Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=O)C.[CH2:23]([O:25][C:26](C1C=CC(C2C=CC(CBr)=CC=2)=CC=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+].SCCO>CN(C=O)C>[CH2:23]([O:25][C:26]([C:11]1[CH:6]=[CH:7][C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(CSCCO)cc2)cc1

Procedure:
4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was prepared as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 4′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.2 g, 13.16 mmol, 1 eq.) in anhydrous DMF (100 mL) was treated with potassium carbonate (5.46 g, 39.48 mmol, 3 eq.) and 2-mercaptoethanol (1.23 g, 15.79 mmol, 1.2 eq.). When the reaction was complete, the reaction was worked up as described leaving a yellow oil upon removal of the solvent.
Reaction SMILES: [OH-].[Na+].N[C@H:4]([C:16](O)=O)[CH2:5]C1C=C2C(C=CC=C2)=CC=1.[CH3:19][C:20]([CH:22]([CH3:24])[CH3:23])=[O:21].[CH2:25](Cl)C(=C)C>O>[CH3:23][C:22]([CH3:25])([CH2:24][C:4]([CH3:16])=[CH2:5])[C:20](=[O:21])[CH3:19]
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: C=C(C)CCl
Reactant: CC(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)CC(C)(C)C(C)=O
Yield: 569.2 %

Procedure:
93 g of NaOH, 12 g of Nal and 6.8 g of Emkapol 400 (polyethyleneglycol) were charged into a 1 l three-neck flask. 100 g of methylisopropyl ketone were added and, at 50°, 290 g of methallyl chloride. The mixture was heated to reflux for 4 h and then hydrolysed with 200 ml of water. The reaction product was washed to neutrality and distilled to provide 69.6 g of raw product (B. p. 56°-65°/5.0×103Pa). Distillation of this raw product on a Widmer column gave 44.5 g of the desired ketone.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[O:34][CH3:35].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=4[O:34][CH3:35])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(=O)C(F)(F)F)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)C(F)(F)F)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 55.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.5 g, 6.7 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone (2.0 g, 6.7 mmol), K2CO3 (0.88 g), KI (0.1 g) and acetonitrile (50 ml) was stirred and refluxed for 16 hours. After cooling, the reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed (H2O), dried (MgSO4), and the solvent was concentrated to an oil, which upon evacuation at high vacuum afforded 3.2 g of a waxy solid. The solid was chromatographed on a Waters preparative LC (silica columns, eluting with 3% methanol-dichloromethane). Concentration of the appropriate fractions gave 1.8 g (56%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-2,2,2-trifluoro-ethanone solid, m.p.=94°-96° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].CC(C)([O-])C.[K+].Cl[C:16]1[C:21](Cl)=[CH:20][CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].[ClH:26]>C(OCC)(=O)C.CCCCCC.O>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1([Cl:26])[N+:23]([O-:25])=[O:24])[C:6]#[N:7])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC#N
Reactant: Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)C1C=CC=CC1(Cl)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cold solution of ethylcyanoacetate (10.9 mL, 102.4 mmol) in anhydrous THP (170 mL) under nitrogen, was added potassium tert-butoxide (12.7 g, 107.5 mmol). The formed white suspension was stirred for 15 minutes, then treated with 2,3-dichloronitrobenzene (9.83 g, 51.2 mmol). The suspension was heated at reflux for 48 hours. The resulting reddish brown solution was poured into water, and the aqueous mixture was acidified to pH 2 with concentrated HCl. The mixture was extracted with ether (3×150 mL) and then the combined organic phase was dried (using Na2SO4) and concentrated to give a dark oil. Flash chromatography using 10:1 hexane:ethyl acetate in a column packed with silica gel, 10 times the weight of the dark oil, provided a viscous yellow liquid 4, which was used without further purification for the next step. TLC Rf 0.23 (hexane-ethyl acetate 3:1). 1H NMR δ 1.33-1.38 (t, 3H, CH3); 4.29-4.35 (q, 2H, CH2); 7.59-8.14 (m, 3H, phenyl).
Reaction SMILES: [C:1]([O:10]CC)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[H-].[Na+].[CH3:15][S:16]([CH3:18])=[O:17].Cl>C1C=CC=CC=1.CO.CCOC(C)=O>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1](=[O:10])[CH2:15][S:16]([CH3:18])=[O:17]
Reactant: CS(C)=O
Reactant: CCOC(=O)c1ccccc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)CC(=O)c1ccccc1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
From ethyl anthranilate: A mixture of sodium hydride (60% dispersion in mineral oil, 24.00 g, 0.6 mole, 3 equiv.), dry DMSO (71.0 ml, 1.0 mole, 5 equiv.), and benzene (130 ml) was heated at 80° C. until gas evolution ceased (1.5 hr), then was cooled in ice/H2O. A solution of ethyl anthranilate (29.6 ml, 0.2 mole, 1 equiv.) in benzene (100 ml) was added at a rate such that the internal temperature did not exceed 25° C., and the mixture was stirred for 0.5 hr The reaction was poured into ice/H2O and the pH was adjusted to 5-6 with concentrated HCl. EtOAc extraction, drying (MgSO4) and concentration gave a cloudy, orange oil. Silica gel chromatography (3% MeOH/EtOAc, then 5% MeOH/EtOAc) gave 1-(2-aminophenyl)-2-(methylsulfinyl)ethanone (23.43 g, 59%) as a yellow solid. Material prepared in this way was identical to that prepared from isatoic anhydride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH2:23]2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (Example 9) and propionyl chloride (Aldrich 98%) using the procedure described in Example 12. HRMS, observed: 370.1807, Calcd for M+: 370.1805.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.Cl[S:8]([OH:11])(=O)=[O:9].[OH-].[NH4+:13]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:8]([NH2:13])(=[O:11])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccsc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1ccsc1S(N)(=O)=O

Procedure:
The procedure of Example 3A was followed with 3-methylthiophene (10.0 g, 102 mmole), chlorosulfonic acid (29.58 g, 255 mmoles) in chloroform (200 ml), concentrated ammonium hydroxide, to provide 3-methyl-2-thiophenesulfonamide.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][F:23])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[ClH:1].[ClH:1].[F:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FCCN1CCNCC1
Reaction time: 8 h

Procedure:
Add 4 N HCl in 1,4-dioxane (21.52 mL, 86.1 mmol) to a stirred solution of 4-(2-fluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.00 g, 8.61 mmol) in dry dichloromethane (60 mL) at room temperature under nitrogen. Stir overnight under nitrogen. Concentrate the reaction under reduced pressure to afford the title compound (1.78 g). ES/MS m/z 133 (M+1).
Reaction SMILES: ClC1C=CC=C([C:8]([O:10]O)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20](C=O)=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1>ClCCl>[CH:8]([O:10][C:20]1[C:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[CH:25]([CH3:26])[CH3:27])=[O:9]
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)c1cccc(-c2ccc(F)cc2)c1OC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
3-Chloroperbenzoic acid (4.73 g) was added to a solution of 4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-carboxaldehyde (3.55 g) in dichloromethane (100 mL) and the reaction mixture was stirred at room temperature overnight. The precipitated solids were removed by filtration and the filtrate was washed in turn with water, saturated sodium bisulfite solution, sodium bicarbonate solution and brine. After the dried (MgSO4) organic layer was evaporated, the crude product was purified by HPLC (ethyl acetate-hexane; 1:49) to afford 2.5 g of 4'-fluoro-3-(1-methylethyl)[1,1'biphenyl]-2-ol formate as a oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CI.[C:36](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH3:36])[C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cncnc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)c1cncnc1
Yield: 35 %

Procedure:
In a solution of 0.25 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-(5-pyrimidinyl)benzoic acid amide in 4 mL of N,N-dimethylformamide, 0.36 g of methyl iodide and 0.35 g of potassium carbonate were added at room temperature with stirring, and stirred at 80° C. for 1 hour. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (20 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.09 g of the aimed product as white crystal.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:8][C:9]([NH:17][C:20](=[O:21])[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:18])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C(=O)Cl)C(C)(C)C
Reactant: CC(C)(N)c1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C(=O)NC(C)(C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Into a 200 ml four-necked flask, there were charged toluene (100 ml), α,α-dimethylbenzylamine (9 g) and pyridine (5.8 g), and α-methyl-tert-butylacetyl chloride (9.9 g) was dropwise added thereto while stirring at room temperature. Stirring was continuted for 3 hours. The reaction mixture was washed with water to remove pyridine hydrochloride. After the toluene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 13.8 g of N-(α,α-dimethylbenzyl)-α-methyl-tert-butylacetamide. M.P., 162.5°-163.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:22])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(C(C)C)C(C)C)C.O1CCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:16][C:14]([C:7]1[C:8](=[O:13])[N:9]([CH3:12])[C:10]2[C:5]([C:6]=1[OH:22])=[CH:4][CH:3]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2)=[O:15]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
In a sealed tube was combined methyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.75 g, 2.0 mmol), Dichlorobis(triphenylphosphine)palladium(II) (0.14 g, 0.20 mmol), copper(I) iodide (0.077 g, 0.41 mmol), ethynyltrimethylsilane (1.4 ml, 10 mmol), and N-ethyl-N-isopropylpropan-2-amine (2.8 ml, 16 mmol) in tetrahydrofuran (20.0 ml, 2.0 mmol). The tube was flushed with Ar, sealed, and placed in an oil bath at 100° C. for 5 hours. The dark mixture was cooled to rt, filtered and washed with ethyl acetate (2×30 mL). The crude mixture was concentrated, adsorbed onto silica and purified by flash chromatography (15% to 40% EtOAc:Hex gradient) to afford the product as a solid (0.59 g, 75% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=C(Cl)[N:3]=1.C(N1CCNCC1)C.[C:21](=[O:24])([O-])[O-].[K+].[K+].CN(C)C=[O:30]>>[C:21]1(=[O:24])[NH:3][C:2](=[O:30])[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:6]2[CH2:5]1
Reactant: CN(C)C=O
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: O=C([O-])[O-]
Agent: CCN1CCNCC1
Agent: [K+]
Product: O=C1Cc2ccccc2C(=O)N1

Procedure:
1,3-Dichloroisoquinoline (9.30 g), N-ethylpiperazine (5.90 g) and potassium carbonate (10.0 g) were reacted in dimethylformamide (70 ml) at 70° C. for 5 hr. The reaction solution was evaporated and partitioned between ethyl acetate and water. The resulting organic phase was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 12.80 g of the title compound as a pale brown oil. (17-4) 3-[(1,3-Dioxolan-2-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(C2=CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: Fc1cc(F)cc(C2CCOCC2)c1
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of 4-(3,5-difluorophenyl)-3,6-dihydro-2H-pyran (1.0 equiv.) in methanol (0.2 M) was added 10% Pd/C (0.05 equiv.). The reaction was placed under an atmosphere of hydrogen and stirred for 18 hours. Upon completion, the solution was filtered over a pad of Celite, the pad was washed with DCM, the filtrate was concentrated in vacuo to give 4-(3,5-difluorophenyl)tetrahydro-2H-pyran in 71% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.76 (br. s., 4H), 2.75 (br. s., 1H), 3.50 (br. s., 2H), 4.08 (d, J=9.78 Hz, 2H), 6.56-6.94 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)=[O:24])=[CH:20][CH:21]=2)[CH:12]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.1 %

Procedure:
To Methyl 3-methyl-2-(3-(4-(3-(4-(trifluoromethyl)phenyl)ureido)phenyl)isoxazole-5-carboxamido)butanoate (250 mg) dissolved in THF (5 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (1 ml) and stirred at RT for 14 h. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over. Na2SO4 and concentrated under reduced pressure to get off white solid which was crystallized from EtOAc to yield 185 mg (76%) white solid. MS (ES+): m/z 491 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ 12.82 (bs, 1H), 9.22 (s, 1H), 9.12 (s, 1H), 8.93 (d, 1H), 7.85 (d, 2H), 7.68 (s, 1H), 7.65 (d, 2H), 7.61 (d, 2H), 7.56 (d, 2H), 4.26 (m, 1H), 2.21 (m, 1H), 0.95 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccccc1B(O)O
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C
Yield: 85.8 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.500 g, 1.35 mmol), (2-methoxycarbonylphenyl)boronic acid (0.290 g, 1.62 mmol), sodium carbonate (0.857 g, 8.10 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.088 g, 0.135 mmol) in DME (10 mL) and H2O (2.5 mL) was heated at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the product as a yellow oil (0.494 g, 86%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N[C:12]1[CH:13]=[CH:14][C:15](O)=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])(=O)C.N1CCOCC1>CO.C(OCC)(=O)C>[NH:1]1[CH2:6][CH2:5][C:4]2([NH:19][C:17](=[O:18])[C:16]3[CH:20]=[CH:12][CH:13]=[CH:14][C:15]=3[O:7]2)[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(O)c(C(N)=O)c1
Reactant: O=C1CCNCC1
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1NC2(CCNCC2)Oc2ccccc21

Procedure:
A mixture of 24 mg (0.077 mmol) of N-[4,8-dimethoxyquinoline-2-yl)carbonyl]-4-piperidone, 15 mg (0.077 mmol) of 5-acetamido-2-hydroxybenzamide, and 0.020 mL of morpholine in 3 mL of methanol is refluxed for 48 hr. The reaction mixture is diluted with ethyl acetate, and washed with water, brine, and dried over Na2SO4. After solvent removal by rotoevaporation, the crude product is purified by preparative TLC to give 11 mg (0.022 mmol, 30% yield) of 6-acetamido-1′-[4,8-dimethoxyquinoline-2-yl)carbonyl]spiro[2H-1,3-benzoxazin-2,4′-piperidin]-4-(3H)-one (Compound 9): 1H NMR (DMSO-d6): δ 2.02 (s, 3H), 3.95 (s, 3H), 4.06 (s, 3H), 7.03 (d, 1H), 8.19 (s, 1H), 7.24 (d of d, 1H), 7.52 (d of d, 1H), 7.67 (m, 2H), 8.02 (d, 1H), 8.82, (s, 1H) and 9.98 ppm (s, 1H). MS m/z: 491.1 (M+H)+, 513.2 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([N:8]2[C:12](I)=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:7]=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([N:8]2[C:12]([C:20]#[N:21])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:7]=1
Reactant: N#C[Cu]
Reactant: COc1ccc(Cl)cc1-n1nc(C(F)(F)F)cc1I
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1-n1nc(C(F)(F)F)cc1C#N
Temperature: 200 °C
Yield: 106.3 %

Procedure:
To a stirred solution of 1-(5-chloro-2-methoxyphenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole (4.83 g, 12.01 mmol, 1.0 eq) in NMP (20 mL) was added CuCN (1.03 g, 12.01 mmol, 1.0 eq) and the mixture heated to 200° C. for 2 h. The reaction mixture was passed through a celite pad and washed with excess of ethyl acetate. The filtrate was washed with water and the ethyl acetate layer was separated, dried (Na2SO4), and the solvent evaporated. The resulting residue was purified by CC using ethyl acetate/PE (1:19) to get 1-(5-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (3.85 g, crude, yellow solid; TLC system: EtOAc/PE (1:4) Rf: 0.65).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]=[C:15]3[N:10]([CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14]3)[C:9]=2[CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[CH:6][CH:7]=1.[CH3:24][S:25]([OH:28])(=[O:27])=[O:26]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]=[C:15]3[N:10]([CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14]3)[C:9]=2[CH2:18][C:19]([N:21]([CH3:22])[CH3:23])=[O:20])=[CH:4][CH:3]=1.[CH3:24][S:25]([O-:28])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)O
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)N(C)C)cc1
Solvent: CCO
Product: CS(=O)(=O)[O-]
Reaction time: 0.08 h

Procedure:
One gram of zolpidem free base is dissolved in 10 ml of ethanol at 50° C. Then 0.313 g (a molar equivalent) of methane sulfonic acid is added at this temperature, the mixture is stirred for 5 minutes and evaporated to dryness under reduced pressure. The residue is treated with 10 ml of acetone, the remaining solid is filtered off and washed with 5 ml of acetone and dried in vacuum oven at 40° C. to yield zolpidem methanesulfonate. A representative DSC curve is shown in FIG. 12.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25](OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:38]=[CH:37][C:36]([CH:39]2[CH2:43]C(OC)O[CH:40]2OC)=[CH:35][CH:34]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:24]1[CH:25]=[CH:40][C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:34][CH:35]=2)=[CH:43]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]cn1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H](C(=O)N[C@H](CO)Cc1c[nH]cn1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Yield: 37 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,1 6-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-(t-butoxycarbonylamino)-N-[2-hydroxy-1(S)-[(1H-imidazol4-yl)methyl]ethyl]succinamic acid benzyl ester was deprotected, and the resultant crude amine salt was condensed with 3-(biphenyl-4-yl)-2,5-dimethoxy-tetrahydrofuran (produced as described in Example 1(a)) in 1,2-dichloroethane in the presence of trifluoroacetic acid to give in 37% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester as a yellow solid.