Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(Cl)(=O)C(Cl)=O.O[C:27]1[CH:62]=[CH:61][C:30]([CH2:31][N:32]([CH2:53][C:54]([O:56]C(C)(C)C)=[O:55])[C:33](=[O:52])[C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:51])[CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)=[CH:36][CH:35]=2)=[CH:29][CH:28]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([CH2:42][C:41]([NH:40][C:37]2[CH:36]=[CH:35][C:34]([C:33]([N:32]([CH2:53][C:54]([OH:56])=[O:55])[CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:16][C:15](=[O:17])[C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:19][CH:18]=4)=[CH:62][CH:61]=3)=[O:52])=[CH:39][CH:38]=2)=[O:51])=[CH:48][CH:47]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: CCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-(nonyloxy)benzoic acid (31 mg, 0.119 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.011 mL, 0.127 mmol). The reaction mixture was stirred at room temperature for 30 min. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 2 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 6.6 mg (12%) of 2-(4-(2-(4-methoxyphenyl)acetamido)-N-(4-((4-(nonyloxy)benzoyl)oxy)benzyl)benzamido) acetic acid 16. LCMS-ESI (m/z) calculated for C41H46N2O8: 695; found 694 [M−H]−, tR=10.43 min (Method 4). 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.47-7.27 (m, 4H), 7.23 (d, J=8.0 Hz, 4H), 7.10 (d, J=8.9 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.62 (d, J=35.9 Hz, 2H), 4.07 (t, J=6.5 Hz, 2H), 3.92 (d, J=40.2 Hz, 2H), 3.71 (s, 3H), 3.56 (s, 2H), 1.85-1.66 (m, 2H), 1.53-1.10 (m, 12H), 0.85 (t, J=6.7 Hz, 3H).
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:12]([NH2:15])[CH2:13][NH2:14]>O1CCOCC1>[C:4]([O:3][C:1]([NH:14][CH2:13][CH2:12][NH2:15])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: NCCN
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCN
Reaction time: 24 h

Procedure:
This compound was prepared as described previously (Krapcho et al., 1990, Synthetic Commun. 20:2559-2564). Briefly, a solution of tert.butyl dicarbonate (5.0 g, 0.023 mol) in dioxane (50 ml) was slowly added to ethylenediamine (11.0 ml, 0.165 mol) in dioxane (60 ml). After 24 hrs of stirring the solvent was evaporated and the residue was dissolved in water (80 ml), insoluble byproduct was filtered off and the filtrate was extracted with dichloromethane (3-100 ml). After evaporation of the solvent the product was crystallized from solvent mixture of diethylether-petroleum ether or ethyl acetate-petroleum ether. Yield 2.6 g (71%). NMR (300 MHz, DMSO-d6, 25° C.) d: 1.39 (s, 9H, tBu), 2.83 (m, 2H, CaH2), 3.16 (q, 2H, CbH2), 6.93 (t, 1H, NH), 7.77 (br, 2H, NH2). M.p. 75° C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:10]2[CH2:13][N:12]([CH3:14])[CH2:11]2)[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:22].[OH-:26].[Na+]>>[OH:26][CH2:13][CH:10]1[CH2:11][N:12]([CH3:14])[C:8](=[O:22])[C:7]1([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: CN1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: CN1CC(CO)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
Forty grams (0.153 mole) of α,α-diphenyl-α-(1-methyl-3-azetidinyl)acetonitrile was heated in 150 g. of 70% sulfuric acid solution for 48 hrs. at 130° C. The reaction mixture was poured onto ice and made basic with a 50% sodium hydroxide solution while cooling with the addition of more ice. This mixture was extracted with chloroform, combined extracts dried, filtered, and concentrated in vacuo. The residue was crystallized from toluene, weighed 34.5 g. and melted at 148°-150° C. Ten grams was recrystallized twice from toluene, weighed 7.5 g., and melted at 149°-151° C.
Reaction SMILES: O1CC1CO[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=O)[NH:9]2.[CH2:16](O)[CH3:17]>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC=C2C=1CC(=O)N2>[NH2:9][CH:8]1[CH2:17][CH2:16][C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7]1
Reactant: CCO
Reactant: O=C1Cc2c(cccc2OCC2CO2)N1
Agent: Cl
Agent: O=C1Cc2c(cccc2OCC(O)CNC2CCc3ccccc3C2)N1
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-2-oxoindoline (20.3 g, see JP 49-094666) and 2-aminotetralin (14.81 g) in ethanol (100 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-oxoindolin-4-yloxy)-propanamine hydrochloride is obtained ((i): R=H, Ar=radical 36, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [C@@H:1]1([N:10]2[CH2:17][CH2:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].N.[H][H]>[Rh].O>[OH:15][CH:14]1[CH2:16][CH2:17][N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[NH:13]1.[C@@H:1]1([N:10]2[CH2:17][CH2:16][CH2:14][NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: [H][H]
Reactant: O=C1CCN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C(=O)N1
Agent: [Rh]
Agent: N
Solvent: O
Product: O=C1NC(O)CCN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: O=C1NCCCN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
One and six tenths grams of the dihydrouridine obtained above in 60 ml. of water containing 0.6 ml. of concentrated ammonia was reduced with 0.5 g. of 5% rhodium on alumina in the presence of 42 pounds of hydrogen for a period of 18 hours. The resulting material was filtered to remove the catalyst, evaporated in vacuo and then extracted in a 500 tube Craig apparatus in a system consisting of 2-butanol-water as in Example 1. In this manner, 4-hydroxy-1-β-D-ribofuranosyl-tetrahydro-2(1H)-pyrimidinone and 1-β-D-ribofuranosyl-tetrahydro-2(1H)-pyrimidinone were obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[CH:15]=[C:14]([NH2:16])[NH:13][N:12]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27]#[N:28])=[CH:21][CH:20]=1>C(#N)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:26]([C:27]#[N:28])=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)[NH:16][C:14]2[NH:13][N:12]=[C:11]([CH3:10])[C:15]1=2
Reactant: Cc1cc(N)[nH]n1
Reactant: O=Cc1ccccc1F
Reactant: COc1ccc(C(=O)CC#N)cc1
Solvent: CC#N
Product: COc1ccc(C2=C(C#N)C(c3ccccc3F)c3c(C)n[nH]c3N2)cc1
Yield: 241.1 %

Procedure:
1.5 ml (14.27 mmol) of 2-fluorobenzaldehyde and 1.66 g (5.18 mmol) of 3-methyl-1H-pyrazol-5-amine are added respectively to a solution of 2.5 g (14.27 mmol) of 3-(4-methoxyphenyl)-3-oxopropanenitrile in 60 ml of acetonitrile. The reaction mixture is carried at reflux for 16 hours. The solution is allowed to return to room temperature and then the solid is filtered and rinsed several times with acetonitrile to yield 4.5 g (87%) of 4-(2-fluorophenyl)-6-(4-methoxyphenyl)-3-methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]([OH:28])[CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C:21]3=[O:26])=[C:16]([F:27])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[C:29](=C1N=CC=N1)=[O:30].CN(C1C=CC=CN=1)C.C(#N)C>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:28][C:29](=[O:30])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][C:21]4=[O:26])=[C:16]([F:27])[CH:15]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCC(O)CNc1ccc(N2CCOCC2=O)c(F)c1)c1ccc(Cl)s1
Reactant: O=C=C1N=CC=N1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(NCC1CN(c2ccc(N3CCOCC3=O)c(F)c2)C(=O)O1)c1ccc(Cl)s1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
260 mg (0.608 mmol) of 5-chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]-amino}-2-hydroxypropyl)-2-thiophenecarboxamide (from Example 61), 197 mg (1.22 mmol) of carbonylimidazole and: 7 mg of dimethylaminopyridine in 20 ml of dioxane are boiled under reflux for 5 hours. 20 ml of acetonitrile are then added, and the mixture is stirred in a closed vessel in a microwave oven at 180° C. for 30 minutes. The solution is concentrated using a rotary evaporator and chromatographed on an RP-HPLC column. This gives 53 mg (19% of theory) of the target compound.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][C:22]([C:28]([OH:30])=O)=[CH:21][C:20]=3[CH:31]=2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH3:9])[CH3:2].S(Cl)(Cl)=O.[CH3:36][N:37]([CH:39]=O)[CH3:38]>>[CH2:1]([N:3]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][C:22]([C:28]([NH:3][C:10]4[CH:15]=[CH:14][C:13]([CH2:39][N:37]([CH3:36])[CH:38]5[CH2:8][CH2:7][O:6][CH2:5][CH2:4]5)=[CH:12][CH:11]=4)=[O:30])=[CH:21][C:20]=3[CH:31]=2)=[CH:14][CH:15]=1)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Solvent: O=S(Cl)Cl
Product: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (7 ml) was dissolved 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25 g). To the solution was added, under ice-cooling, thionyl chloride (0.11 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (25 ml). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.16 g) and triethylamine (0.41 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 6) (0.27 g) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoate (3.7 g, 9.7 mmol) in THF/MeOH/H2O (V:V:V=4:1:1) (50 mL) were added lithium hydroxide monohydrate (1.3 g, 29.1 mmol). The mixture was stirred at room temperature for 3 hours and quenched with water (200 mL). To the solution was added 1M HCl to adjust the pH value to 2-3, then a white solid precipitated and was filtered to afford the desired compound (3.3 g, yield 96.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH2:18][N:19]2[CH2:22][C:21]3([CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:20]2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:20]1[C:21]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:22][N:19]1[CH2:18][C:17]1[CH:16]=[N:15][N:5]2[CH:6]=[C:7]([C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=12
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(CN3CC4(CCN(C(=O)OC(C)(C)C)CC4)C3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnn(C)c2)cn2ncc(CN3CC4(CCNCC4)C3)c12
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]methyl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (47 mg, 0.10 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.008 mL, 0.1 mmol). After 30 minutes, the reaction mixture was concentrated. The residue was dissolved in methanol and eluted through a bicarbonate resin cartridge (StratoSpheres SPE, PL-HCO3 MP SPE) to give 3-(2,7-diazaspiro[3.5]non-2-ylmethyl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a solid. 1H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H); 8.24 (s, 1H); 7.97 (s, 1H); 7.12 (s, 1H); 6.77 (s, 1H); 3.95 (s, 3H); 3.85 (s, 3H); 3.79 (s, 2H); 2.89 (s, 4H); 2.50-2.54 (m, 4H); 1.47-1.50 (m, 4H). LRMS (ESI) calculated for C20H27N6O [M+H]+, 367.3; found 367.1.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:19]3[S:20][C:21]([C:25]([O-:27])=[O:26])=[C:22]([CH3:24])[N:23]=3)[CH:9]=[CH:10][C:11]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCCC1.CO.[OH-].[Na+].Cl>O>[N:1]1([C:6]2[CH:7]=[C:8]([C:19]3[S:20][C:21]([C:25]([OH:27])=[O:26])=[C:22]([CH3:24])[N:23]=3)[CH:9]=[CH:10][C:11]=2[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1nc(-c2ccc(Oc3ccccc3)c(-n3ccnc3)c2)sc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccc(Oc3ccccc3)c(-n3ccnc3)c2)sc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A reaction mixture solution was prepared by dissolving 20.2 mg of 2-[3-(1H-imidazol-1-yl)-4-phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 1 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.2 mL of 2 M sodium hydroxide aqueous solution. The reaction mixture was stirred at 50° C. for 2 hours. After the addition of 0.2 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using 4 mL of ethyl acetate. The organic phase was concentrated, followed by purifying using a conventional method to obtain 9.0 mg of 2-[3-(1H-imidazol-1-yl)-4-phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccco2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reaction time: 0.25 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.16 mmol), furfuryl alcohol (0.10 mL, 1.16 mmol), and triphenylphosphine (0.33 g, 1.28 mmol) in tetrahydrofuran (5 mL). Add diethyl azodicarboxylate (0.20 mL, 1.28 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine. Cool 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol), and dichloromethane (5 mL). Slowly add a cold solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 mL). After 15 minutes, partition the reaction mixture between dichloromethane and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:18]([CH2:20][C:21](Cl)=[O:22])=[CH2:19]>C(Cl)Cl>[CH:18]([CH2:20][C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:22])=[CH2:19]
Reactant: NCCc1ccc(O)cc1
Reactant: C=CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(=O)NCCc1ccc(O)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A 1000 mL 3-neck, round bottom flask connected with a reflux condenser and a drying tube, is charged with 250 mL of methylene chloride, 5.48 grams (0.04 mole) 4-aminoethylphenol and 4.04 grams (0.04 mole) triethylamine. The contents are chilled with an ice bath. Through a dropping funnel, 4.18 grams (0.04 mole) of vinylacetyl chloride is added into the flask over a period of 30 minutes. The ice bath is then removed and the contents are continuously stirred overnight. The mixture is then filtered and then condensed using a rotavapor. HPLC analysis indicates only one major product. The product is then passed through silica gel chromatography to give a final purified product with a yield of at least 80 percent. The product is identified by NMR and Mass Spectroscopy.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]=[CH:10]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of 1-benzyl-5-nitroindole (0.51 g, 0.02 mol) in a mixture of ethyl acetate (25 ml) and methanol (25 ml) was carefully added to 10% palladium on charcoal (45 mg). The resulting suspension was stirred at room temperature under an atmosphere of hydrogen. When the reaction was complete (indicated by tlc or calculated uptake of hydrogen) the suspension was filtered through a pad of Harbolite™, and the filtrate evaporated to dryness to give 5-amino-1-benzylindole (0.40 g, 91%) as an off-white solid; m.p. 66-68° C.; δH [2H6]-DMSO 7.30-7.12 (6H, m, 2-H, 2″-H, 3″-H, 4″-H, 5″-H, 6″-H), 7.08 (1H, d, J 8, 7-H), 6.70 (1H, s, 4-H), 6.49 (1H, d, J 8, 6-H), 6.18 (1H, s, 3-H), 5.28 (2H, s, CH2), 4.38 (2H, br s, NH2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][CH:14]([CH:19]1[CH2:21][CH2:20]1)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](NC(CC)C(O)=O)(OC(C)(C)C)=O>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][CH3:22])[C:11]([NH:13][CH:14]([CH:19]1[CH2:20][CH2:21]1)[C:15]([O:17][CH3:18])=[O:16])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C1CC1
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)O
Product: CCC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)OC)C1CC1

Procedure:
Following the procedure for the preparation of methyl {[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)acetate but substituting N-Boc-alpha-aminobutyric acid and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.40-0.62, 0.94-0.99, 1.09-1.12, 1.46, 1.63-2.06, 3.77, 4.04, 5.02, 6.54.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[CH:14]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:13]=2[C:12]([CH3:29])=[C:11]([O:30][CH3:31])[C:10]=1[CH3:32])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:14]2[C:13]3[C:12]([CH3:29])=[C:11]([O:30][CH3:31])[C:10]([CH3:32])=[C:9]([NH2:8])[C:17]=3[O:16][C:15]2([CH3:19])[CH3:18])=[CH:21][CH:22]=1)([CH3:28])[CH3:27]
Reactant: COc1c(C)c(NCc2ccccc2)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1c(C)c(N)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 83 %

Procedure:
Using N-benzyl-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amine obtained in Reference Example 95, the title compound was synthesized in the same manner as in Reference Example 30. Yield 83%. Melting point: 111-112° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][C:20]1[C:25](=[O:26])[N:24]2[CH2:27][CH2:28][CH2:29][CH:30]([OH:31])[C:23]2=[N:22][C:21]=1[CH3:32].C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>CO.ClCCl>[CH3:32][C:21]1[N:22]=[C:23]2[N:24]([CH2:27][CH2:28][CH2:29][CH:30]2[OH:31])[C:25](=[O:26])[C:20]=1[CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 67.5 °C
Reaction time: 24 h

Procedure:
To the solution of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (formula-8) (10.0 grams) in methanol (50 ml), 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-7) (11 grams) and diisopropyl ethyl amine (9 grams) were added. The reaction mixture heated to 65-70° C. and stirred for 24 hrs at the same temperature. The reaction mixture was cooled. Dichloromethane (100 ml) and sodium borohydride (0.086 grams) were added to it and stirred for 60 minutes at the same temperature. The solvent was distilled off under reduced temperature. Methanol was added to the residue and heated to reflux for 30 min. The reaction mixture was cooled to 20° C. and stirred for 1 hour. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.[CH:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([C@H:42]([NH2:45])[CH2:43][OH:44])[CH:36]=1>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2](=[O:4])[NH:45][CH:42]([C:37]2[CH:36]=[CH:35][CH:40]=[C:39]([Cl:41])[CH:38]=2)[CH2:43][OH:44])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)NC(CO)c2cccc(Cl)c2)CC1
Temperature: -78 °C
Yield: 39.2 %

Procedure:
Triphosgene (264 mg, 0.89 mmol) was dissolved in methylene chloride (20 mL) and the mixture cooled to −78° C. under nitrogen atmosphere. A mixture of t-butoxycarbonyl-piperazine (500 mg, 2.4 mmol) and diisopropylethylamine (2 mL) in CH2Cl2 was added dropwise to the cold stirring solution over 30 minutes. When the addition was complete, a mixture of (S)-(+)-3-chlorophenylglycinol (500 mg, 2.4 mmol) and DIEA (2 mL) in CH2CL2 (5 mL) was added. The reaction warmed to ambient temperature and concentrated in vacuo. The resulting residue was purified by preparative HPLC (Gilson: Column=CombiHT SB-C189 5 μM 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2O gradient) to afford the desired compound as a yellow oil (134 mg) Rt=6.72 minutes.