Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[C:1]([CH:3]([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.6 %

Procedure:
To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a pale-yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH2:20]1[C:23]2([CH2:26][NH:25][CH2:24]2)[CH2:22][O:21]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:23]4([CH2:20][O:21][CH2:22]4)[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: C1NCC12COC2
Product: O=C(c1ccc(N2CCCC2)c(OCC2CC2)n1)N1CC2(COC2)C1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and 2-oxa-6-azaspiro[3.3]heptane (CAN 174-78-7) as starting materials, MS (EI): m/e=344.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:9]([NH2:11])=[N:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[NH:5][C:4]=2[S:3][CH:2]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C@H:21]1[CH2:26]N[CH2:24][CH2:23][NH:22]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[NH:22][CH2:23][CH2:24][N:11]([C:9]2[C:10]3[CH:1]=[CH:2][S:3][C:4]=3[NH:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[N:8]=2)[CH2:26]1
Reactant: NC1=Nc2ccccc2Nc2sccc21
Reactant: COCCC[C@H]1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 45 h
Yield: 16.2 %

Procedure:
Combine 4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (1.10 g, 5.11 mmol), (S)-2-(3-methoxy-propyl)-piperazine (1.62 g, 10.22 mmol), DMSO (4.0 ml), and toluene (16.0 ml). Stir and heat the mixture at 105° C. After 45 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (85:15) to give 296.0 mg (16%) of the title compound: mass spectrum (ion spray): m/z=357.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=O)[C:6]=2[CH:18]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[CH2:7][C:6]=2[CH:18]=1
Reactant: CN1C(=O)C2CCCN2C(=O)c2cc(Cl)ccc21
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2cc(Cl)ccc21

Procedure:
The above compound is obtained when (+)-7 -chloro-1,2,3,11a-tetrahydro-10-methyl-5 H-pyrrolo[2,1-c] [1,4] -benzodiazepin-5,11(10H)-dione (melting point 155°-157°C. is prepared from L-proline and 5-chloro-N-methylisatoic acid as described in Example 1) is treated with 1M borane in tetrahydrofuran as described in Example 1. The hydrochloride salt melts at 270°-272°C., [α]D 25 + 377° (1.03%) methanol).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Ic1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(-c2cccs2)cc1
Yield: 86.1 %

Procedure:
2-iodothiophene (1.05 g, 5 mmol) was dissolved in 6 mL of mixed solution (dimethyl ether and water, v:v=2:1), followed by addition of 4-fluorophenylboronic acid 9a (700 mg, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(triphenyl phosphine)palladium (173 mg, 0.15 mmol). The mixture was microwaved for 30 minutes at 100° C. Thereafter, the reaction mixture was extracted with ethyl acetate (20 mL×3) after 10 mL water were added. The organic extract was washed with saturated sodium chloride solution (20 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system C to obtain the title compound 2-(4-fluorophenyl)thiophene 9b (767 mg, white solid), yield: 86.1%.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:17]=C(C(OC)=O)C=1>C(O)(=O)C>[CH2:10]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:17]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1)[CH3:11]
Reactant: COC(=O)c1cc(C)n(Cc2ccc(C)cc2)n1
Reactant: CCOC(=O)C(=O)CC(=O)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n(Cc2ccc(C)cc2)n1

Procedure:
A solution of ethyl 2,4-dioxohexanoate (Step 1, 2.0 g, 11.6 mmol) and 4-(methylbenzyl)-hydrazine dihydrochloride (Step 3 of Intermediate A, 2.67 g, 12.8 mmol) in acetic acid (15 mL) was stirred for 4 h at 90° C. After removal of the solvent (rotavapor), the residue was subjected to MPLC (silica, cyclohexane/ethyl acetate 5:1) to afford the title compound as a highly viscous oil (1.93 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 2H), 6.98 (d, 2H), 6.62 (s, 1H), 5.33 (s, 2H), 4.40 (quart, 2H), 2.48 (quart, 2H), 2.31 (s, 3H), 1.40 (t, 3H), 1.18 (t, 3H); DCI(NH3)-MS m/z 273 (MH)+; HPLC RT (Method I) 4.75 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3ccc(F)cc3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccc(F)cc1)Oc1ccc(Br)cc12
Temperature: 120 °C
Yield: 51 %

Procedure:
A suspension of 6-bromo-2-(4-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.77 mmol) and Lawesson's Reagent (310 mg, 0.77 mmol) in dry 1,4-dioxane (4 mL) was heated at 120° C. for 30 min with microwave. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(4-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (160 mg, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]([O-:20])([O-:19])=[O:18].[Na+:21].[Na+].COC(C)(C)C>O>[Na+:21].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][S:17]([O-:20])(=[O:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])[O-]
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: O=S(=O)([O-])Cc1ccc(OCc2ccccc2)cc1
Temperature: 75 °C
Reaction time: 21 h
Yield: 18.8 %

Procedure:
A mixture of 25.51 g of 4-benzyloxybenzyl chloride and 28.78 g of sodium sulfite in 96 ml of water was stirred at 75° C. for 21 hours. After cooling to room temperature, the reaction solution was stirred with 100 ml of tert-butyl methyl ether, and the solids were filtered off with suction, washed twice with 20 ml of tert-butyl methyl ether, once with 20 ml of ice-water, twice with 20 ml of acetone and twice with 20 ml of dichloromethane. The precipitate was dried in a vacuum drying cabinet at 40° C. overnight. This gave the product (6.20 g) with a molecular weight of 300.3 g/mol (C14H13O4S.Na); MS (ESI): m/e=301 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3]Br.[S:5]([O-:8])([O-:7])=[O:6].[Na+:9].[Na+]>O>[CH2:2]([S:5]([O-:8])(=[O:7])=[O:6])[CH2:3][S:5]([O-:8])(=[O:7])=[O:6].[Na+:9].[Na+:9]
Reactant: O=S([O-])[O-]
Reactant: BrCCBr
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCS(=O)(=O)[O-]
Yield: 65.1 %

Procedure:
A mixture of 1,2-dibromoethane (37.6 g, 0.20 mol) and sodium sulfite (63.0 g, 0.5 mol) in water (225 mL) was heated at reflux temperature for 20 h. After the mixture was cooled in the refrigerator, crystals were collected. The crude product was repeatedly recrystallized from water-ethanol. The trace amount of inorganic salts was removed by treating the aqueous solution with a small amount of silver(I) oxide and barium hydroxide. The basic solution was neutralized with Amberlite-120 ion-exchange resin and treated three times with Amberlite-120 (sodium form) ion-exchange resin. After removal of the water, the product was recrystallized from water-ethanol to afford the title compound (30.5 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].O>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: Nc1ccccc1Cl
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ccccc2Cl)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (5 g) and 2-chloroaniline (2.5 mL) in toluene (60 mL) is heated at reflux under a Dean and Stark water trap for 3 hours. After concentration, the residue is dissolved in methanol (60 mL) and the stirred solution is treated at 0° C. with sodium cyanoborohydride (2.1 g). The temperature is allowed to rise to room temperature, and the stirring is continued for 2 hours, before dilution with ethyl acetate (100 mL) and washing with saline (100 mL). The organic layer is dried and concentrated, to give a brown oil. This oil is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1:4v/v), to give N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzylamine (0.64 g), in the form of an oil. [Elemental analysis: C,69.5; H,6.8; N,4.1; Cl,10.6%; calculated: C,68.8; H,6.7; N,3.2; Cl,10.7%].
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cn1nc(C(F)(F)F)cc1-c1ncc(N)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(F)(F)F)cc1-c1ncc(NC(=O)c2ccccc2Cl)s1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a mixture of 5-amino-2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole (66, 8.1 mg, 0.03 mmol) in 1 ml DCM were added 2-chlorobenzoyl chloride (3.8 μl, 2 eq), DIEA (52 μl, 3 eq) and DMAP (2 mg). After stirred at r.t for 2 h, the reaction mixture was worked up with DCM/aq. NaCO3, the DCM phase was concentrated to dryness. The solid residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1). 0.06 ml of 1N NaOH were added and mixture was stirred at r.t for 1 h before worked up DCM//aq. NaCO3. DCM phase was concentrated and subjected to prep HPLC purification to give 3.7 mg of (2-chlorophenyl)-N-{2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl](1,3-thiazol-5-yl)}carboxamide (67) as yellow solid (yield: 31.9%; purity>90%). LC-MS: calcd. for C15H10ClF3N4OS: 387 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]>[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A suspension of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (1.0 g, 3.3 mmol) and 100 mg of palladium on carbon (10%) in THF (10 mL) was stirred at r.t. for 2 h under hydrogen (5 bars). The mixture was then filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 60, hexanes/EtOAc 2:1) to give 2-acetylamino-5-(1-hydroxy-ethyl)-4-trifluoromethyl-benzoic acid methyl ester (917 mg, 3.0 mmol, 91%) as a white solid, m.p. 120-122° C., ESI-MS: m/z 306 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])CC[CH2:5]2.O[C:19]1C=CC(CCC(OCC)=O)=C(C)C=1C>>[OH:1][C:2]1[CH:11]=[C:10]([CH3:19])[C:9]([CH2:8][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH3:5])[CH:3]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCOC(=O)CC1CCCc2cc(O)ccc21
Product: CCOC(=O)CCc1c(C)cc(O)cc1C

Procedure:
Similar reaction routes used for the synthesis of (514) was used to synthesize the intermediate ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (570) (1.2 g, 89.3%) as a white solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylethyl)-3-pyridinecarboxamide (Intermediate 9, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylethyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[Br-:23].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: CCCCCCBr
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Product: CCCCCC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 44.4 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and 1-bromohexane (0.035 mL, 0.249 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0306 g, 44.3%). EI-MS m/z 373 (M+) Rt (1.83 min).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[S:3].Br[CH:24]1[C:30](=O)[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[O:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CCO>[CH2:15]([O:14][C:13](=[O:22])[NH:12][CH:9]1[CH2:10][CH2:11][CH:6]([CH2:5][NH:4][C:2]2[S:3][C:24]3[CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=4[C:30]=3[N:1]=2)[CH2:7][CH2:8]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=S)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: O=C1c2ccccc2OCCC1Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1)OCc1ccccc1
Yield: 64.3 %

Procedure:
A solution containing benzyl N-(4-{[(aminocarbothioyl)amino]methyl}-cyclohexyl)carbamate (3.45 g, 10.73 mmol), 4-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-one (2.60 g, 10.78 mmol), diisopropylethylamine (2.50 ml) and EtOH (50 ml) was heated at reflux for 4 hours. The solvent was removed and the residue was chromatographed on silica-gel eluting with 1:3 EtOAc/Hexane to yield 65% (3.2 g) of the product as a white solid: m.p. 124-127° C.; 1H-NMR (CDCl3) δ 1.09 (4H, pentet, J=10.4 Hz), 1.55 (1H, broad), 1.83 (2H, m), 2.04 (2H, broad), 3.10 (2H, t, J=6.2 Hz), 3.15 (2H, t, J=5.2 Hz), 3.43 (1H, broad) 4.33 (2H, t, J=5.2 Hz), 4.62 (1H, d, J=8.0 Hz), 5.08 (2H, s), 5.31 (1H, m), 7.00 (1H, dd, J=1.2 Hz, 7.8 Hz), 7.12 (2H, m), 7.35 (5H, s), 8.25 (1H, dd, J=1.7 Hz, 7.8 Hz); 464 (ESMS, MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:35][C:36](Cl)=[O:37].C(=O)([O-])O.[Na+].C(N(CC)CC)C.[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36](=[O:37])[CH2:35][N:55]4[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]4)[S:3][C:4]=3[C:10]=2[C:11]#[N:12])[CH:15]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3C#N)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(NC(=O)c5cccc(C(C)(C)C#N)c5)c4)c(C#N)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.33 mmol) produced in Example 1 (iv) in N,N-dimethylacetamide (3 mL) was added chloroacetyl chloride (58 μL, 0.73 mmol), and the mixture was stirred at room temperature for 2 hr. 5% Aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The extract was washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (3 mL). Triethylamine (136 μL, 0.99 mmol) and 1-methylpiperazine (110 μL, 0.99 mmol) were added to the mixture, and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed successively with water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→15/85). The obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diisopropyl ether to give the title compound (126 mg, 64%) as a white powder.
Reaction SMILES: C1[O:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[C:3](=[O:4])[O:2]1.C(N([CH2:20][CH3:21])CC)C.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)C>[CH2:22]([CH:7]([C:5]([CH2:11][C:12]([OH:14])=[O:13])([C:3]([OH:2])=[O:4])[OH:6])[C:8]([OH:10])=[O:9])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:20][CH3:21]
Reactant: CCCCCCCCCCO
Reactant: CCN(CC)CC
Reactant: O=C(O)CC1(CC(=O)O)OCOC1=O
Solvent: CCO
Product: CCCCCCCCCCCCC(C(=O)O)C(O)(CC(=O)O)C(=O)O
Yield: 86 %

Procedure:
A mixture of 2 (50 g), triethylamine (75 ml) and decanol (110 ml) in ethanol-free chloroform (500 ml) was refluxed for 42 hours. GC analysis indicated a 10:1 mixture of the 2- and 1-monodecyl ester in addition to about 9% of unreacted starting material. Processing as indicated above gave the crude product (69.6 g, 86%) as an opalescent oil. This oil was dissolved in hot toluene (200 ml) on the steam bath, filtered from a small amount of insoluble material, which was washed with two additional portions of hot toluene (50 ml) and the combined filtrates cooled at room temperature.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C:23]([OH:27])(=[O:26])[CH2:24][OH:25]>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[C:23]([O-:27])(=[O:26])[CH2:24][OH:25]
Reactant: O=C(O)CO
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CC(C)=O
Product: O=C([O-])CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 75 g olanzapine free base in 1500 ml acetone, was added slowly 18.0 g glycolic acid in 100 ml acetone at room temperature. The resulting mixture was stirred at room temperature overnight. The formed crystals were isolated by filtration and dried overnight at 40° C. in vacuo. Isolated yield: 84.1 gram (90%). 1H-NMR confirms the molar ratio olanzapine:acid=1:1.