Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([Cl:18])[C:12]=3[C:11]([I:19])=[CH:10]2)[CH2:6]1)=O.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:18][C:17]1[C:12]2[C:11]([I:19])=[CH:10][N:9]([C@H:7]3[CH2:6][C@H:5]([CH2:3][OH:2])[CH2:8]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COC(=O)[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: OC[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Reaction time: 0.67 h

Procedure:
To a solution of trans-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid methyl ester (trans/cis=5:1) (116.5 mg, 0.297 mmol) in CH2Cl2 (5 mL), cooled by dry ice/acetone, was added DIBAL (1M in toluene, 0.65 mL, 0.65 mmol). After 40 min, the dry ice/acetone bath was replaced with and ice/water bath. The reaction was quenched 2 h later by adding potassium sodium tartrate solution, the mixture was extracted with CH2Cl2 (3×20 mL), the combined extracts were washed with NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated to give the target compound as 5:1 trans/cis mixture. This material was chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-8)→CH2Cl2:EtOAc 9:1 (9-19)→CH2Cl2:EtOAc 5:1 (20-47)→CH2Cl2:EtOAc 3:1 (48-60)] to give the title compound with trans/cis=25:1. A forerunning fraction enriched with the cis isomer was also isolated. 1H NMR (CDCl3, 400 MHz) δ 2.42-2.57 (m, 2H), 2.58-2.72 (m, 3H), 3.85 (brs, 2H), 5.36-5.48 (mc, 1H), 7.61 (s, 1H), 8.60 (s, 1H). MS (ES+): m/z 363.9/365.9 (100/36) [MH+]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][NH:2][C:3]1([C:9]([NH2:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>C(#N)C>[CH:19]([N:6]1[CH2:7][CH2:8][C:3]([NH:2][CH3:1])([C:9]([NH2:11])=[O:10])[CH2:4][CH2:5]1)([CH3:21])[CH3:20]
Reactant: CNC1(C(N)=O)CCNCC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC1(C(N)=O)CCN(C(C)C)CC1
Yield: 48.3 %

Procedure:
4-(methylamino)piperidine-4-carboxamide (250 mg, 1.59 mmol), potassium carbonate (264 mg, 1.91 mmol) and 2-bromopropane (0.179 ml, 1.91 mmol) in acetonitrile (10 ml) were heated at reflux for 1.5 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residues were purified by column chromatography on silica eluting with ammonia in methanol/dichloromethane (90/10) to give 1-isopropyl-4-(methylamino)piperidine-4-carboxamide (153 mg, 48%) as a white solid. 1H NMR Spectrum: (DMSO-d6) 0.92 (d, 6H); 1.45 (m, 2H); 1.77 (m, 2H); 1.86 (s, 1H); 2.06 (s, 3H); 2.38 (m, 4H); 2.59 (m, 1H); 6.82 (s, 1H); 7.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.Cl.[CH:14]12[O:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:15][CH:14]3[O:21][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: C1CC2CNCC1O2
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CC2CCC(C1)O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4,6-Trichloro-5-nitropyrimidine (45, 1.43 g, 6.26 mmoles) was dissolved in dichloromethane and cooled to 0° C. A solution of 8-oxa-3-azabicyclo[3.2.1]octane (2, 0.934 g, 6.26 mmoles) in dichloromethane and triethylamine (0.873 mL, 6.26 mmoles) was slowly added over 1 hour. The solution was allowed to stir at 0° C. for 2 hours, then warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was filtered, the filtrate was concentrated, dissolved in ethyl acetate, washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried, and concentrated to provide 3-(2,6-dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (46). Yield: 1.53 g (80%). HRMS; [M+H]+ Obs'd=305.0200, [M+H]+ Calc'd=305.0203.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10](C4C=CC=CC=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]([F:44])([F:43])[O:31]C1C=C2C(=CC=1)NC(=O)C2=O.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:31][C:30]([F:44])([F:43])[F:29])[CH:13]=3)[N:8]=2)=[CH:27][CH:28]=1
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2ccc(OC(F)(F)F)cc12
Yield: 50 %

Procedure:
This compound was synthesized according to the procedure described above for Compound 2, reacting 5-trifluoromethoxyisatin (1.4 g, 6.06 mmol) with 3-(4-chlorophenyl)-2-oxopropyl acetate, Intermediate 2 (1.72 g, 7.57 mmol). The crude acid was recrystallized from ethanol to give pure product as a yellow powder Compound 14 (1.2 g, 50% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 4.32 (s, 2H) 7.26-7.40 (m, 4H) 7.47 (d, J=9.09 Hz, 1H) 8.00 (d, J=8.84 Hz, 1H) 8.86 (s, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:41])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C@H:24]3[C@H:28]([F:29])[CH2:27][N:26](C(OCC4C=CC=CC=4)=O)[CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:40])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[OH-].[K+]>CO>[O:41]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C@H:24]3[C@H:28]([F:29])[CH2:27][NH:26][CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:40])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CN(C(=O)OCc4ccccc4)C[C@H]3F)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CNC[C@H]3F)c2c1

Procedure:
To a suspension of benzyl trans-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-4-fluoropyrrolidine-1-carboxylate (320 mg, 0.557 mmol) in methanol (5 mL) was added an aqueous solution of potassium hydroxide (40%, 5 mL). The suspension was heated under reflux for 30 minutes. The organic solvent was removed by concentration in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J=6.57 Hz, 1 H), 7.85 (d, J=7.33 Hz, 1 H), 7.67 (s, 1 H), 7.63 (t, J=7.07 Hz, 1 H), 7.53-7.40 (m, 2 H), 7.30 (d, J=8.84 Hz, 1 H), 6.18 (s, 1 H), 5.15 (s, 2 H), 5.10 (brs, 1 H), 4.97 (brs, 1 H), 3.60 (dd, J=12.00, 6.44 Hz, 3 H), 3.28 (brs, 1 H), 3.23 (dd, J=8.84, 5.31 Hz, 1 H), 3.18-3.12 (m, 1 H), 3.04 (dd, J=12.00, 4.67 Hz, 1 H), 2.42 (s, 3 H).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]CCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCC/C=C\CCCCCCCC(O)=O>>[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 0.3 %

Procedure:
At the end of the six-week period, the third group of 5 rats was switched to a diet of palm oil (35% of total calories), protein (about 25% of total calories) and dextrose (the remainder of total calories) for two weeks, with vitamins and minerals continued as before. The palm oil was found by analysis to contain the following percentages of fatty acids (total fatty acid basis): 0.4% C12:0, 1.2% C14:0, 44.8% C16:0, 3.9% C18:0, 50.0% C18:1n-9, 8.4% C18:2n-6 and 0.3% C20:0, providing totals of 50.6% saturated fatty acid and 8.4% polyunsaturated fatty acid. At the end of the two-week period, the five rats of this group were sacrificed and determinations were made as described below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccccc2F)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A mixture of 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (105 mg, 0.48 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (74 mg, 0.54 mmol) and PS-DCC (501 mg, 1.28 mmol/g, 0.64 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (29.9 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (385 mg, 3.75 mmol/g, 1.44 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide (60 mg, 63%) as a solid. MS: 294 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:39].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:39])=[O:26])[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 100 %

Procedure:
In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(hydroxycarbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione g, 0.19 mmol) prepared in example 55d was reacted with cyanuric fluoride (51 mg, 0.38 mmol) (Alfa) and pyridine (45 mg, 0.57 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.1 g, 100%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C:41]1([CH:46]=[O:47])[CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C:41]1([CH:46]([OH:47])[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1)[CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C=O
Product: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCCN4C(=O)OC(C)(C)C)c3n2)cc(OC)c1OC

Procedure:
2-{Hydroxy-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methyl}-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 72 (15), 5608-5617, 2007) following the general procedures described in these Examples.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.Cl[CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[C:17]([C:16]1[C:15]([S:19][CH2:25][C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=[O:30])=[N:14][C:13]([O:20][CH3:21])=[C:12]([C:22]#[N:23])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1)#[N:18]
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: O=C(O)c1cccc(CCl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(SCc2cccc(C(=O)O)c2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
50 mg (0.153 mmol) of the compound from Example 10A together with 29 mg (0.168 mmol) of 3-(chloromethyl)benzoic acid and 38.5 mg (0.458 mmol) of sodium bicarbonate are stirred in 0.6 ml of DMF at room temperature for 2 h. Water is added and the reaction mixture is purified by preparative HPLC (with 0.15% hydrochloric acid added).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:21][CH:22]=3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)ccn2)c1
Agent: Cl
Product: NC(=O)Cc1ccc(Nc2ccnc(-c3cccc(Cl)c3)c2)cc1
Yield: 40.1 %

Procedure:
Following general procedure A2, 4-chloro-2-(3-chlorophenyl)pyridine hydrochloride (0.115 g, 0.44 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.080 g, 0.53 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.066 g, 40%) as a light yellow solid. MW=374.26. 1H NMR (DMSO-d6, 500 MHz) δ 14.01 (s, 1H), 10.64 (s, 1H), 8.29 (d, J=7.0 Hz, 1H), 7.97-7.95 (m, 1H), 7.81-7.77 (m, 1H), 7.73-7.69 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.41-7.29 (m, 5H), 7.13-7.09 (m, 1H), 6.91 (s, 1H), 3.42 (s, 2H); APCI MS m/z 338 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=2)[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([CH3:27])[CH2:16][C:15]1([CH3:35])[CH3:34])(=[O:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:25])=[CH:21][CH:22]=2)[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([CH3:27])[CH2:16][C:15]1([CH3:35])[CH3:34])(=[O:13])[CH3:12]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccc(CO)cc1
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: ClCCl
Product: COc1ccc(COC(=O)c2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 4-methoxybenzyl alcohol (6.2 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 l) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11](N)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:17].N([O-])=O.[Na+].[OH-].[Na+].[Na+].[Cl-]>O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([OH:17])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cncc(OCc2ccccc2)c1
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Oc1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The 5-(phenylmethoxy)-3-pyridylamine (1.61 g, 8.00 mmol) was stirred into concentrated sulfuric acid (1.7 mL), water (2.5 mL) and ice (4 g). This mixture was allowed to stir for 10 min until the solution became homogeneous. To this cold, stirring solution was added a solution of sodium nitrite (552 mg, 8.00 mmol) in water (2 mL). The mixture was allowed to stir for 10 min. A boiling solution of concentrated sulfuric acid (5 mL) and water (4 mL) was added. The mixture was heated until all solids dissolved. Ice was added to cool the reaction. The pH was adjusted to 8 with 10% NaOH solution and saturated NaCl solution was added. The product was extracted with ethyl acetate (4×100 mL). The combined ethyl acetate extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and briefly vacuum to give 1.52 g (94.4%).
Reaction SMILES: C([C@@H:7]([C@H:9]([C:11]([O:13][CH:14]([CH3:16])C)=O)O)[OH:8])(OC(C)C)=O.C(OO)(C)(C)C.[OH-].[Na+].[Cl-].[Na+].[C:27]1(C)[CH:32]=[CH:31]C=[CH:29][CH:28]=1>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CO.O>[O:13]1[CH:14]([CH:16]2[CH2:31][CH2:32][CH2:27][CH2:28][CH2:29]2)[C@H:11]1[CH2:9][CH2:7][OH:8]
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Reactant: Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: OCC[C@H]1OC1C1CCCCC1
Temperature: -5 °C
Reaction time: 6 h

Procedure:
A 1 L three-necked flask equipped with thermometer, mechanical stirrer, nitrogen inlet and cooling bath was charged with 15 g 4 anstrom 600-mesh molecular seives, 400 mL dichloromethane, and 7.23 mL (+)diisopropyl L-tartrate (Aldrich). The stirred mixture was cooled to -5° C. and 6.75 mL titanium tetraisopropoxide was added, followed by 227 mL 3.OM t-butyl hydroperoxide in toluene (Aldrich), neither of which produced appreciable exotherm. To the stirred mixture at -20° C. was added a solution of 70 g of the product of Example 3C in 30 mL dichloromethane over 10 min. so that the temperature did not rise about -20° C. The mixture was stirred 6 h at -10° C., then placed (without stirring) in a refrigerator (-10° C.) for 60h. The mixture was again stirred in an ice bath and 120 mL water was added, followed by 30 mL 6N sodium hydroxide solution and the mixture was saturated with sodium chloride. Methanol (50 mL) was added and the mixture was filtered, treated with 100 mL 0.1M pH 7 phosphate buffer and after vigorous shaking was allowed to stand until partial separation occurred. The lower (organic) layer was separated, and the top (aqueous) and middle (emulsion) layers were extracted with dichloromethane (3×200 mL). The remaining emulsion (middle layer) was filtered through Celite, causing its complete separation into organic and aqueous layers. The combined organic layers were washed with pH 7 phosphate buffer (3×100 mL), aqueous bicarbonate, brine, dried (magnesium sulfate), filtered and concentrated to give 85 g of a viscous oil which was distilled using an 8" Vigreux column to give 12 g, bp 60°-122° C. at 0.5 mm, then 51 g of the title substance, bp 122°-130° C. at 0.45 mm, TLC Rf 0.20 in 2:1, system B.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7].N(CC(OCC)=O)=C=O.COC(OC)CN>C(Cl)Cl>[O:7]=[C:6]1[NH:5][CH:4]=[CH:3][N:8]1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CNC(=O)NCC(OC)OC
Agent: CCOC(=O)CN=C=O
Agent: COC(CN)OC
Solvent: ClCCl
Product: CCOC(=O)Cn1cc[nH]c1=O
Reaction time: 0.5 h

Procedure:
Ethyl N-{[(2,2-dimethoxyethyl)amino]carbonyl}glycinate To a solution of ethyl isocyanatoacetate (8.84 mL, 77 mmol) in CH2Cl2 (100 mL) at 0° C. was added aminoacetaldehyde dimethyl acetal (8.86 mL, 81 mmol) over a period of 10 min. The mixture was further stirred for 30 min, quenched with water. The CH2Cl2 layer was separated, washed with water, dried (Na2SO4) and concentrated to give the crude title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[O:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17]OS(C)(=O)=O.O>CN(C=O)C>[O:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: CS(=O)(=O)OC[C@H]1CCCO1
Reactant: O=C1CCc2cc(O)ccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(OC[C@H]3CCCO3)ccc21

Procedure:
A solution of 5-hydroxyindanone (80 mg) and methanesulfonic acid (R)-1-(tetrahydrofuran-2-yl)methyl ester (107 mg) in DMF (1 mL) was stirred at 70° C. for 16 h. After adding water it was extracted with ether, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel. In this way the product was obtained with molecular weight 232.28 (C14H16O3); MS (ESI): 233 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=[CH:14][CH:13]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Product: Cc1ccc(CNC(=O)c2cccc(-c3ccccc3)c2)cc1

Procedure:
Using preparation method 1, 3-phenylbenzoic acid (125 mg, 0.63 mmol) was reacted with 4-methylbenzylamine (96 mg, 0.7 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100%. White crystals were obtained (115 mg, 58%). NMR 1H (ppm, CDCl3): 7.99 (s, 1H), 7.73-7.69 (m, 2H), 7.58 (dd, J3=7.0 Hz, J4=1.4 Hz, 2H), 7.48 (t, J3=7.8 Hz, 1H), 7.43 (t, J3=7.6 Hz, 2H), 7.35 (tt, J3=7.2 Hz, J4=2.4 Hz, 1H), 7.29 (d, J3=8.6 Hz, 2H), 6.88 (d, J3=8.7 Hz, 2H), 6.36 (br. s, 1H), 4.59 (d, J3=5.5 Hz, 2H), 3.79 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:8][CH2:7][CH2:6]1)(O)=[O:2].S(Cl)(Cl)=O.CN1CCCC1=O.[CH:37]([NH2:40])([CH3:39])[CH3:38]>ClCCl>[CH:37]([NH:40][C:1]([CH2:4][C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:8][CH2:7][CH2:6]1)=[O:2])([CH3:39])[CH3:38]
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC(=O)O)c3ccccc32)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC(=O)NC(C)C)c3ccccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of (5R)-5-carboxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (115.6 g) in dry dichloromethane (700 ml) are added thionyl chloride (70 ml) and 1-methyl-2-pyrrolidone (1 ml), and the mixture is refluxed with stirring for three hours. The solution is added dropwise into a solution of isopropylamine (274 ml) in dichloromethane (300 ml) under ice-cooling, and the mixture is stirred for 12 hours. The mixture is evaporated under reduced pressure to remove the dichloromethane, and to the residue is added a 3N aqueous sodium hydroxide solution (1 liter), and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from a 75% aqueous methanol (700 ml) to give (5R)-5-isopropylaminocarbonylmethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (63.2 g).