Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])C=CC=1OC1C2C(=CC(OC)=C(C(OC(C)(C)C)=O)C=2)N=CC=1.N[C:42]1[CH:63]=[CH:62][C:45]([O:46][C:47]2[C:56]3[C:51](=[CH:52][C:53]([O:60][CH3:61])=[C:54]([C:57]([OH:59])=[O:58])[CH:55]=3)[N:50]=[CH:49][CH:48]=2)=[C:44]([F:64])[CH:43]=1.[F:65]C(C1C=CC=CC=1)C(SN=C=O)=O.CN(C)C(=O)C>C(O)C.C1(C)C=CC=CC=1>[F:65][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][C:32]([NH:31][C:29](=[S:30])[NH:28][C:43]1[C:44]([F:64])=[C:45]([CH:62]=[CH:63][CH:42]=1)[O:46][C:47]1[C:56]2[C:51](=[CH:52][C:53]([O:60][CH3:61])=[C:54]([C:57]([OH:59])=[O:58])[CH:55]=2)[N:50]=[CH:49][CH:48]=1)=[O:40]
Reactant: O=C=NSC(=O)C(F)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)O
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)OC(C)(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1cc2nccc(Oc3cccc(NC(=S)NC(=O)Cc4ccccc4F)c3F)c2cc1C(=O)O

Procedure:
Similar to the synthesis of compound 1d, from compound 39c (1.79 g), 2-fluorophenylacetyl thioisocyanate (1.97 g), and a solvent mixture of N,N-dimethylacetamide (30 mL), toluene (30 mL), and ethanol (6 mL), carboxylic acid 39d was yielded as a crude product (1.89 g, yield: 89%). The crude product was employed in a subsequent reaction without further purification.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.C1C(=O)N([I:26])C(=O)C1>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([I:26])=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)Nc1nc2ccc(Cl)nn2c1I
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a CHCl3 (20 mL) solution of N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (320.4 mg, 1521 μmol) was added n-iodosuccinimide (167.4 μl, 1673 μmol) as a solid in a single portion. The solution was maintained at rt for 20 min, then poured into water. The resulting mixture was extracted with CH2Cl2 (1×50 mL). The layers were separated and the organic layer was washed with saturated aqueous Na2S2O3 (1×20 mL) and brine (1×10 mL). The organic layer was dried (Na2SO4) and concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The residue was taken up in minimal CH2Cl2/MeOH and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (80 g) (Teledyne Isco, Lincoln, Nebr.) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford N-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (427.0 mg, 83.41% yield) as a grey solid. LCMS (ESI positive ionization) m/z: 337.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]([Si](C)(C)C)[CH2:14][CH2:13][CH:12]1[Si](C)(C)C>C(#N)C>[CH3:10][N:11]1[CH:15]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=3)[CH2:9][CH:12]1[CH2:13][CH2:14]2
Reactant: C=Cc1ccc(Cl)nc1
Reactant: CN1C([Si](C)(C)C)CCC1[Si](C)(C)C
Solvent: CC#N
Product: CN1C2CCC1C(c1ccc(Cl)nc1)C2
Reaction time: 2.25 h
Yield: 80 %

Procedure:
To a acetonitrile solution containing 3 gms of Ag(1)F. 1.2 gms of dipolarophile (6-chloro-3-vinyl pyridine) was added to 2 gms of N-methyl-2,5-di(trimethyl silyl) pyrrolidine at 25° C. After stirring the reaction mixture for 2 to 2.5 hours, the reaction mixture was filtered through a plug of celite. The solvent was evaporated to give N-methyl Epibatidine in 80% yield which was further purified by column chromatography. Hydrogenation of N-methyl Epibatidine with pd/c for 22 hours gave 70% yield of Epibatidine.
Reaction SMILES: N12CCCN=C1CCC[CH2:3][CH2:2]2.[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][N:23]=1.ICC>O>[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[N:32]([CH2:2][CH3:3])[N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n2)CC1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCI
Product: CCn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 35 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (76 mL, 511.14 mmol) was added to a suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (150 g, 319.46 mmol) in 2-methylTHF (1.2 L). Iodoethane (46 mL, 575.03 mmol) was added and the mixture was stirred for 16 hours at 35° C. Further iodoethane (46 mL, 575.03 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (76 mL, 511.14 mmol) were added and stirring was continued for 24 hours at 35° C. The mixture was poured into water and the insoluble material was isolated by filtration, washed with water and MTBE and dried in vacuo to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (116 g, 73.0%) as a yellow solid. The filtrate was extracted with DCM and the organic solution was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (30% MTBE/heptane to 100% MTBE). A second crop of the desired product (12 g, 24.12 mmol, 7.55%), was thus isolated as a yellow solid which was later combined with the first crop: 1H NMR Spectrum: (DMSO-d6) 1.41 (9H, s), 1.44 (9H, s), 1.48 (3H, t), 1.52-1.69 (2H, m), 1.87-2.04 (2H, n), 2.79-3.03 (3H, m) 3.86-4.03 (2H, m, 4.59 (2H, q), 7.89 (2H, s), 8.85 (1H, s); Mass Spectrum [M+H]+=498.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[C:11]1[N:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:2]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1Oc1cccnc1
Temperature: 120 °C
Yield: 55.8 %

Procedure:
To a solution of pyridin-3-ol (1.3 g, 10 mmol) in N,N-dimethyl formamide (25 ml) was added 60 % NaH in mineral oil (0.3 g, 15 mmol) and 2-chloronicotinonitrile (1.38 g, 10 mmol) and heated at 120° C. for overnight. The reaction mixture was quenched with 1M NaHCO3 and extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with saturated NaCl (50 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.1 g (50%) of product. MS (ESI+) m/z 198 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=C(C)[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[CH2:66]([Cl:68])Cl>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:66]([Cl:68])[N:41]=5)=[O:56])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCl
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccc(C)n4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccc(Cl)n4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.51 g) was dissolved in methylene chloride (15.3 ml), and to the mixture was added dropwise a solution of m-chloroperbenzoic acid (0.20 g) in methylene chloride (10.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(6-chloro-2-pyridinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 216) (0.34 g).
Reaction SMILES: C(OC([P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](C)(C)Cl>ClCCl>[CH2:14]([PH:9](=[O:13])[O:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCP(=O)(OCC)C(C)(OCC)OCC
Agent: C[Si](C)(C)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCC[PH](=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 176 g of ethyl 1,1-diethoxyethyl(n-butyl)phosphinate in 540 ml of absolute dichloromethane containing 10% of absolute ethanol is treated with 143.6 g of trimethylchlorosilane. After stirring for 48 hours at room temperature, the solvent is removed in vacuo to afford a pale yellow oil. Distillation in vacuo affords ethyl n-butyl-phosphinate, b.p. 27°-34° (2×10-2 mbar).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])(C)(C)C.C(OC([NH:24][C@H:25](C(O)=O)[CH:26]([CH3:28])[CH3:27])=O)(C)(C)C.[C:32]([O:36][C:37]([NH:39][C@H:40]([C:44]([OH:46])=O)[C@@H:41]([CH3:43])[OH:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:44]([NH:24][C@H:25]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])[CH:26]([CH3:28])[CH3:27])=[O:46])[C@@H:41]([CH3:43])[OH:42])=[O:38])([CH3:33])([CH3:34])[CH3:35]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)C(C)C)C(=O)O
Reaction time: 24 h

Procedure:
A solution of 5.3 grams of t-butyloxycarbonyl-L-isoleucine (21.2 mmole), 2.5 milliliters of triethylamine (18 mmole) in a 2-methyltetrahydrofuran solvent is prepared and 20 grams of Merrifield resin is added thereto. Prior to use, the resin is washed with methanol, distilled water, ethanol, and methylene chloride and then dried in vacuo at 100° C. Prior to use, the 2-methyltetrahydrofuran is distilled over a sodium dispersion, and the triethylamine is distilled over phenylisocyanate and then redistilled over a sodium dispersion. The mixture is refluxed for approximately 72 hours to effect esterification of the blocked amino acids to the resin. After the esterification reaction, the resin is washed with tetrahydrofuran, ethanol, glacial acetic acid, ethanol, distilled water, ethanol, and methylene chloride, and then dried in vacuo at 100° C. for three hours. Approximately 21.5-22 grams of t-butyloxycarbonyl-L-isoleucine resin ester is obtained. This coupling of the t-butyloxycarbonylvaline to the t-butyloxycarbonylisoleucine resin ester is performed in essentially the same manner as the coupling of t-butyloxycarbonyl-L-valine to the t-butyloxycarbonyl-L-isoleucine resin ester disclosed in Example 8. However, because of the even greater steric hindrance, the reaction is allowed to proceed for 24 hours. The resin is then washed as usual to remove by-products and completeness of the reaction is checked by the Kaiser color reaction. The addition to t-butyloxycarbonyl-threonine to obtain t-butyloxycarbonyl-threonylvalylisoleucine resin ester, the cleavage of the peptide from the resin to obtain t-butyloxycarbonyl-threonylvalylisoleucine, and its subsequent isolation and purification are performed in essentially the same manner as in the preparation of threonylvalylleucine disclosed in Example 8. The tripeptide, threonylvalylisoleucine, is obtained in an amount of about 600 milligrams (68% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[CH3:32][OH:33].Cl>C(OCC)C>[CH:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[C:18]([C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=2)[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:33][CH3:32])[N:7]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(Cl)n1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COc1nccc(Nc2cc(NC(=O)c3cccc4c3oc3ccccc34)ccc2C)n1
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-4-[5-(4-dibenzofuranylcarbonylamino)-2-methylanilino]pyrimidine (0.1 g), methanol (2 ml) and a 2M solution of hydrogen chloride in diethyl ether (0.5 ml) was stirred and heated to 70° C. for 24 hours. The reaction was evaporated and the residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.025 g); NMR Spectrum: (DMSOd6) 2.26 (s, 3H), 3.85 (s, 3H), 6.36 (d, 1H), 7.34 (m, 1H), 7.46-7.7 (m, 4H), 7.87 (m, 1H), 7.92 (m, 1H), 8.01 (s, 1H), 8.09 (d, 1H), 8.29 (d, 1H), 8.4 (d, 1H), 9.09 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[O-:24]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>C(O)C.OO.O>[CH3:10][C:6]1[CH:5]=[N:4][C:3]([CH2:11][S+:12]([O-:24])[C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)=[C:2]([CH3:1])[C:7]=1[O:8][CH3:9]
Reactant: O=S([O-])([O-])=S
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
0.35 g of 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]thio]-5-methoxy-1H-benzimidazole was suspended in 5 ml of ethanol at room temperature. 0.035 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.099 g H2O2 (35% aqueous solution), and further diluted with 2 ml of water. The oxidant/catalyst solution was added to the reactant suspension dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 6 hours while stirring. 2 ml of 10% Na2S2O3 aqueous solution was then, added, and the resulting mixture was subjected to a reduced pressure to remove ethanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Omeprazole with a yield of about 69% (LC purity>80%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][CH:17]([CH2:19][CH3:20])[CH3:18])=[S:15])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([Cl:25])=[O:24]>CC(C)=O>[ClH:25].[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[N:16][CH:17]([CH2:19][CH3:20])[CH3:18])[S:15][C:23]([O:22][CH3:21])=[O:24])([CH3:2])[CH3:3]
Reactant: CCC(C)NC(=S)Nc1c(C(C)C)cccc1C(C)C
Reactant: COC(=O)Cl
Solvent: CC(C)=O
Product: CCC(C)N=C(Nc1c(C(C)C)cccc1C(C)C)SC(=O)OC
Product: Cl
Reaction time: 10 h

Procedure:
8.8 g of N-(2,6-diisopropylphenyl)-N'-sec.-butylthiourea are dissolved in 50 ml of acetone, and 3.78 g of chloroformic acid methyl ester are added thereto while stirring. The reaction mixture is stirred for a further 3 hours and then left to stand at room temperature for 10 hours. The product which crystallises out is filtered off with suction and dried. The title compound of the formula ##STR6## is obtained in the form of colourless crystals; m.p. 136°-138° C. with decomposition.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[CH:19]1([C:29]([O:31][CH3:32])=[O:30])[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]1.C(I)C=C>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:32][O:31][C:29]([C:19]1([CH2:7][CH:5]=[CH2:6])[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]1)=[O:30]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: C=CCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: C=CCC1(C(=O)OC)CCC(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 102.4 %

Procedure:
Diisopropylamine (4.55 g, 6.36 mL, 45.0 mmol) was dissolved in THF (100 mL) and cooled to −78° C. To this solution was added 2.5 M n-butyl lithium in hexane (18 mL, 45.0 mmol). The solution was stirred for 15 min, warmed up to 0° C. and stirred for an additional 20 min, then re-cooled to −78° C. Dimethyl 1,4-cyclohexanedicarboxylate (7.5 g, 37.50 mmol) in THF (10 mL) was then added and the reaction mixture was allowed to stir at −78° C. for 1.0 h followed by the addition of a mixture of hexamethyl-phosphoramide (HMPA) (5.0 g, 4.85 mL, d=1.03) and allyl iodide (8.19 g, 4.48 mL, 48.8 mmol). This mixture was stirred at −78° C. for 20 min. Then, the dry ice bath was removed and the stirring was continued to allow the reaction mixture to warm to room temperature over 1 h. The reaction mixture was poured into ice-water (100 mL) and ether (50 mL). The two layers were separated and the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to afford 9.23 g (97%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26](Cl)=[O:27].[CH2:33](N(CC)CC)C>CN(C)C=O.O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1([CH3:33])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:27]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CC
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(N2Cc3cc(CNC(=O)c4ccc(Cl)c(Cl)c4)ccc3C2=O)CCC(=O)NC1=O
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.4 g, 1.20 mmol) and 3,4-dichlorobenzoyl chloride (0.26 g, 1.20 mmol) in N,N-dimethylformamide (15 mL), was added triethylamine (0.34 mL, 2.40 mmol) at room temperature under nitrogen. After 2 h, the mixture was diluted with water (40 mL) and stirred for 1 h. The product was isolated by filtration, washed with water (50 mL) and dried in vacuo providing 3,4-dichloro-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as an off-white solid (0.44 g, 79% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 45/55 CH3CN/0.1% H3PO4, 3.46 min (96.23%); mp: 220-222° C.; 1H NMR (DMSO-d6) δ 1.66 (s, 3H), 1.80-1.98 (m, 1H), 2.52-2.82 (m, 3H), 4.51-4.72 (m, 4H), 7.45 (d, J=7.7 Hz, 1H), 7.54 (s, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 8.14 (s, 1H), 9.34 (t, J=5.2 Hz, 1H), 10.86 (br. s., 1H); 13C NMR (DMSO-d6) δ 20.74, 27.81, 29.01, 42.89, 47.65, 57.12, 121.92, 122.59, 127.13, 127.61, 129.24, 130.76, 131.08, 131.31, 134.15, 134.49, 142.41, 143.28, 164.04, 166.97, 172.43, 173.53; LCMS: MH=460 462; Anal Calcd for C22H19Cl2N3O4+1.15H2O: C, 54.93; H, 4.46; N, 8.74. Found: C, 54.60; H, 4.07; N, 8.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O[C:17](=O)[NH:18][C@@H:19]1[CH2:24][CH2:23][C@@H:22]([CH:25]=[O:26])[O:21][CH2:20]1)(C)(C)C.[O:28]=[C:29]1[CH2:34][S:33][C:32]2[CH:35]=[CH:36][C:37](C=O)=[N:38][C:31]=2[NH:30]1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:25]([C@H:22]3[O:21][CH2:20][C@H:19]([NH:18][CH2:17][C:37]4[CH:36]=[CH:35][C:32]5[S:33][CH2:34][C:29](=[O:28])[NH:30][C:31]=5[N:38]=4)[CH2:24][CH2:23]3)=[O:26])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1cccc2scnc12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C=O)OC1
Product: COc1cccc2sc(C(=O)[C@@H]3CC[C@@H](NCc4ccc5c(n4)NC(=O)CS5)CO3)nc12

Procedure:
Using the same method as for Example 23, steps 23.a to 23.f, the title compound was synthesised from 4-methoxybenzothiazole, (3R,6S)-(6-formyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde. After chromatography on SiO2 (EtOAc/MeOH 9:1 +1% NH4OH) and crystallisation from ether/MeOH, a yellowish solid (30 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:3]=1.[Mg].[F:14][C:15]([F:26])([C:22]([F:25])([F:24])[F:23])[C:16](N(OC)C)=[O:17].Cl>C1COCC1>[F:14][C:15]([F:26])([C:22]([F:25])([F:24])[F:23])[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:3]=1)=[O:17]
Reactant: COCOCc1cccc(Br)c1
Reactant: CON(C)C(=O)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOCc1cccc(C(=O)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
In THF (15 mL), a Grignard reactant was prepared from 1-bromo-3-((methoxymethoxy)methyl)benzene (2.54 g) and magnesium (292 mg). Under a nitrogen atmosphere, the obtained Grignard reactant (entire amount) was added to a solution of 2,2,3,3,3-pentafluoro-N-methoxy-N-methylpropanamide (3.70 g) in THF (10 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.28 g) as a yellow oil.