Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].C(Cl)(Cl)Cl>C1COCC1>[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:22]
Reactant: COc1cccnc1N
Reactant: O=C(Cl)c1cccc(I)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cccnc1NC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
2-Amino-3-methoxypyridine (1.50 g) was dissolved in THF (20 mL), and at 0° C., triethylamine (3.37 mL) and 3-iodobenzoyl chloride (3.23 g) were added thereto and stirred at room temperature for 30 minutes. Triethylamine (3.37 mL) and 3-iodobenzoyl chloride (3.23 g) were further added and stirred at room temperature for 18 hours. Chloroform was added to the reaction liquid, then washed with aqueous saturated sodium hydrogencarbonate solution, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was suspended in ethyl acetate (about 50 mL) added thereto, then the solid was collected through filtration as a colorless solid (5.96 g). Methanol (50 mL) and aqueous 2 M sodium hydrogencarbonate solution (3.42 mL) were added to the obtained solid (2.00 g), and stirred at room temperature for 18 hours. Methanol was evaporated off under reduced pressure, then ethyl acetate was added to the residue, washed with water and saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 100%, gradient) to give the entitled compound (1.15 g, 80%) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:23](O)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (60 g, 274 mmol) in anhydrous THF (700 mL) at 0° C. was added DMF (2 mL) followed by oxalyl chloride (48 mL, 548 mmol) portionwise over 1 hour. The mixture was stirred at 0° C. for 30 min, and then at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue dissolved in DCM (700 mL). tert-Butyl alcohol (97 g, 1315 mmol) and pyridine (150 mL) were added, and the reaction mixture was stirred at room temperature for 64 h. The mixture was transferred to a separating funnel and washed with water (400 mL), 2 N NaOH aqueous solution (400 mL) and brine (2×200 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0 to 5% ethyl acetate in heptane over 30 min) to give tert-butyl 4-bromo-2-fluorobenzoate (60 g, 80%) as an oil. LCMS (m/z): 218/220 (MH+ (−tBu)), 1.11 min; 1H NMR (500 MHz, CDCl3) δ ppm 7.81-7.71 (m, 1H) 7.39-7.30 (m, 2H) 7.29 (s, 1H) 1.68-1.55 (m, 9H).
Reaction SMILES: P(Br)(Br)[Br:2].C(Cl)Cl.[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=1[CH:17](O)[CH3:18]>O>[Br:2][CH:17]([C:10]1[C:9]([Cl:8])=[C:14]([F:15])[CH:13]=[CH:12][C:11]=1[F:16])[CH3:18]
Reactant: BrP(Br)Br
Reactant: CC(O)c1c(F)ccc(F)c1Cl
Solvent: O
Solvent: ClCCl
Product: CC(Br)c1c(F)ccc(F)c1Cl
Temperature: 0 °C
Yield: 78 %

Procedure:
Phosphorus tribromide (1.3 mL) and anhydrous CH2Cl2 (50 mL) were combined and then cooled over ice water for 20 minutes. The cooled solution was then added to a mixture of 1-(2-chloro-3,6-difluorophenyl)ethanol (2.71 g) and methylene chloride (50 mL), and the resulting mixture was stirred at room temperature for two (2) hours. The mixture was then poured into H2O and extracted into CH2Cl2. The organic phase was isolated, dried with magnesium sulfate, filtered, and concentrated to give the title compound (78% yield).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[F:6][C:7]([F:12])([F:11])[C:8](Cl)=[O:9]>>[CH2:1]([O:3][CH:4]=[CH:5][C:8](=[O:9])[C:7]([F:12])([F:11])[F:6])[CH3:2]
Reactant: C=COCC
Reactant: O=C(Cl)C(F)(F)F
Product: CCOC=CC(=O)C(F)(F)F

Procedure:
Reaction between ethyl vinyl ether and trifluoroacetyl chloride to form 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (“ETFBO”) in the absence of an acid-capturing agent and in the presence of a stabilizer for the alkenone that is to be prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[C:24]1([C@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:32][C@@H:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:31])=[O:7]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: C[C@@H](N)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](NC(=O)c1ccc(Cl)c(Br)c1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid 71 (5.30 g, 23 mmol) in DCM (10 mL) at room temperature was added DMF (5 drops) and oxalyl dichloride (3.0 mL, 34 mmol). The reaction mixture was heated to 40° C. for 1 h. The solvent and excess oxalyl chloride were removed under a stream of nitrogen followed by high vacuum. The acid chloride was dissolved in DCM (100 mL), cooled to 0° C., and then pyridine (2.8 mL, 34 mmol) was added followed by (R)-1-phenylethanamine (3.8 mL, 30 mmol). The reaction mixture was stirred at 0° C. for 1 h and concentrated under reduced pressure. The crude amide was dissolved in EtOAc, washed with 1 M HCl (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give (R)-3-bromo-4-chloro-N-(1-phenylethyl)benzamide 72 (8.15 g, 71% yield) as a white solid which was used without further purification. Mass spectrum: calculated for C15H13BrClNO 337.0. found 338.0 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[CH:6][C:5]3[C:8]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)=[N:9][N:10]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[C:4]=3[CH:3]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1
Reactant: Cn1cc(-c2nn(C3CCCCO3)c3cc(Cl)ncc23)cn1
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(OC)cc(-c2cc3c(cn2)c(-c2cnn(C)c2)nn3C2CCCCO2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.06 g, 0.2 mmol), 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.060 g, 0.23 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (10 mg, 0.02 mmol), and potassium phosphate (80. mg, 0.38 mmol) in 1,4-dioxane (0.5 mL) and water (0.07 mL) in a reaction vial was degassed and sealed. The mixture was stirred at 90° C. for 2 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (80 mg). LCMS (M+H)+=420.2.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[N:25][N:24]=[C:23]2[CH2:30]O)=[C:11]([CH:21]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[O:13])(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[N:25][N:24]=[C:23]2[CH2:30][N:36]2[C:32](=[O:42])[C:33]3=[CH:41][CH:40]=[CH:39][CH:38]=[C:34]3[C:35]2=[O:37])=[C:11]([CH:21]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[O:13])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CCCc1nnc(CO)n1-c1ccc(S(=O)(=O)C(C)C)cc1C(=O)c1ccccc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(S(=O)(=O)C(C)C)cc1C(=O)c1ccccc1F

Procedure:
In the manner given in Example 3, a mixture of 5-isopropylsulfonyl-2'-fluoro-2-[3-(hydroxymethyl)-5-propyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 5-isopropylsulfonyl-2'-fluoro-2-[3-(phthalimidomethyl)-5-propyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][F:11])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:29]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl.O>[CH2:29]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([O:1][C:2]2[CH:21]=[CH:20][C:5]([C:6]([O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][F:11])=[O:7])=[CH:4][CH:3]=2)=[O:43])=[CH:45][CH:46]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCC(CF)OC(=O)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OC(CF)CCCCCCCC)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of the 1-monofluoro-2-decyl 4-hydroxybenzoate prepared in (1) (0.1 g) and triethylamine (0.04 g) in methylene chloride (10 ml) was slowly added under ice cooling a solution of 4-n-octyloxybenzoic acid chloride (0.1 g) in methylene chloride (10 ml). The mixture was left to stand until it reached room temperature and stirred overnight. The mixture was poured in water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dehydrated over anhydrous magnesium sulfate. After the solution was distilled under reduced pressure to remove the solvent, the product was purified by silica-gel column chromatography to obtain the titled compound (0.13 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:9])[CH3:8].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12]>ClCCl>[C:7]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)(=[O:9])[CH3:8]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 722.1 %

Procedure:
Powdered potassium carbonate (276 mg, 2 mmol) and then acetyl chloride (0.14 mL, 2 mmol) were added to a solution of 1-(4-nitrophenyl) piperazine (2.1 g, 1 mmol) (Acros Organics) in dichloromethane (75 mL). The mixture was stirred at room temperature overnight and then further quantities of powdered potassium carbonate (500 mg, 3.6 mmol) and acetyl chloride (0.2 mL, 2.8 mmol) were added. The mixture was stirred at room temperature overnight, then it was filtered and the filter cake was washed with dichloromethane. The solvent was evaporated from the filtrate, and the residue was chromatographed (0–66% acetone/dichloromethane) to give 1-acetyl-4-(4-nitrophenyl)piperazine (1.8 g, 72%).
Reaction SMILES: C=C.[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16](=[O:37])[CH2:17][C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:19][N+:20]([O-])=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:38][C:39](OC(OC(OC(C)(C)C)=O)=O)(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16](=[O:37])[CH2:17][C@@H:18]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:28]=1)[CH:19]1[CH:39]=[CH:38][O:21][NH:20]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(C[C@H](C[N+](=O)[O-])c1ccc(OCc2ccccc2)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(C[C@@H](c1ccc(OCc2ccccc2)cc1)C1C=CON1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.8 %

Procedure:
Ethylene was bubbled into 7.3 (882 mg, 1.86 mmol) in 40 mL ACN at room temperature for 20 minutes. (Boc)2O (610 mg, 2.79 mmol) was added at room temperature, followed by the addition of DMAP (23 mg, 0.19 mmol). The mixture was stirred at room temperature for 6 hours. After HPLC indicated that all the 7.3 was consumed, the reaction mixture was taken into EtOAc (500 mL) and saturated sodium bicarbonate (400 mL). The organic layer was separated, washed with brine, dried, and concentrated under vacuum. The crude product was purified by flash chromatography to give 9.1 800 mg). MS ESI (pos.) m/e: 485 (M+H).
Reaction SMILES: Cl.[F:2][CH:3]([F:12])[C@H:4]1[CH2:9][NH:8][CH2:7][C@@H:6]([OH:10])[C@@H:5]1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:19]([N:8]1[CH2:9][CH:4]([CH:3]([F:2])[F:12])[CH:5]([OH:11])[CH:6]([OH:10])[CH2:7]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: O[C@H]1[C@H](O)CNC[C@@H]1C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CC(O)C(O)C(C(F)F)C1
Temperature: 60 °C
Yield: 80 %

Procedure:
A mixture of 6 (0.30 g, 1.4 mmol), K2CO3 (0.48 g, 3.5 mmol) and BuBr (0.20 g, 1.4 mmol) was combined in DMF (10 mL) and heated overnight at 60° C. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc, washed with water and then brine and dried over Na2SO4. After filtration, the filtrate was evaporated in vacuo to give the crude product which was purified by chromatography (CH2Cl2/(9:1) MeOH/NH4OH) to give the title compound (0.25 g, 80%) as a colorless syrup. MH+=224. 1H NMR (DMSO-d6) 6.2 (t, 1H, J=57 Hz), 5.13 (d, 1H, ex), 4.91 (d, 1H, ex), 3.3 (m, 1H), 3.1 (m, 1H), 2.9 (m, 2H), 2.3 (m, 2H), 1.95 (m, 2H), 1.75 (t, 1H), 1.2-1.5 (2 m, 4H), 0.9 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:25])[F:24])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[OH-:27].[Na+:28]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)=[O:26])[C:8]=1[O:9][CH3:10].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)=[O:26])[C:8]=1[O:9][CH3:10].[OH2:27].[OH2:2].[OH2:2].[Na+:28].[Na+:28]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Product: O
Temperature: 30 °C

Procedure:
Pantoprazole free base (50 grams) was dissolved in a solution of tetrahydrofuran (350 ml) and aqueous sodium hydroxide solution (5.4 grams dissolved in 10 ml of water), and stirred at a temperature of 25-35° C. till the clear solution results. The reaction solution was filtered through hyflow and washed the bed with tetrahydrofuran (2×25 ml). Dichloromethane (400 ml) was added slowly to the filtrate over a period of about 1 hour and stirred for about 5-6 hours to crystallize the solid mass. The separated solid mass was cooled to a temperature of 5-10° C. and further stirred for about 2-3 hours. The solid was filtered, washed with dichloromethane (2×25 ml) and suck dried under vacuum. The wet solid was suspended in dichloromethane (250 ml) and stirred for about 15-30 minutes. Then the solid was filtered and suck dried under vacuum and further dried at a temperature of 40-50° C. to afford crystalline Form-I of Pantoprazole sodium sesquihydrate.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([CH3:12])=[N:8][O:9][C:10]=1[CH3:11])=[O:5].[CH3:14][Mg]Br.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOCC.Cl>[CH3:12][C:7]1[C:6]([C:4](=[O:5])[CH3:14])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CON(C)C(=O)c1c(C)noc1C
Reactant: C[Mg]Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1c(C)noc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A solution of 580 mg (3.15 mmol) of N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide in 20 mL of THF is cooled to 0° C. A solution of 1.57 mL (4.72 mmol) of 3 M methylmagnesium bromide in ether is added. After stirring for 4 hours at room temperature, the reaction medium is taken up in 10 mL of 1 N HCl and stirred for a further 1 hour at room temperature. The mixture is then basified with K2CO3 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 420 mg of 1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the following characteristics:
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=[O:2].[ClH:21]>O1CCOCC1>[Cl-:21].[CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][NH2+:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)=[O:2]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Solvent: C1COCCO1
Product: O=Cc1csc(C2CC[NH2+]CC2)n1
Product: [Cl-]
Temperature: 0 °C

Procedure:
To tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (10 g) was added dropwise, at 0° C., a 4 molar solution of hydrogen chloride in 1,4-dioxane (100 ml). The reaction mixture was stirred at 0° C. and then gradually warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride were removed. This gave 4-(4-formyl-1,3-thiazol-2-yl)piperidinium chloride (9 g).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:5]([N+]([O-])=O)[CH:4]=1.[N:17](OCCC(C)C)=[O:18].[O-][CH2:26]C.[Na+].Cl>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]([C:10]([O:12][CH2:13][CH3:26])=[O:11])=[N:17][O:18][C:5]=2[CH:4]=1
Reactant: CC[O-]
Reactant: COC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)CCON=O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1noc2cc(Br)ccc12
Reaction time: 1.5 h

Procedure:
Sodium metal (0.09 g) was dissolved in absolute ethanol (2 ml) under nitrogen. A solution of methyl (4-bromo-2-nitrophenyl)acetate (Intermediate 54) (1.0 g) in ethanol (8 ml) was treated with isoamyl nitrite (0.6 ml) followed by the solution of sodium ethoxide, yielding a black mixture. The mixture was stirred at 60° for 90 min then left at room temp. for 18 h. 2N Hydrochloric acid (20 ml) was added and the mixture was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (×2) and brine, dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified on a Varian Bond-Elut SPE cartridge eluting with cyclohexane:ethyl acetate (100:0 to 97:3) to give the title compound as a cream coloured solid (577 mg).
Reaction SMILES: [CH3:1][C:2]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])([CH2:5][OH:6])[CH2:3][OH:4].C=O.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[CH3:1][C:2]1([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:5][O:6][CH2:18][O:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1COC(C)(CO)CO
Agent: C=O
Solvent: CCCCCC
Product: Cc1ccccc1COC1(C)COCOC1

Procedure:
This compound was prepared in the manner of Intermediate A using 6.00 g of 2-methyl-2-(2-methylbenzyloxy)-1,3-propanediol (Intermediate R), 1.66 g of paraformaldehyde, and 0.13 g of p-toluenesulfonic acid in 150 ml of dry hexane. The crude reaction product was distilled under reduced pressure using a short path distilling system to give in one fraction 3.64 g of 5-methyl-5-(2-methylbenzyloxy)-1,3-dioxane; bp 106°-108°/0.01 mm; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: Br[CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:2]([C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)=[O:4])[CH:22]([C:20]#[N:21])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC#N
Reactant: O=C(c1cccc(Cl)c1)C(Br)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C#N)C(Cc1ccc(Cl)cc1)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of 2-bromo-1-(3-chlorophenyl)-3-(4-chlorophenyl)propan-1-one (358 mg, 1 mmol) in DMF (3 mL) was added ethyl 2-cyanoacetate (226 mg, 2 mmol), followed by K2CO3 (276 mg, 2 mmol). The reaction was stirred at RT for 2 h then diluted with EA (10 mL) and water (3 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4 and concentrated to give ethyl 3-(4-chlorobenzyl)-4-(3-chlorophenyl)-2-cyano-4-oxobutanoate (300 mg, 77% yield) as a yellow solid. LCMS: MH+ 390 and TR=2.334 min. Used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1C#N.C[Mg]Cl.Cl.CC[O:17][CH2:18][CH3:19]>>[NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:18](=[O:17])[CH3:19]
Reactant: CCOCC
Reactant: N#Cc1ccc(Cl)cc1N
Agent: C[Mg]Cl
Agent: Cl
Product: CC(=O)c1ccc(Cl)cc1N
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a vigourosly stirred, Et2O (100 mL) solution of 2-amino-4-chlorobenzonitrile (1.00 g, 6.55 mmol) cooled in an ice-H2O bath was added MeMgCl (3.0 M in THF, 6.5 mL, 19.7 mmol) dropwise over 5 min. During that time the reaction became a thick yellow suspension. Stirring was continued at the temperature for 1 h before the cooling bath was removed and the reaction stirred for 21 h at rt. The resultant light yellow suspension cooled to −60° C. and treated with aq HCl (5 M, 8 mL, 40 mmol) dropwise over ˜3 min. The mixture was allowed to warm slowly to rt within the cooling bath. Later more aq HCl (5 M, 6.5 mL, 33 mmol) was added. The Et2O layer was separated, the aq phase was basicified (pH 4-5) by addition of solid KOH and later extracted with EtOAc (3×). The Et2O and EtOAc layers were combined, dried (Na2SO4) and concentrated under reduced pressure to afford the title material which was used without further purification; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.4 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.60 (dd, J=2.0 Hz, 8.0 Hz, 1H), 6.40 (br, 2H), 2.55 (s, 3H); MS (ES+): m/z 170.07 (100) [MH+]; HPLC: tR=3.12 min (OpenLynx, polar—5 min).