording 2.2 g of the product as a yellow solid (Yield: 75%). The structural identity of this compound was confirmed by ESI-MS rather than by NMR spectroscopy due to limited solubility of the compound in common NMR solvents. ESI-MS, +ve mode, m/z [(M+H]+=296.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18]>N1C=CC=CC=1>[CH3:19][N:16]1[C:17]([CH3:18])=[C:13]([NH:12][S:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:14]([CH3:20])=[N:15]1
Reactant: Cc1nn(C)c(C)c1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(Cl)nc1
Yield: 75.3 %

Procedure:
Prepared from 6-chloropyridine-3-sulfonyl chloride (4.8 g, 22.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (2.84 g, 22.7 mmol) in pyridine (35 ml) according to the method of intermediate 1, to give the title compound as a white solid (5.13 g, 17.1 mmol, 75%). δH (D-6 DMSO, 300K) 9.51 (1H, s), 8.59 (1H, d J 2.3 Hz), 8.03 (1H, dd J 7.6 Hz 2.3 Hz), 7.77 (1H, d J 7.6 Hz), 3.58 (3H, s), 1.84 (3H, s), 1.63 (3H, s). m/z (ES+, 70V) 301.1 (MH+).
Reaction SMILES: N1C2C(=CC=CN=2)C=C[CH:2]=1.[Cl:11][C:12]1[N:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:11][C:12]1[N:20]=[C:19]([Cl:21])[C:18]([F:22])=[C:17]([CH3:2])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: c1cnc2ncccc2c1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(F)c(Cl)nc(Cl)c1C(=O)O

Procedure:
The introduction of the methyl group on the 1,8-naphthyridine substrate was accomplished by the formation of the di-anion of 2,6-dichloro-5-fluoronicotinic acid, preferably with lithium diisopropylamide in THF between -70° C. and -50° C. The di-anion was quenched with iodomethane and the target acid 2, 6-dichloro-5-fluoro-4-methylnicotinic acid is obtained after acidification. The remaining portion of the naphthyridine nucleus was elaborated using previously developed methodology.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[OH:27])[O:23][CH2:22][CH2:21][CH2:20]4)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][C:26]=4[O:27][CH2:35]3)[O:23][CH2:22][CH2:21][CH2:20]5)[C:9]2=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one was obtained (70%) as an off-white solid: mp 208-211° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.41-7.29 (m, 10H), 7.16 (dd, J=6.6, 1.8 Hz, 1H), 7.08 (s, 1H), 7.05-6.94 (m, 2H), 6.52 (d, J=7.8 Hz, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.11 (dd, J=5.1, 5.1 Hz, 2H), 2.56 (t, J=6.3 Hz, 2H), 1.94-1.86 (m, 2H); 13C NMR (75 MHz, CDCl3) δ δ178.1, 160.1, 156.3, 141.8, 137.9, 137.5, 132.9, 128.75, 128.73, 128.53, 128.52, 128.2, 128.00, 127.96, 132.9, 132.8, 123.2, 121.3, 115.2, 112.3, 98.9, 80.3, 66.6, 58.8, 57.5, 24.8, 22.3; MS (ES+) m/z 460.1 (M+1).
Reaction SMILES: C([O-])(O)=O.[Na+].C([O:10][C:11](=[O:22])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:21])[C:18]([CH3:20])=[O:19])(C)(C)C.C([BH3-])#N.[Na+].N1C=CC=CC=1>O.C(O)C.C(O)(C(F)(F)F)=O>[C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:11]([OH:22])=[O:10])(=[O:21])[C:18]([CH3:20])=[O:19]
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
Molecular sieves (1.312 g) were added with stirring to a mixture of 0.206 g of hCl.L-Asp-β-pyrrolide-α-ethyl ester, 0.073 g of NaHCO3 and 0.986 g of N-pyruvoyl-L-proline-t-butyl ester in 0.1 ml of H2O and 2.0 ml of ethanol at room temperature. The mixture was stirred for 30 minutes and then 0.054 g of sodium cyanoborohydride in 1.0 ml of ethanol was added drop-wise over a period of 4 hours. Stirring was continued for another 18 hours. The mixture was filtered and the precipitate was washed with ethanol. Solvent of the combined filtrates was removed by rotary evaporation to yield a yellow oil. The material was chromatographed on LH-20 (2.2×99 cm) and developed with THF/isopropanol (3:7 by vol). The residue obtained by rotary evaporation was dissolved in 1.2 ml of TFA. After 45 minutes at room temperature, TFA was removed and the material was purified by chromatography on AG1-X2 (1.2×38 cm) developed first with H2O and then with a linear gradient between H2O and 0.5M ammonium acetate. Apparently pure product, 31.5 mg, was obtained by chromatography on Sephadex G-10 (1.2×97 cm column) developed with 2% pyridine. The ethoxy group was removed by saponification.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (81 mg, 81%), MS (ISP) m/z=402.5 [(M+H)+], mp 217.5° C., was prepared in accordance with the general method of example 26 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and dimethylcarbamic acid chloride.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:30]([CH3:31])[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1>O1CCOCC1.Cl>[CH3:31][C:30]1[N:17]2[C:18]([C:19]3[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=4)=[N:13][C:14]=3[CH:15]=[CH:16]2)=[N:28][N:29]=1
Reactant: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3ccn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 8-[4-(1,3-dioxolan-2-yl)phenyl]-3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine (5-1, 0.30 g, 0.73 mmol) in dioxane (5 mL) and 3N HCl (5 mL) was stirred at room temperature for 15 min. The mixture was concentrated at 25° C. to remove most of the dioxane. The residue was poured into ice cold water to give a brown solid which was collected via filtration and dried with toluene (×2) azeotropically the give the title compound. LRMS m/z (M+1) Calcd: 365.1. Found 365.2.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]1[CH:13]=[C:14]([CH:18]([CH3:22])[CH2:19][CH2:20]O)[CH:15]=[CH:16][CH:17]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12]1[CH:13]=[C:14]([CH:18]([CH3:22])[CH2:19][CH2:20][N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1=C(/C=C/c2cccc(C(C)CCO)c2)C(C)(C)CCC1
Product: CC1=C(/C=C/c2cccc(C(C)CCN3C(=O)c4ccccc4C3=O)c2)C(C)(C)CCC1

Procedure:
Conversion of (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-1-ol with phthalimide following the method used in Example 18 gave (E)-2-(3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butyl)isoindoline-1,3-dione as a colorless oil. Yield (0.416 g, 93%): 1H NMR (500 MHz, CDCl3) δ 7.75 (m, 2H), 7.64 (m, 2H), 7.18 (s, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.64 (d, J=16.3 Hz, 1H), 6.27 (d, J=16.3 Hz, 1H), 3.67 (t, J=7.1 Hz, 2H), 2.78 (m, 1H), 2.12 (m, 1H), 2.04 (t, J=6.0 Hz, 2H), 1.93 (m, 1H), 1.77 (s, 3H), 1.64 (m, 2H), 1.49 (m, 2H), 1.30 (d, J=7.0 Hz, 3H), 1.08 (s, 6H).
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.[CH2:24]([N:26]([CH2:47][CH3:48])[C:27]1[CH:32]=[C:31]([O:33]C)[CH:30]=[CH:29][C:28]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45]C)[CH:41]=2)[CH2:36]1)[CH3:25]>>[CH2:47]([N:26]([CH2:24][CH3:25])[C:27]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=1[CH:35]1[CH2:44][CH2:43][C:42]2[CH:41]=[C:40]([OH:45])[CH:39]=[CH:38][C:37]=2[CH2:36]1)[CH3:48]
Reactant: CCN(CC)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(CC)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 79.5 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Example 36, diethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (288 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (210 mg).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].OS(O)(=O)=O.[CH2:16](O)[CH2:17][CH2:18][CH3:19]>>[C:6]([C@H:4]([C@@H:2]([C:1]([O:10][CH2:1][CH2:2][CH2:4][CH3:6])=[O:9])[OH:3])[OH:5])([O:8][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7]
Reactant: CCCCO
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=S(=O)(O)O
Product: CCCCOC(=O)[C@@H](O)[C@H](O)C(=O)OCCCC
Temperature: 25 °C

Procedure:
d-Tartaric acid (25 g, 167 mmol), n-butanol (200 mL) and concentrated H2SO4 (59 mL) were heated under reflux overnight. The solution was cooled to room temperature then partitioned between H2O and CH2Cl2. The organic layer was washed with aqueous saturated NaHCO3 then filtered through Celite. The organic solution was then washed with brine, dried (MgSO4), filtered, and the solvent removed in vacuo. The resulting oil was purified by Kugelrohr distillation (bp=100-105° C., 0.06 mm Hg) to yield 38 as a clear light yellow oil: 1H NMR (300 MHz, CDCl3) δ0.9 (t, 6H), 1.4 (m, 4H), 1.65 (m, 4H), 3.2 (m, 2H), 4.35 (m, 4H), 4.5 (m, 2H).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1.O.C(O)(=O)C>C1C=CC=CC=1.C(OCC)C.C1COCC1.C(OCC)C>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:23])[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(=O)C(=O)OC(C)(C)C)cc1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C(O)(C(=O)OC(C)(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30 ml of a 2M solution (60 mol) of phenyllithium in benzene/diethyl ether (3:1) are added dropwise at 0° C. with stirring to 13.2 g (60 mmol) of tert-butyl 2-(4-methyl-phenyl)-2-oxo-acetate under argon in 70 ml of THF and the mixture is stirred at room temperature for a further 1 h. The mixture is diluted with 80 ml of diethyl ether, poured into 150 ml of water with stirring, neutralised with 1N acetic acid and extracted three times with diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated, and the product is chromatographed on silica gel 60 using 40-60 petroleum ether/ethyl acetate (4:1).