Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29](O)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[F:22].S(Cl)(Cl)=O>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[O:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=C(O)C1(c2ccc(F)c(Cl)c2)CCOCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(F)c(Cl)c2)CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
MgCl2 (2.39 g, 25.1 mmol) was added to diethyl malonate (3.45 mL, 22.8 mmol) in ACN (45.7 mL) after cooling the reaction mixture to 0° C. TEA (6.36 mL, 45.7 mmol) was then added dropwise, and the reaction mixture was warmed to ambient temperature and stirred for 2 hours. 4-(3-Chloro-4-fluorophenyl)-tetrahydro-pyran-4-carboxylic acid (5.61 g, 21.7 mmol) was converted to the acid chloride by reaction with thionyl chloride at 70° C. for 1 hour. The acid chloride reaction mixture was concentrated, dissolved in ACN, and added dropwise to the initial reaction mixture. The resulting mixture was stirred at ambient temperature for 2 hours and then quenched with water, acidified with 5N HCl, diluted with 100 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title (3.87 g) after flash chromatography. MS m/e=401 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](/[C:11](=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:19]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(=O)CC(=O)OC(C)(C)C)c(O)c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1ccc(C(=O)/C(=C\c2ccccc2)C(=O)OC(C)(C)C)c(O)c1
Yield: 45.3 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxy4-methoxyphenyl)-3-oxopropanoate (532 mg, 2.0 mmol), benzaldehyde (200 μL, 2.00 mmol), 12.0 mL benzene, piperidine (10 μL, 0.10 mmol) and glacial acetic acid (5.7 μL, 0.10 mmol), refluxed for 3 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 321 mg (46%) of white solid. mp=105-107° C.; IR (film) 2977.5; 1712.8; 1624.0; 1155.6 cm−1; 1H NMR (500 MHz, CDCl3) δ 12.41 (bs, 1H), 7.81 (s, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.37-7.25 (m, 5H), 6.46 (d, J=2.1 Hz, 1H), 6.34 (dd, J=8.8, 2.1 Hz, 1H), 3.83 (s, 3H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 199.4, 166.8, 165.8, 164.0, 141.8, 133.6, 133.1, 131.6, 130.5, 130.3, 129.1, 114.3, 108.4, 101.1, 82.6, 55.8, 28.1; LRMS (electrospray): Mass calculated for C21H22O5 [M]+, 354.14. Found [M+23]+, 377.5.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:31][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12
Reactant: COc1ccc(O)cc1OC
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)cc1OC
Temperature: 155 °C
Yield: 17.7 %

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmoles) was dissolved in 2 mL DMF. 3,4-Dimethoxyphenol 8c (0.035 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered. The organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed and purified to obtain 108 as a white solid (10 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.81 (s, 1H), 7.76-7.40 (m, 4H), 7.14-6.87 (m, 2H), 6.87-6.65 (m, 2H), 4.25 (d, J=16.2, 3H), 3.91 (d, J=31.0, 6H) MS (ESI) m/z 402.2 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10](Cl)([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH3:17][Al](C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([CH3:15])([CH3:17])[C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: COc1ccc(Cl)cc1C(C)(Cl)C(F)(F)F
Reactant: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(C)(C)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-2-(2-chloro-1,1,1-trifluoropropan-2-yl)-1-methoxybenzene (C46) (derived from the preceding step, ≦4.71 mmol) in dichloromethane (30 mL) was cooled to −78° C. Trimethylaluminum (2 M in hexanes, 7.32 mL, 14.6 mmol) was then added drop-wise over a period of 10 minutes, and the reaction mixture was stirred at −78° C. for 30 minutes. It was then allowed to warm to room temperature and stirred for 16 hours, at which time it was cooled to −78° C. and quenched with water (10 mL). The reaction mixture was filtered through Celite, and the filter pad was washed with dichloromethane; the combined filtrates were washed with saturated aqueous sodium chloride solution, concentrated in vacuo, and purified using silica gel chromatography (Eluant: hexanes) to afford the product as a colorless oil. Yield: 746 mg, 2.95 mmol, 63% over 2 steps. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 3.83 (s, 3H), 6.86 (d, J=8.8 Hz, 1H), 7.25 (dd, J=8.8, 2.6 Hz, 1H), 7.35-7.37 (m, 1H).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH:21]=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:23][CH:20]([CH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]=[CH:10][CH:11]=[CH:12]2)[CH:21]=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=CCCc1ccc2ncccc2c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: O=CC(Cl)Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
L-Proline (410 mg, 3.5 mmol) was added to a solution of 3-quinolin-6-ylpropanal (3.27 g, 17.6 mmol) in chloroform (39 mL) at 0° C. followed by addition of N-chlorosuccinimide (2.48 g, 18.5 mmol) and the reaction mixture was slowly warmed to ambient temperature and stirred for 1 h, monitoring by LCMS. The solvent was concentrated under reduced pressure and the residue was purified on a silica gel column with ethyl acetate in hexane (0-50%) to give the desired product. (95%) LCMS: (M+H+H2O)=237.9/239.9.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M31) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (183 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16])=[O:23]
Reactant: O=C(O)c1ncc[nH]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1ncc[nH]1
Yield: 58 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.20 g, 0.87 mmol), 1H-imidazole-2-carboxylic acid obtained in Example (3a) (91 mg, 0.81 mmol), WSC hydrochloride (0.36 g, 1.88 mmol) and DMAP (10 mg, 0.083 mmol), to obtain 138 mg of the title compound as a white solid (58%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[C:13]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:12])[NH:7]3)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(CCCCBr)c1ccccc1
Reactant: O=C1CCc2c(O)cccc2N1
Product: O=C1CCc2c(cccc2OCCCCS(=O)(=O)c2ccccc2)N1

Procedure:
Prepared analogous to Example 4 from 5-hydroxy-3,4-dihydro-carbostyril and 4-phenylsulfonyl-butyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]2O[CH:10]([CH:11]=1)[C:9]1[C:4]2=[CH:5][CH:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)[CH:3]=1
Reactant: FC(F)(F)c1ccc2c(c1)C1C=C(Br)C2O1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)c1ccc2cc(Br)ccc2c1

Procedure:
2-Bromo-6-(trifluoromethyl)-1,4-dihydro-1,4-epoxynaphthalene (624 mg, 2.14 mmol) and sodium iodide (980 mg, 6.54 mmol) were dissolved in 13 mL of dry acetonitrile and trimethylsilyl chloride (0.823 mL, 6.54 mmol) added. The resultant mixture was stirred at ambient temperature for 3.5 h, poured into hexanes, and the organic layer washed successively with two portions of water and one portion of brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the residue purified by flash column chromatography (SiO2, 5% ethyl acetate/hexanes) to give 2-bromo-6-(trifluoromethyl)naphthalene as a white solid. 1H NMR (500 MHz, CDCl3) δ: 8.15 (s, 1H); 8.11 (s, 1H); 7.89 (d, J=8.7 Hz, 1H); 7.83 (d, J=8.7 Hz, 1H); 7.70 (dd, J=1.6, 8.7 Hz, 1H); 7.69 (dd, J=1.8, 8.7 Hz, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([O:18][C@@H:19]([C@H:21]3[CH2:25][NH:24][C:23](=[O:26])[CH2:22]3)[CH3:20])[C:12]3[S:16][CH:15]=[N:14][C:13]=3[CH:17]=2)O1.I[C:29]1[N:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[N:33][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[O:26]=[C:23]1[NH:24][CH2:25][C@H:21]([C@H:19]([O:18][C:11]2[C:12]3[S:16][CH:15]=[N:14][C:13]=3[CH:17]=[C:9]([C:29]3[N:30]=[CH:31][C:32]([N:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[N:33][CH:34]=3)[CH:10]=2)[CH3:20])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(I)cn2)CC1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncsc12)[C@H]1CNC(=O)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1cc(-c2cnc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
(R)-4-((R)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one 4.05 (40 mg, 0.10 mmol), tert-butyl 4-(5-iodopyrazin-2-yl)piperazine-1-carboxylate 7.11 (48 mg, 0.12 mmol), K3PO4 (65.6 mg, 0.31 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.3 mg, 0.002 mmol) were taken up in 1,4-dioxane (1.5 mL) and water (0.15 mL) under Ar. The reaction mixture was stirred at 100° C. for 40 min and was then partitioned between EtOAc, water, and brine. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-15% MeOH in DCM) to afford tert-butyl 4-(5-(7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)benzo[d]thiazol-5-yl)pyrazin-2-yl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H33N6O4S: 525.2; found: 524.9.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:18]([O-])=O)=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)=[O:5].O.NN>[Fe](Cl)(Cl)Cl.CO>[CH3:21][N:2]([CH2:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH2:18])=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CN(C)C)CC2
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1N)CN(C(=O)CN(C)C)CC2
Temperature: 65 °C
Yield: 26.5 %

Procedure:
A suspension of N,N-dimethyl-2-[6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-isoquinolinyl]-2-oxoethanamine (0.9 g, 3.07 mmol), hydrazine hydrate (0.67 mL, 21.5 mmol), iron(III)chloride (0.125 g, 0.77 mmol), activated carbon (1 g), and methanol (100 mL) was maintained at 65° C. for 12 hours, cooled, and filtered through celite (rinsed with additional methanol). Filtrates were concentrated, redissolved in ethyl acetate, and washed twice with saturated aqueous sodium chloride and sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford 2-[(dimethylamino)acetyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (0.214 g, 26%) as a white solid. 1H NMR/80° C. (400 MHz, DMSO-d6) δ ppm 6.56 (s, 1 H), 6.41 (s, 1 H), 4.49 (s, 2 H), 4.38 (s, 2 H), 3.73 (3.64 (s, 2 H), 3.11 (s, 2 H), 2.66 (s, 2 H), 2.20 (s, 6 H).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>O1CCCC1>[CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:8][CH:9]=1
Reactant: CNC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNCc1ccc(Cc2nc3ccccc3[nH]2)cc1
Yield: 83.8 %

Procedure:
1.98 g (0.0075 mol) of N-methyl-p-[(2-benzimidazolyl)methyl]benzamide are added portionwise to a stirred suspension of 0.58 g (0.0075 mol) of lithium aluminium hydride in 40 ml of tetrahydrofuran and subsequently heated to reflux for 4 hours. At 5°-10° there are added dropwise 1.5 ml of water, then 2.3 ml of a 10% solution of potassium hydroxide and again 1.5 ml of water. The precipitate is filtered off and boiled three times with 20 ml of tetrahydrofuran each time. The combined filtrates are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue is chromatographed on 150 g of silica gel with methanol/concentrated ammonium hydroxide (100:1) as the elution agent. There are obtained 1.58 g (84%) of 2-[4-[(methylamino)methyl]benzyl]benzimidazole, m.p. 157°-160°, as a colourless crystalline powder.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][O:21][C:20]3=[O:25])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:26][NH2:27]>O1CCCC1>[CH2:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][NH:19][C:20](=[O:25])[O:21][CH2:22][C:23]([NH:27][CH3:26])=[O:24])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CN
Reactant: CC(C)Cc1cccc(N2CCC(CCN3C(=O)COC3=O)CC2)n1
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2cccc(CC(C)C)n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 0.72 g (2.08 mmol) of 3-{2-[1-(6-isobutyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 13.4, and 5.20 ml (10.40 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, followed by crystallization from diisopropyl ether, 0.540 g of pure product is obtained in the form of a white solid.
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][CH:7]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:10])[CH3:9])=O.C[O-].[Na+].Cl>C1(C)C=CC=CC=1>[CH:11]([CH:7]1[C:8](=[O:10])[CH2:9][C:3](=[O:2])[CH2:5][S:6]1)([CH3:13])[CH3:12]
Reactant: COC(=O)CSC(C(C)=O)C(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)C1SCC(=O)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
204 g (1 mol) of 3-methoxycarbonylmethylthio-4-methyl-2-pentanone are added dropwise within one hour, at 0° C. with vigorous stirring, to a suspension of 108 g (2 mol) of freshly prepared sodium methylate in 2 liters of absolute toluene. The reaction mixture is stirred at 0° C. for a further 30 minutes, then poured into a mixture of 200 ml of concentrated hydrochloric acid and 800 ml of ice-water, and the organic phase is separated off, and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are concentrated to 500 ml in vacuo and extracted with 500 ml of ice-cold 4N sodium hydroxide solution. The aqueous extracts are immediately acidified with a total of 400 ml of ice-cold hydrochloric acid and extracted three times with 200 ml of dichloromethane each time. The combined dichloromethane phases are dried over sodium sulphate and the solvent is removed in vacuo. The remaining solid is recrystallized from ligroin/ethanol. 150 g (87% of theory) of 2-isopropyltetrahydrothiopyran-3,5-dione of melting point 71° C. are obtained. ##STR53##
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[C:7](O)(=O)[CH2:8][CH3:9]>CCOCC>[NH2:1][N:2]1[C:7]([CH2:8][CH3:9])=[N:6][N:5]=[C:3]1[SH:4]
Reactant: NNC(=S)NN
Reactant: CCC(=O)O
Solvent: CCOCC
Product: CCc1nnc(S)n1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiocarbohydrazide, 212.2 grams, is added to 500 ml. of propionic acid and heated to its reflux temperature for approximately 90 minutes. The reaction mixture is cooled to room temperature and diluted with anhydrous ether. After standing overnight in the refrigerator, the desired 4-amino-5-ethyl-4H-1,2,4-triazole-3 -thiol is filtered, washed with anhydrous ether and air dried to yield a product having a m.p. of 143°-6° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([O:26][C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:38]>C(OCC)(=O)C>[ClH:38].[NH2:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([O:26][C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29])=[CH:15][CH:14]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OC(C)(C)C(=O)O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(OC(C)(C)C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
2-[(3-{[(Tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoic acid (0.13 g, 0.25 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give 2-{[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}-2-methylpropanoic acid hydrochloride (0.10 g, 90.9%) as crystals.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][C:11]1[N:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:15](=[O:22])[C:14]([N+:23]([O-:25])=[O:24])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=1.Cl>O1CCCC1>[CH3:10][C:11]1[N:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:15](=[O:22])[C:14]([N+:23]([O-:25])=[O:24])=[C:13]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1c(C)cc(Oc2ccccc2)c([N+](=O)[O-])c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.38 g (14.7 mmol) of phenol in solution in 20 ml of tetrahydrofuran are added dropwise to a suspension of 0.58 g (14.5 mmol) of sodium hydride in tetrahydrofuran. The mixture is left for 0.5 hour at room temperature, it is cooled to −70° C. and 5.24 g (14 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(tri fluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate in solution in 20 ml of tetrahydrofuran are added dropwise. The temperature of the reaction medium is allowed to return to 0° C. and the medium is stirred at this temperature for 1 hour. The mixture is poured over 20 ml of a 1 N aqueous hydrochloric acid solution and extracted with twice 200 ml of dichloromethane. The medium is washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The product is recrystallized from methanol.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: CC(C)CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 15 %

Procedure:
6-Amino-9-benzyl-2-(3-methylbutyl)thiopurine (260 mg, 0.79 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 7 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (49 mg, yield 15%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:13])[C:9]([F:10])([F:11])[F:12])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N1CCC[C@H]1CO)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CCCN1C(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of the product of step A (1.002 g, 5.08 mmol) and triethylamine (0.78 ml, 5.60 mmol) in CH2Cl2 (50 ml) at -25° C. was added methane sulfonyl chloride (0.40 ml, 5.17 mmol) over a period of 5 min and stirring was continued for 1 hr. The solvent was evaporated in vacuo and the residue purified by chromatography (SiO2, 33% EtOAc in hexanes, elution). The title compound was obtained as a colorless oil.