Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8][O:7][N:6]=1)[NH2:4].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N>>[Br:19][C:20]1[CH:21]=[C:22]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: CS(=O)(=O)NCCCNc1nonc1C(N)=NO
Product: CS(=O)(=O)NCCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Yield: 12 %

Procedure:
The title compound was prepared according to the procedure of Example 17, step E, using N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-bromo-4-fluoroaniline [Oakwood Products, Inc., product #013091] as the starting materials in 12% yield. LCMS for C13H17BrFN6O4S (M+H)+: m/z=451.0, 453.0. 1H NMR (400 MHz, CD3OD): δ 7.12 (dd, J=5.9, 2.4 Hz, 1H), 7.05 (t, J=8.7 Hz, 1H), 6.83 (m, 1H), 3.39 (t, J=6.8 Hz, 2H), 3.14 (t, J=6.6 Hz, 2H), 2.94 (s, 3H), 1.87 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Cc1ccc(N)c(N)c1
Solvent: CC(C)O
Product: Cc1ccc2nccnc2c1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 4-methylbenzene-1,2-diamine (50.0 g, 0.41 mol) in isopropanol (300 mL) was added a solution of glyoxal (40% in water, 65.3 g, 0.45 mol) at room temperature. The reaction mixture was heated at 80° C. for 2 hours and evaporated under vacuum to give 6-methylquinoxaline (55 g, 93%), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.77 (dd, J=1.5, 7.2 Hz, 2H), 7.99 (d, J=8.7 Hz, 1H), 7.87 (s, 1H), 7.60 (dd, J=1.5, 8.4 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CCN(CC)CC.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH3:10])[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CCCCCCCNCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(CC)C(=O)CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3.2 gms of the N-heptyl-N-ethylamine in 96 ml of CH2Cl2 are added 5.7 ml of Et3N followed by 3.63 ml of hexanedioic acid monochloride monomethyl ester. This mixture is stirred at room temperature for 18 hours; and after concentrating under vacuum, the residue obtained is partitioned between ethyl acetate and an aqueous 2N HCl solution. The organic layer is separated and washed with aqueous saturated NaHCO3, then brine, and dried over MgSO4. Following filtration and concentration under vacuum, the residue is flash chromatographed on normal phase silica gel using a 3/1 ratio of hexane and ethyl acetate to yield N-heptyl-N-ethyladipamic acid, methyl ester.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](Br)[CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1.Cl.CCN(C(C)C)C(C)C>C(O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[N:7]=[C:6]([N:18]2[CH2:17][CH2:16][N:15]([CH:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)[CH2:20][CH2:19]2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Brc1ccnc(Br)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Brc1nccc(N2CCN(C3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of 2,4-dibromopyrimidine (50 mg, 0.210 mmol) and 1-(tetrahydro-2H-pyran-4-yl)piperazine, 2 Hydrochloride (51.1 mg, 0.210 mmol) in Ethanol (1 mL) was treated with DIPEA (0.147 mL, 0.841 mmol) and DMAP (cat.) and stirred at ambient temperature for 1 h. The reaction mixture was concentrated in vacuo and triturated with water, filtered and the solid washed with water then dried in vacuo to provide 2-bromo-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyrimidine (43 mg, 0.130 mmol, 61.9% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (s, 2H) 1.73 (br. s., 2H) 2.48 (br. s., 1H) 2.61 (br. s., 4H) 3.38 (t, J=11.24 Hz, 2H) 3.65 (br. s., 4H) 4.02 (br. s., 2H) 6.40 (d, J=6.25 Hz, 1H) 7.95 (d, J=5.86 Hz, 1H). LC/MS (m/z) ES+=327 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>C(Cl)Cl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[O:19]1[CH2:20][CH2:21][N:16]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCNCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF:water (1:1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), followed by 4-morpholinocarbonyl chloride (0.752 mL, 6.4 mmol) in 5 mL of ether were added, and stirred at 0° C. for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL×3) and dried over anhydrous sodium sulfate. After filtered, the filtrate was concentrated in vacuo to yield 1.39 g of N-tert-butyloxycarbonyl-N'-morpholinocarbonyl-piperazine in 87% yield as a solid. MS m/z M+H=300, M+NH4 =317; H1 -NMR (in CDCl3) δ=1.49 (s, 9H, Boc), 3.25 (m, 8H, 4×CH2), 3.52 (m, 4H), 3.65 (m, 4 H). The obtained N-tert-butyloxycarbonyl-N'-morpholinocarbonyl-piperazine (1.38 g, 4.62 mmol) was dissolved in 10 mL of 20% trifluoroacetic acid in methylene chloride and stirred at room temperature for 1 hour. Solvent and trifluoro acetic acid were removed to obtain N-morpholinocarbonylpiperazine trifluoroacetic acid salt in quantitative yield. MS m/z M+H=200, H1 -NMR (in MeOH-d4) δ=3.22 (m, 4H), 3.3 (m, 4H), 3.45 (m, 4H), 3.65 (m, 4H). The obtained N-morpholinocarbonylpiperazine trifluoroacetic acid salt is dissolved in 30 mL of acetonitrile and cooled in an ice bath. Solid sodium bicarbonate is added to the acetonitrile solution and stirred for an additional 2 hours. Solid is filtered off and the filtrate is concentrated in vacuo to yield N-morpholinocarbonylpiperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-morpholinocarbonylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-morpholinocarbonylpiperazine (1.212 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCC.[Li+].CCC[CH2-].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>O>[CH3:1][N:2]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CNc1ccccc1
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add 23.6 g (0.22 mol) N-methylaniline into 92 g (0.2 mol) 14% hexane solution of N-butyllithium and stir it for 10-20 minutes. Add 33.3 g (0.1 mol) octadecylbromide into the above solution, while stirring it. Add 200 ml water into the solution, after heating and refluxing the solution for about 17 hours and cooling it down to room temperature. Add 6N hydrochloric acid to the solution after concentrating the solution extracted by 300 ml diethyl ether and deposit it. 32.3 g (0.09 mol) N, N-methyloctadecyl-aniline is obtained by refinement through crystaiization with ethyl alcohol and water. Dissolve the obtained 32.3 g (0.09 mol) N, N-methyloctadecyl-aniline into 250 ml concentrated sulfuric acid. Add 30 ml concentrated nitric acid into the solution while stirring it in an ice water bath. Leave it about one hour after adding the nitric acid. Add the solution into ice water, filter off the deposit from it, and refine it by crystallization with ethyl alcohol and water. With the above step, 14.5 g (0.036 mol) N, N-octadecylmethyl-o -nitroaniline is obtained. Add 100 ml 2N hydrochloric acid into this 14.5 g (0.036 mol) N, N-octadecylmethyl-o-nitroaniline which is dissolved into 200 ml ethyl alcohol. 11.7 g (0.031 mol) N, N-octadecylmethyl-o-phenylene-diamine is obtained after adding 11.75 (0.18 mol) zinc dust into the above solution to be heated and refluxed for one hour.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:31][CH:32]([CH3:35])[CH2:33]O.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:31][CH:32]([CH3:35])[CH3:33])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)CO
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 46 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.1 g, 3.1 mmol) dissolved in 30 mL of dichloromethane was reacted with 1.8 mL (3.6 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 2-methylpropanol (0.57 mL, 0.46 g, 6.2 mmol) and 0.50 mL of pyridine (0.49 g, 6.2 mmol) in 20 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:5) to provide 0.62 g (48% yield) of the title compound (30a) as a colorless oil. Rf=0.69 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.98 (d, J=6.4 Hz, 1H), 1.07 (s, 3H), 1.09 (s, 3H), 1.99 (septet, J=6.4 Hz, 1H), 2.25-2.34 (m, 2H), 3.22-3.26 (m, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.86 (s, 1H), 3.89-4.01 (m, 3H), 4.23-4.25 (m, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.64 (d, J=11.2 Hz, 1H), 7.29-7.39 (m, 5H) ppm. MS (ESI) m/z 435.16 (M+H)+, 457.11 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[O:3][C:4]1[CH:5]=[C:6]([CH:45]=[CH:46][CH:47]=1)[O:7][C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][O:11][CH2:12][CH:13]1[CH2:40][CH2:39][C:16]2[N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=[N:19][C:15]=2[CH2:14]1.FC(F)(F)OC1C=C(C=CC=1)OC1C=CC=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1>C(O)(=O)C.O>[F:49][C:2]([F:1])([F:48])[O:3][C:4]1[CH:5]=[C:6]([CH:45]=[CH:46][CH:47]=1)[O:7][C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][O:11][CH2:12][CH:13]1[CH2:40][CH2:39][C:16]2[NH:17][CH:18]=[N:19][C:15]=2[CH2:14]1
Reactant: FC(F)(F)Oc1cccc(Oc2ccccc2COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1
Agent: FC(F)(F)Oc1cccc(Oc2ccccc2COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)c1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)Oc1cccc(Oc2ccccc2COCC2CCc3[nH]cnc3C2)c1
Temperature: 70 °C

Procedure:
A solution of a mixture of 5-[2-(3-(trifluoromethoxy)phenoxy)benzyloxymethyl]-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-[2-(3-(trifluoromethoxy)phenoxy)benzyloxymethyl]-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (600 mg, 0.91 mmol) in a mixture of acetic acid (9 ml) and water (1 ml) was heated to 70° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using DCM/methanol/−25% aqueous ammonia as eluent, to give 251 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C1=COCCC1
Reactant: OCc1ccc(Br)c2cccnc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: Brc1ccc(COC2CCCCO2)c2ncccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 128.4 %

Procedure:
To a solution of (5-bromoquinolin-8-yl)methanol (8.0 g, 33.6 mmol) in methylene chloride (120 mL) were added pyridinium p-toluenesulfonate (844 mg, 3.3 mmol) and 3,4-dihydro-2H-pyran (6.1 mL, 67.2 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with methylene chloride, dried with magnesium sulfate and concentrated. Purification by MPLC (20% ethyl acetate in hexanes) afforded 13.9 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH3:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[N:16][C:17]=1[CH3:18]>>[CH3:11][C:12]1[C:13]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:14][C:15]([Cl:19])=[N:16][C:17]=1[CH3:18]
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: c1ccc2c(c1)CCNC2
Product: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Yield: 68.7 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1,2,3,4-tetrahydroisoquinoline(2.9 g, 23 mmol) and 5,6-dimethyl-2,4-dichloropyrimidine(3.8 g, 21 mmol) and 1,2,3,4-tetrahydroisoquinoline(2.9 g, 23 mmol) prepared in Step 1 of Example 12 were used as starting materials, 3.95 g of the titled compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:15][CH:16]=1)(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of diethyl 4-(amino)benzylphosphonate (2.02 g; 8.3 mmoles) and triethylamine (1.02 g; 9 mmoles) in toluene (7 ml) cooled to 0-5° C., is added dropwise a solution of acryloyl chloride (0.91 g of 95% purity; 10 mmoles) in toluene (2 ml) for 30 min. Thereafter, more toluene (5 ml) is poured into the flask and the mixture is stirred at room temperature for two more hours. The reaction is terminated by addition of water (10 ml). The organic phase is extracted with diethyl ether, dried over MgSO4 and stripped of solvent under vacuum to afford a pale-yellow solid (2.22 g; yield 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]([CH3:20])[C@@H:8]([C:17](O)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6].N[C@@H](C(O)=O)CC1C=CC(O)=CC=1.Cl.C[O:40][C:41](=[O:54])[C@H:42]([CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)[NH2:43]>>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[C:5]([N:7]([CH3:20])[C@@H:8]([C:17]([NH:43][C@H:42]([C:41]([OH:40])=[O:54])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:6]
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(O)cc2)C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: N[C@H](Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(O)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (prepared from (D)-tyrosine following the procedure described in example 55) with (L)-tryptophan methyl ester hydrochloride according to example 1 followed by hydrolysis of the methyl ester moiety according to example 12 gives N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosyl-(L)-tryptophan; FAB-MS m/e 512 (M-H)-.
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.N1CCCC1>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)=[C:13]2[C:24]1[C:33]2[CH2:32][CH:31]=[C:30]([Cl:34])[CH2:29][C:28]=2[N:27]=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(O)Cn1c(CN2CCCC2)c(-c2ccnc3c2CC=C(Cl)C3)c2cc(Cl)ccc21
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
1-Bromo-2,5-pyrrolidinedione (165 mg) was added to a solution of the product from Example 27 (0.3 g) in DMF (3 ml), and the solution stirred for 10 min. Pyrrolidine (0.5 ml) was then added and the mixture stirred for a further 30 min. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid which was filtered off and dried to yield the title compound as a white solid (70 mg).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.[Br-].[Na+].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>CN(C)C=O>[C:12]([O:15][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)(=[O:14])[CH3:13]
Reactant: CC1(C)OCC(CCl)O1
Reactant: CC(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC1COC(C)(C)O1
Temperature: 150 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a mixture of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (51.60 g, 0.343 mol) prepared by Example 1 and N,N-dimethylformamide (400 ml), sodium bromide (37.04 g, 0.36 mol) and sodium acetate (29.53 g, 0.36 mol) were added and the resulting mixture was stirred for 15 hours at 150° C. After cooling, the salt was filtered off and N,N-dimethylformamide was removed in vacuo. Water was added to the residue and it was extracted with toluene and the extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 38.24 g of 4-acetoxymethyl-2,2-dimethyl-1,3-dioxolane (yield 64%, b.p. 81° C. at 12 mmHg).
Reaction SMILES: Cl.[C:2]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[C:14]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:15]3[C:20]([CH:21]=2)=[C:19]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:18](=[O:30])[CH:17]=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3]>CO.C(OCC)(=O)C.[Pt]=O>[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:15]3[C:20]([CH:21]=2)=[C:19]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:18](=[O:30])[CH:17]=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1CC=C(c2cc(-c3ccccc3Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)N1CCC(c2cc(-c3ccccc3Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Reaction time: 1 h

Procedure:
A solution of 8-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one hydrochloride (Example 19, 24 mg) in methanol/ethyl acetate=1/5 was added platinum oxide (9 mg). The solution was hydrogenated under hydrogen (1 atm) for 1 h. The mixture was filtered though celite and concentrated. The residue was purified by silica gel (methylene chloride/methanol/2N ammonia=10/1/0.2) to give the title compound.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:8][C:7]=2[CH:31]=1.[CH3:32][OH:33]>>[ClH:1].[ClH:1].[OH:33][CH2:32][C:4]1[CH:3]=[CH:31][C:7]2[CH2:8][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[C:6]=2[CH:5]=1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Reactant: CO
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2cc(CO)ccc2C1

Procedure:
Example 274 was prepared as an off white solid from Compound B as described for Compound F of Example 41, with chromatography using 5% MeOH/0.5% NH4OH/methylene chloride, and Compound D of Example 1, with purification by prep HPLC before formation of the HCl salt. MS (M+H) 413.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[O:3].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]([C:4]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[CH:11][O:12][CH2:13][CH3:14])=[O:3]
Reactant: CC(=O)Cc1ccncc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)c1ccncc1

Procedure:
In one of its aspects, the invention resides in the three-step process which comprises reacting pyridinylmethyl lower-alkyl ketone of the formula ##STR1## with tri-(lower-alkyl)orthoformate, acetic anhydride and acetic acid to produce 2-(lower-alkoxy)-1-(pyridinyl)ethenyl lower-alkyl ketone of formula II, ##STR2## reacting said ketone (II) with cyanoacetamide or malonamide in the presence of a basic condensing agent and neutralizing the reaction mixture to produce 1,2-dihydro-6-R-2-oxo-5-PY-nicotinonitrile or 1,2-dihydro-6-R-2-oxo-5-PY-nicotinamide of formula III, ##STR3## where R and R' are each lower-alkyl, PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, and Q is cyano or carbamyl, respectively. In preferred embodiments 4(or 3)-pyridinylmethyl methyl ketone is first reacted with triethyl or trimethyl orthoformate, acetic anhydride and acetic acid to produce 2-ethoxy(or methoxy)-1-(4- or 3-pyridinyl)ethenyl methyl (or ethyl) ketone, the latter ketone is next reacted with cyanoacetamide or malonamide in the presence of an alkali lower-alkoxide, preferably sodium methoxide, and then the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl(or ethyl)-2-oxo-5-[4(or 3)-pyridinyl]-nicotinonitrile or 1,2-dihydro-6-methyl(or ethyl)-2-oxo-5-[4(or 3)-pyridinyl]nicotinamide, respectively. In a particularly preferred embodiment 4-pyridinylmethyl methyl ketone is first reacted with triethyl orthoformate, acetic anhydride and acetic acid to produce 2-ethoxy-1-(4-pyridinyl)ethenyl methyl ketone, said latter ketone is reacted with cyanoacetamide in the presence of sodium methoxide, and the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.