Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=C[C:9]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1.FC1C=CC(C(=O)C(=[O:45])C2C=CC(F)=CC=2)=CC=1.CCOC(CC(CC(OCC)=O)=O)=O.[OH-].[Na+]>CO>[C:26]([C:9]1[C:11](=[O:45])[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCOC(=O)CC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1=C(c2ccc(F)cc2)C(c2ccc(F)cc2)=C(C(=O)OCC)C1=O
Reaction time: 8 h
Yield: 81 %

Procedure:
Diethyl 2,3-di(4-fluorophenyl)-1,4-benzenedicarboxylate In a 500 mL round bottom flask was loaded difluorobenzil (12.3 g, 50.0 mmol), diethyl acetonedicarboxylate (12.1 g, 60.0 mmol) and methanol (100 mL) with stirring. This was cooled in an ice/water bath and methanolic NaOH (2 g in 50 mL of methanol) added to the mixture. This was stirred overnight. The resultant yellow precipitate was filtered and washed with methanol (2×20 mL) and air-dried. The yellow precipitate was then added to acetic anhydride (300 mL). The mixture was cooled in an ice/water bath and then sulfuric acid was added dropwise until an orange solution resulted. Several more drops of sulfuric was then added and the solution stirred for 30 min. The excess acetic anhydride was destroyed by addition of water. Excess water (1 L) was added to precipitate out the orange product. The orange precipitate was filtered and washed repeatedly water and air-dried to give 2,5-dicarboethoxy-3,4-di-(4-fluorophenyl)-cyclopentadienone (16.7 g, 81% yield). In a 100 mL round-bottom flask was loaded 2,5-dicarboethoxy-3,4-di-(4-fluorophenyl)-cyclopentadienone (2.6 g, 6.3 mmol), norbornadiene (2.9 g, 31.5 mmol) and toluene (45 mL) with stirring. The mixture was refluxed for 5 hour and then the solvent was removed. Methanol was then added to precipitate out the white product. The white precipitate was filtered and washed with methanol (2×5 mL) and air-dried (1.22 g, 47% yield).
Reaction SMILES: C([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C:11]=3[C@H:12]([O:32][CH3:33])[CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=O)C.C1COCC1.[OH-].[Na+].O>CO>[CH3:33][O:32][C@H:12]1[C:11]2[C@:23]([CH3:31])([CH2:24][CH2:25][C@H:26]3[C:10]=2[CH2:9][CH2:8][C@@H:7]2[C@:27]3([CH3:30])[CH2:28][CH2:29][C@H:5]([OH:4])[CH2:6]2)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13]1
Reactant: CO[C@@H]1C[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC[C@H]3C(=C12)CC[C@H]1C[C@@H](OC(C)=O)CC[C@@]13C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@H]1C[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC[C@H]3C(=C12)CC[C@H]1C[C@@H](O)CC[C@@]13C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 (0.070 g, 0.15 mmol) dissolved in methanol (0.8 mL) and THF (0.4 mL) was added 2N sodium hydroxide (0.2 mL) and the reaction mixture was stirred at ambient temperature for 1 h. Some starting material was still present and the reaction mixture was stirred for an additional 2 h at 50° C. To the reaction mixture was added water (~10 mL). The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and saline and dried over sodium sulfate. Evaporation of the solvent afforded a white solid that was purified on a silica gel flash column (1×10 cm) and eluted with ethyl acetate/dichloromethane (1:9). Yield of pure compound 31, 0.057 g (89%) mp 127°-128° C. 1H NMR: δ4.21 (dd, 1H, J=6.5, 7.6 Hz), 3.67-3.59 (m, 1H), 3.27 (s, 3H) 2.72-2.68 (m, 1H). 2.26 (ddd, 1H, J=8.0, 8.1, 13.2 Hz), 0.98 (s, 3H), 0.93 (d, 3H, J=6.6 Hz), 0.87 (d, 3H, J=6.7), 0.867 (d, 3H, J=6.6 Hz), 0.74 (s, 3H). IR: 3263, 1336, 1283, 1212, 1131, 1092, 1041. EIMS (m/z): 416.
Reaction SMILES: C1(C2N=C(/C=C/[C:12]3[CH:13]=[C:14]([CH:18]=[O:19])[CH:15]=[CH:16][CH:17]=3)SC=2)CCC1.CC(C)([O-:23])C.[K+].C(O)(C)(C)C>C(O)(=O)C>[C:18]([OH:19])(=[O:23])[C:14]1[CH:13]=[CH:12][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture composed of 3.15 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzenecarboxaldehyde, 1.44 g of potassium tert-butoxide and 100 ml of tert-butanol was heated to reflux for 2 hr while exposed to air. The mixture was then diluted with 100 ml of ice water. This mixture was then acidified with acetic acid and extracted with methylene chloride. The combined extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo to yield (E)-3-[2-(4-cyclobutyl)-2-thiazolyl)ethenyl]benzoic acid; m.p. 172°-175° C. from ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28]([NH:22][CH2:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])[CH2:16][CH2:17]2)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1
Reactant: CN(CCCCCN1CCC(CN)CC1)Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(C)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
1H-NMR (CDCl3,ppm) δ: 1.20-1.88(11 H,m), 2.20(3 H,s), 2.63(2 H,t,J=6.8 Hz), 2.60-2.32(4 H,m), 3.78(2 H,s), 7.25-7.36(5 H,m) (3) A suspension of N-benzyl-N-methyl-5-(4-aminomethylpiperidin-1-yl)-pentylamine (3.52 g), 4-amino-5-chloro-2-methoxybenzoic acid (2.34 g), dicyclohexylcarbodiimide (2.39 g), 1-hydroxybenzotriazole (1.57 g) and triethylamine (2.35 g) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 12 hr. The solvent was evaporated, and water was added to the residue, which was followed by extraction with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.86 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(N-benzyl-N-methylamino)pentyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:2].[NH:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[NH:28][CH:29]=[CH:30]4)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(I)cc2)cc1)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccc4[nH]ccc4c3)cc2)cc1)OC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of (2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (0.10 mmol, 50 mg) (Step A), 5-indolyl-boronic acid (0.114 mmol, 18 mg) and powered cesium carbonate (0.23 mmol, 35 mg) in DME (0.5 mL) was added Pd(PPh3)4 (0.003 mmol, 4 mg). The mixture was flushed with nitrogen and maintained under nitrogen while being heated at reflux in a 100° C. oil bath. The mixture was stirred for 6 hours, and then cooled to room temperature and diluted with ethyl acetate and water. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel (CH2Cl2/EtOAc 96:4) to afford the title compound 1H-NMR (CDCl3, 200.15 MHz): δ 8.20 (broad s, 1H), 7.80 (d, 1H, J=0.8), 7.56 (d, 3H, J=8.9), 7.41 (d, 2H, J=1.6), 7.23 (dd, 1H, J=3.2, 2.4), 7.15 (d, 3H, J=8.6), 6.99 (d, 2H, J=8.9), 6.85 (d, 3H, J=8.6), 6.60–6.58 (m, 1H), 4.24–4.11 (m, 8H), 3.92 (dd, 1H, J=7.3, 5.9), 3.35 (s, 4H), 2.98–2.94 (m, 3H), 2.28 (qn, 2H, J=5.9), 1.24 (t, 4H, J=7.3).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].N1C(C)=CC(C)=CC=1C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC1(C)CCNc2ccccc21
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)CCN(c2ccccc2[N+](=O)[O-])c2ccccc21
Temperature: 250 °C
Reaction time: 1 h

Procedure:
1b (0.762 g, 4.73 mmol), ortho-fluoronitrobenzene (0.88 g, 5.67 mmol, 1.19 eq), and 2,4,6-collidine (0.66 mL, 1.05 eq) were pre-stirred 40s in a conical microwave container. It was then heated with stirring at a Personal Chemistry Microwave reactor with normal absorption at 250° C. for 1 h. The crude mixture was dissolved in CHCl3, and was purified by flash chromatography (hexanes/EtOAc) to give 0.66 g of crude 1c. LC-MS ESI 283 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH:13]=[O:14])[C:7]([OH:9])=[O:8].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C)C=O>[CH2:15]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[C:4]([F:3])[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(C(=O)O)cc1F
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
60% NaH (0.23 mol) is added portionwise to a solution of 3-fluoro-4-formyl benzoic acid (3, 0.19 mol) in dry dimethylformamide (DMF) (570 mL). The mixture is stirred at room temperature for 45 min. Benzyl bromide (0.23 mol) is added dropwise to the mixture. After stirring at room temperature for 5 h, the reaction mixture is poured into 1N HCl (ca. 1000 mL) and extracted twice with EtOAc. The combined extracts are washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and evaporated in vacuo to give crude 3-fluoro-4-formyl benzoic acid benzyl ester (6).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]1>>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:13]=2[NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:25][CH2:26]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN1CCC(N)CC1
Reactant: Cc1cccc(C(=O)O)c1Nc1ccnc2cc(Cl)ccc12
Product: CCCCN1CCC(NC(=O)c2cccc(C)c2Nc2ccnc3cc(Cl)ccc23)CC1

Procedure:
2-(7-Chloro-4-quinolylamino)-3-methyl benzoic acid is converted to the acid chloride which is reacted with 4-amino-1-n-butyl piperidine as in Example 1 to give the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])[N:5]=[N:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=3[Cl:14])[N:5]=[N:4][N:3]=2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(C2CCCN2)cc1
Reactant: Clc1cccc(-n2nnnc2Cl)c1Cl
Product: Clc1ccc(C2CCCN2c2nnnn2-c2cccc(Cl)c2Cl)cc1
Yield: 10.1 %

Procedure:
The compound from Example 75B (0.1 g) was reacted with 2-(4-Chloro-phenyl)-pyrrolidine (0.1 g) according to the method of Example 75C to provide 0.016 g of the title compound as a white solid. MS (ESI/NH3) m/z 395 (M+H)+; 1H NMR (δ, DMSO-d6) 1.78-1.9 (m, 4H), 3.3-3.6 (m, 2H), 4.8-5.0 (m, 1H) 6.8-6.9 (m, 1H), 7.05-7.19 (m, 4H), 7.60-7.65 (t, 1H), 7.79-7.85 (d, 1H), 7.99-8.1 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH:33]([CH3:35])[CH3:34])[N:3]=1.[C:36]1([C@H:42]([NH:44][C:45]([NH2:47])=[O:46])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(Cl)Cl>[CH:33]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([NH:47][C:45]([NH:44][C@@H:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:43])=[O:46])[CH:11]=[C:10]3[N:12]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:13]=[C:8]1[C:9]=23)([CH3:35])[CH3:34]
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: CC(C)N1CCc2nc(Cl)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(C)N1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
7-chloro-3-isopropyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (116 mg, 0.242 mmol), (R)-1-(1-phenylethyl)urea (60 mg, 0.363 mmol), cesium carbonate (237 mg, 0.726 mmol) and BrettPhos pre-catalyst (22 mg, 0.024 mmol) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (1.2 mL) before the mixture was heated reaction at 100° C. for 1 hour. The reaction mixture was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-75% EtOAc-hexanes) gave (R)-1-(3-isopropyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C39H38N6O [M+H]+ 607. found 607.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:10]([O:9][C:3]1[C:2]([Br:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ncc(Cl)cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Clc1cnc(OCc2ccccc2)c(Br)c1
Temperature: 70 °C

Procedure:
A mixture of 3-bromo-5-chloro-2-hydroxypyridine (81 g), benzyl bromide (52 mL) and silver carbonate (97 g) in benzene (1 L) was heated at 70° C. for 1 h. The mixture was cooled to r.t. and then filtered through a bed of celite. The filtrate was concentrated and the residual off-white solid was recrystallized from hexane to provide the title compound as a white solid (102 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].CS(O[CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17]1)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:21][N:18]1[CH2:19][CH2:20][CH:16]([N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:17]1
Reactant: CN1CCC(OS(C)(=O)=O)C1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC(n2cc([N+](=O)[O-])cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Nitro-1H-pyrazole (0.452 g, 4.00 mmol) was dissolved in DMF (8 mL) and cooled to 0° C. NaH (0.192 g, 60% dispersion in oil, 4.80 mmol) was added and the mixture was stirred for 10 minutes. 1-Methylpyrrolidin-3-yl methanesulfonate A22 (0.717 g, 4.00 mmol) was added and the mixture was stirred for 16 hours at 100° C. The mixture was diluted with EtOAc (5 mL) and washed with sat. NH4Cl (5 mL) and water (4×5 mL). The organics were concentrated in vacuo affording a crude pale yellow oil which was purified by flash chromatography (0-30% MeOH in DCM) to give the title compound A23 as a pale yellow oil (0.575 g, 73% yield). LCMS-B: rt 1.12 min; m/z 197 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.O.C([C@H]([C@@H](C(OCC)=O)O)O)(OCC)=[O:26].C(N(C(C)C)CC)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1>C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(CC(C)(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[O:26])=[N:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 5.01 of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 ml (5.0 mol) of (-)-diethyl D-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consisted of 71.4% sulphoxide with an enantiomeric excess (e.e.) of 72.9%. The mixture was cooled to 10° C. and after addition of 1.7 l of isooctane, the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 10 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 l). The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added to facilitate the removal of solvent. Acetone (2.5 l ) was added to precipitate the racemate of omeprazole which was filtered off (254 g). HPLC-analyses (achiral and chiral columns) of the filtrate showed that this solution consited of 88% sulphoxide with an optical purity of 96.3% e.e. and thus the optical purity has been improved from 72.9% e.e. to 96.3% e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 0.8 kg (46%). The (-)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole was not isolated in its neutral form but further processed to corresponding sodium salt.
Reaction SMILES: BrCCBr.[Mg].[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:26]=[O:27])=[N:19][C:20]=1[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:26]([OH:27])[CH2:29][C:30]2[CH:43]=[CH:42][CH:41]=[C:32]([CH2:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH:31]=2)=[N:19][C:20]=1[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: BrCc1cccc(COC2CCCCO2)c1
Reactant: COc1ccc(F)c(-c2ccc(C=O)nc2CC(C)(C)C)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(C(O)Cc3cccc(COC4CCCCO4)c3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
Under a nitrogen atmosphere, 1,2-dibromoethane (34 μL) was added to a mixture of magnesium (578 mg) and THF (15 mL) at room temperature, and the mixture was stirred at 50° C. for 10 min. To the reaction mixture were added 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpicolinealdehyde (2.39 g) and then 2-((3-(bromomethyl)benzyl)oxy)tetrahydro-2H-pyran (4.52 g) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water 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 (980 mg) as an orange oil.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C>[O:8]=[C:7]1[CH:6]=[CH:5][O:4][CH:3]=[C:2]1[O:1][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=c1ccocc1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1coccc1=O
Reaction time: 1.25 h

Procedure:
A mixture of 3-hydroxy-4H-pyran-4-one (1.12 g), ethyl 2-bromoacetate (1.7 g) and potassium carbonate (1.4 g) in ethanol (30 ml) was stirred at 67° to 70° C. for 75 minutes. The reaction mixture was allowed to stand at room temperature. An insoluble substance was filtereed off, and the filtrate was adjusted to pH 4 to 5 with conc. hydrochloric acid and the ethanol was removed. To the residue was added ethyl acetate, and the resultant mixture was washed with an aqueous solution saturated with sodium chloride and dried over magnesium sulfate. After removal of the solvent, the residue was chromatographed on silica gel (15 g) with an eluent (ethyl acetate:benzene= 1:5) to give crystals of ethyl 2-(4-oxo-4H-pyran-3-yloxy)acetate, mp 58° to 60° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[CH3:9][C:4]1[C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(C)noc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dimethyl-1,2-oxazole (6.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (611 mg, 4.3 mmol), and triethylamine (5 mL, 36.0 mmol) in absolute ethanol (25 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered, evaporated, and co-evaporated with EtOAc (20 mL). The solid residue was treated with water (200 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo, affording the title compound (783 mg, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (m, 6H), 2.40 (s, 3H), 4.16 (s, 2H), 5.99 (s (br), 1H); M+ 252.