Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:25]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[CH:1]1([CH2:6][C@@H:7]([C:8]([F:25])=[O:9])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (Tetrahedron, 2001, 57(36), 7675-7683) (4.0 g, 15.60 mmol) in DCM was added pyridine (1.38 ml, 17.2 mmol) and a solution of 2,4,6-trifluoro-1,3,5-triazine (2.3 g, 17.2 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 2 h. The solution was then washed with citric acid (20 mL×2) and brine (20 mL), then concentrated to provide the crude product, 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-fluoro-4-oxobutanoate, as a yellow oil (3.8 g, 57% yield), which was used directly in the next step. MS: 257 ([M−H]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15])=[N+:18]=[N-:19]
Reactant: COCC(C)(C)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)c1ccc(N=[N+]=[N-])c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Fluoro-4-(1-methoxy-2-methylpropan-2-yl)-2-nitrobenzene (2.227 g, 9.80 mmol) was dissolved in DMF (25 ml) and sodium azide (1.274 g, 19.6 mmol) was added at r.t. and the reaction stirred overnight. The reaction was quenched with water (75 ml) and the mixture was extracted with TBME (3×75 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% heptane to 15% EtOAc:85% heptane as eluent to give the product as a yellow oil (2.301 g, 75%, 80% pure): LC purity 79% (ret. time, 2.15 min);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH3:27][O:28][CH2:29][CH:30](O)[CH3:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:27][O:28][CH2:29][CH:30]([CH3:31])[O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: COCC(C)O
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)COC)c2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.0 g) in tetrahydrofuran (80 mL) were added 1-methoxypropan-2-ol (1.04 mL), tributylphosphine (2.46 mL) and 1,1′-(azodicarbonyl)dipiperidine (2.69 g) at room temperature. The mixture was stirred at 50° C. for 1 h. Then 1-methoxypropan-2-ol (0.5 mL), tributylphosphine (1.2 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.34 g) were added to the mixture and the mixture was stirred at 50° C. overnight. The mixture was concentrated in vacuo. Ethyl acetate was added to the residue and insoluble materials were filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9 to 6:4, volume ratio) to give the title compound (2.08 g, 87%) as a brown oil. MS 448 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20](Br)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
To a solution of (±)-3-benzyl-2-(1-bromo-2-methyl-propyl)-7-chloro-3H-quinazolin-4-one (a compound of Formula 105, 250 mg, 0.616 mmol) in DMF (3 mL) was added triethylamine (0.130 mL, 0.924 mmol) and imidazole (63.0 mg, 0.924 mmol) followed by tetrabutylammonium iodide (228 mg, 0.616 mmol). The resultant solution was heated to 90° C., stirred for 18 h and allowed to cool to room temperature. The reaction mixture was quenched with water (3 mL) and diluted with ether (10 mL). The aqueous layer was extracted with ether (10 mL) ad the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:1 hexanes:ethyl acetate) to provide 38 mg (16%) of the title compound as a yellow solid. MS(ES+) m/e 393.0 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][O:13]C(C)(C)[N:11]2C(OC(C)(C)C)=O)[CH:6]=[C:7]([F:9])[CH:8]=1.Cl.O1CCOCC1>C(Cl)Cl>[NH2:11][C@@H:10]([C:5]1[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([CH2:2][Cl:1])[CH:4]=1)[CH2:14][OH:13]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(CCl)c2)COC1(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H](CO)c1cc(F)cc(CCl)c1
Temperature: 80 °C
Yield: 84.5 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-(chloromethyl)-5-fluorophenyl)-2,2-dimethyloxazolidine-3-carboxylate (140 mg, 0.407 mmol) in anhyd DCM (1.357 mL) was added 4 N HCl in Dioxane (1.018 mL, 4.07 mmol) portionwise. The mixture was refluxed at 80° C. overnight. The reaction was not completed. More 4N HCl in dioxane (1. 018 mL, 4.07 mmol) was added, and refluxed for another 24 h. Solvent was removed under reduced vacuum to provide (S)-2-amino-2-(3-(chloromethyl)-5-fluorophenyl)ethanol (70 mg, 84%). LCMS (m/z): 204 (MH+), 0.41 min.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=1)[C:18]([O-:20])=[O:19])=[O:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19])=[O:2]
Reactant: COc1cc(C=O)c(OCc2cncc(C(=O)[O-])c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C=O)c(OCc2cncc(C(=O)O)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (96 mg, 0.32 mmol, 1 eq.) in a mixture of MeOH/THF (1/3, 8.0 mL) was added NaOH (3 N, 1.7 mL, 5.1 mmol, 16 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid (86 mg, 93%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 10.34 (s, 1H), 9.06 (d, J=1.9 Hz, 1H), 8.96 (d, J=2.0 Hz, 1H), 8.42 (t, J=2.0 Hz, 1H), 8.34 (s, 1H), 7.02 (s, 1H), 5.44 (s, 2H), 3.86 (s, 3H). LRMS (M+H+) m/z 289.1.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:17]3[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=3[OH:22])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:26])(=[O:25])[CH2:6][CH2:5]1.[CH2:27](Br)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:17]3[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=3[O:22][CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:25])(=[O:26])[CH2:6][CH2:5]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(=NOC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(=NOC)CCS3(=O)=O)c1OCC(=O)c1ccccc1

Procedure:
0.4 Gram (1.1 mmol) of 4-methoxyimino-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4- yl) carbonylthiochroman-1,1-dioxide, 0.23 g (1.2 mmol) of phenacyl bromide and 0.15 g of potassium carbonate were added to 10 ml of acetone, and the mixture was stirred under heat for 8 hours. Insolubles were removed by filtration, and then the acetone was distilled off. The remainder was dissolved in ethyl acetate, and the resultant solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the remainder was subjected to column chromatography (hexane/ethyl acetate) to give intended 4-methoxyimino -5-methyl-6-(1- ethyl -5-phenacyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound 26) at a yield of 52%.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH3:31])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl[C:33]1[N:38]=[CH:37][N:36]=[C:35]2[NH:39][N:40]=[CH:41][C:34]=12.C(N(CC)CC)C>ClCCl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[NH:19][CH:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:33]4[N:38]=[CH:37][N:36]=[C:35]5[NH:39][N:40]=[CH:41][C:34]=45)[CH2:14][CH2:13]3)[N:16]([CH3:31])[CH:17]=2)=[CH:21][C:22]=1[C:27]([F:29])([F:28])[F:30]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C=C(c2ccc(F)c(C(F)(F)F)c2)NC1C1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Add hydrogen chloride (4.00 equiv; 81.41 mmoles; 20.35 mL) to a solution of 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (8.7 g; 1.00 equiv; 20.35 mmoles) in dichloromethane (101.77 mL), at RT. Stir the solution at RT for 1 hour. Remove the solvent under reduced pressure, and dissolve the crude in isopropyl alcohol (101.77 mL). Add 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.65 equiv; 33.58 mmoles; 5.19 g) and triethylamine (10 equiv; 203.54 mmoles; 28.37 mL). Stir the mixture at reflux for 1 hour. Remove the solvent under reduced pressure and triturate the crude in water overnight. Filter the solid and triturate in hot acetonitrile, filter and dry in vacuo. 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-3-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine (8.42 g; 18.86 mmoles; 92.66% yield) is obtained as a light yellow solid.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5].C(=O)=O.CC(C)=O.[CH2:30]([Mg]Br)[CH2:31][CH:32]=[CH2:33]>C1COCC1>[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH2:33][CH2:32][CH:31]=[CH2:30]
Reactant: C=CCC[Mg]Br
Reactant: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
While under an argon atmosphere, a solution of benzyl 4-(methoxy(methyl) carbamoyl)piperidine-1-carboxylate (15.0 g, 49.0 mmol) in THF (100 mL) was cooled to −78° C. (dry ice/acetone bath) and treated with 3-butenylmagnesium bromide (250 mL, 0.5 M sol. in THF, 125 mmol, Aldrich) via canula. After the addition was complete, the cooling bath was removed allowing the solution to slowly warm to room temperature. After stirring overnight (16 h), the reaction mixture was quenched with 0.1N HCl (200 mL) and diluted with ethyl acetate (300 mL). After stirring an additional 5 min, the organic phase was separated, washed with saturated sodium bicarbonate (200 mL), dried over MgSO4, filtered and concentrated. Purification by MPLC (100 g column, 20-50% ethyl acetate in heptane) gave benzyl 4-pent-4-enoylpiperidine-1-carboxylate (14.5, 98%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.38-7.32 (m, 5H), 5.79 (dddd, J1=17.1 Hz, J2=10.2 Hz, J3=6.9 Hz, J4=6.6 Hz, 1H), 5.12 (s, 2H), 5.02 (dd, J1=17.1 Hz, J2=1.5 Hz, 1H), 4.97 (dd, J1=10.2 Hz, J2=1.5 Hz, 1H), 4.28-4.10 (m, 2H), 2.86 (br t, J=12 Hz, 2H), 2.58-2.43 (m, 3H), 2.35-2.28 (m, 2H), 1.9-1.74 (m, 2H), 1.62-1.48 (m, 2H). ESI MS found for C18H23NO3 m/z [302.3 (M+1), 324.1 (M+23)].
Reaction SMILES: [C:1]1([S:7][CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:37])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:27][CH:26]=3)=[CH:16][CH:15]=2)[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([S:7][CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:37])[C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:29][CH:30]=3)=[CH:16][CH:15]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Sc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 94.6 %

Procedure:
In a similar manner to that described in Example 2, methyl 2-phenylthio-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (150 mg), which is the product of Example 152, was reacted with aqueous sodium hydroxide solution (1N, 0.58 ml) and the reaction mixture was treated to give the title compound (138 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:27]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:26]=1)[C:10]([O:12][C@H:13]([CH3:23])[CH2:14][O:15][Si](C(C)(C)C)(C)C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F.F.F.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:27]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:26]=1)[C:10]([O:12][C@H:13]([CH3:23])[CH2:14][OH:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](CO)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
(1R)-1-Methyl-2-(tert-butyldimethylsilyloxy)ethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (16) (4.7 g, 7.2 mmol) was dissolved in anhydrous tetrahydrofuran. Triethylamine trihydrofluoride (9.4 mL, 57.0 mmol) was slowly added. The mixture was stirred at room temperature for 4 hours. Removal of solvent under reduced pressure gave 3.8 g (98% yield) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.09 (d, J=6.4 Hz, 3H), 1.41 (s, 9H), 2.78 (s, 1H, br), 2.96 (m, 2H), 3.51 (m, 1H), 3.68 (m, 1H), 4.36 (dd, J=14.0, 6.4 Hz, 1H), 4.98 (m, 1H), 5.05 (d, 1H, NH), 5.10 (s, 4H), 6.66 (d, J=8.0 Hz, 1H), 6.77 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 7.26-7.43 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:41])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([O:39]C)=[O:38])[CH:33]=[CH:34][CH:35]=1)[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:41])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=1)[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCN3CCOCC3)Cc3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCN3CCOCC3)Cc3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-35 (50 mg) lithium hydroxide (20 mg) were added to tetrahydrofuran (5 ml) and water (1 ml), and the same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 35 mg (76%); MS APCI+ve 556 (M+H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Br:11][C:12]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][N:13]=1>>[Br:11][C:12]1[CH:17]=[C:16]([CH2:18][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1ccnc(Br)c1
Product: O=C(O)c1ccccc1NCc1ccnc(Br)c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2-bromo-pyridine-4-carbaldehyde (prepared as described in WO 2004/013102 A1).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=O)C1C=CC=CC=1.[N:29]1[C:38]2[C:33](=[N:34][C:35]([CH:39]=O)=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.N1CCCCC1>CC(O)C>[N:34]1[C:33]2[C:38](=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:37]=[CH:36][C:35]=1[CH:39]=[C:15]1[NH:11][C:12]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:27])[F:28])=[N:13][C:14]1=[O:16]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2C(F)(F)F)=N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccccc2C(F)(F)F)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 4-oxo-2-(2-trifluoromethyl-benzylamino)-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (70.4 mg, 0.18 mmol), 1,5-naphthyridine-6-carboxaldehyde (28.7 mg, 0.18 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH and ether. The solid was then re-crystallized from AcOEt-MeOH to give 5-[1,5]naphthyridin-2-ylmethylene-2-(2-trifluoromethybenzylamino)-1,5-dihydro-imidazol-4-one as a light yellow crystalline material (11.6 mg, 16.2%). HR-ES (+) m/e calcd. for C20H14F3N5O: (M+H)+ 398.1223. Found: 398.1222.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]=2[CH:21]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]3[C:25]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([O:40][Si](C(C)(C)C)(C)C)[CH:34]=3)=[N:24]2)[CH3:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>Cl.CCO>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]=2[CH:21]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]3[C:25]([C:33]3[CH:34]=[C:35]([OH:40])[CH:36]=[C:37]([F:39])[CH:38]=3)=[N:24]2)[CH3:22])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2c(C(C)n3nc(-c4cc(F)cc(O[Si](C)(C)C(C)(C)C)c4)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Agent: Cl
Solvent: CCO
Product: CC(=O)N1CC=C(c2c(C(C)n3nc(-c4cc(O)cc(F)c4)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-one single enantiomer (intermediate T.2, first eluted enantiomer under the conditions described above, 0.350 g, 0.535 mmol) was dissolved in a solution of 1M HCl in EtOH (1.7 ml) and the mixture was stirred at RT overnight. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel cartridge (DCM to DCM:MeOH=95:5) to afford title compound as a yellow solid (0.270 g, 0.500 mmol, 93%). This compound proved to be the second eluted enantiomer under Chiral HPLC conditions of Method A11: Rt=15.8 min, ee=99.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1>>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:9]=2[CH:8]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Reactant: CN1CCNCC1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1

Procedure:
The process disclosed herein comprises reaction of 2-(2-aminoanilino)-5-methylthiophene-3-carbonitrile [10] with N-methylpiperazine in conjunction with N-methyl piperazine acid salt to give Olanzapine. The reaction is carried out at 90-138° C., preferably at 110-125° C. in 6-12 hours.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].[Br:24][C:25]1[CH:26]=[C:27]([CH2:32][OH:33])[CH:28]=[C:29]([F:31])[CH:30]=1.O>CN(C)C=O>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:32][O:33][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(F)cc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1cc(F)cc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Imidazole (3.3 g) and tert-butyl-diphenylchlorosilane (10.0 g) were added to a solution of (3-bromo-5-fluorophenyl)methanol (5.0 g) in dimethylformamide (50 ml), and the mixture was stirred over night at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [(3-bromo-5-fluorobenzyl)oxy] (tert-butyl)diphenylsilane (9.5 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>ClCCl>[Br:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(C(=O)CBr)CC2)cc1
Temperature: 25 °C

Procedure:
530 μl (6.09 mmol) Bromoacetylbromide are added dropwise to an ice cold mixture of 1.50 g (6.09 mmol) (S)—N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) and 1.03 mL (7.31 mmol) TEA in 20 mL dichloromethane. Then the cooling is removed and the mixture is allowed to warm to rt and then quenched by the addition of water. The mixture is extracted with DCM, the org. layers are combined, washed with water and dried with MgSO4. The solvent is removed in vacuo and the crude product is used without further purification.