Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=[O:23].IC>C1COCC1.O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:1])[C:22]([OH:24])=[O:23]
Reactant: COc1ccccc1CC(=O)O
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85 %

Procedure:
As shown in step 4-i of Scheme 4, to a solution of diisopropylamine (6.70 g, 9.28 mL, 66.2 mmol) in THF (60 mL) at −78° C. under N2 was added n-butyllithium (33.1 mL of 2.0 M in cyclohexane, 66.2 mmol) and the solution was stirred for 40 minutes. A solution of 2-(2-methoxyphenyl)acetic acid (5.00 g, 30.1 mmol) in THF (30 mL) was added dropwise, then the reaction was allowed to warm to room temperature over one hour. The reaction was then cooled to −78° C. and iodomethane (4.27 g, 1.87 mL, 30.1 mmol) was added to the reaction in one portion. The reaction was warmed to room temperature 18 hours, 15 mL of water was added, and the organics were collected and the volatiles removed under reduced pressure. The residue was acidified with 1N HCl and the crude product extracted with Et2O (3×). The combined organics were dried over MgSO4, filtered, concentrated under reduced pressure, and the residue purified by medium pressure chromatography on silica gel (25 to 50% EtOAc in hexanes) to give 2-(2-methoxyphenyl)propanoic acid as a white solid (Compound 2008, 4.86 g, 85% yield): 1H NMR (CDCl3) δ 7.31-7.21 (m, 2H), 7.01-6.84 (m, 2H), 4.09 (q, J=7.2 Hz, 1H), 3.84 (s, 3H), 1.49 (d, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl.CO>[CH2:10]([NH:17][CH:5]1[CH2:6][CH2:7][C:2]([CH3:9])([OH:1])[CH2:3][CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CC1(O)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: CC1(O)CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.8 %

Procedure:
4-hydroxy-4-methylcyclohexanone (270 mg, 1.48 mmol) was dissolved in 1,2-dichloroethane (8.3 ml), followed by sequential addition of benzylamine (0.2 ml, 1.83 mmol), NaBH(OAc)3 (560 mg, 2.66 mmol), and acetic acid (0.1 ml, 1.66 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 72 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 5% MeOH/MC (50 ml×3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 350 mg of yellow solid (96%).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].CO.C1COCC1.[CH3:14][C@H:15]1[CH2:20][NH:19][C@H:18]([CH3:21])[CH2:17][N:16]1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1>[Cl-].[Na+].O>[CH3:14][C@H:15]1[CH2:20][NH:19][C@H:18]([CH3:21])[CH2:17][N:16]1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:4][CH3:2])[CH:23]=1
Reactant: CC(C)(C)[O-]
Reactant: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2C[C@@H](C)NC[C@@H]2C)ccc1C#N
Reaction time: 0.5 h

Procedure:
A 1.35 g portion of potassium tert-butoxide and 0.48 ml of methanol were added to 5 ml of THF, and the mixture was stirred for 30 minutes. Next, this was mixed with 934 mg of trans-4-(2,5-dimethylpiperazin-1-yl)-2-fluorobenzonitrile synthesized in Reference Example 14 and stirred at room temperature for 2 days. This was mixed with saturated brine and extracted with ethyl acetate, the organic layer was washed with water, and then the solvent was evaporated and the resulting mixture was subjected to a silica gel column chromatography and eluted with ethyl acetate-methanol-28% aqueous ammonia (9:1:0.1, v/v/v) to obtain 900 mg of the title compound.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([OH:12])=O)[CH2:2][CH:3]([CH3:5])[CH3:4].CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:31]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([O:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])=[O:45])[CH2:32][CH:33]([CH3:35])[CH3:34]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:38]([CH2:43][C:44]([O:46][CH2:47][CH2:48][CH:49]([CH3:50])[CH3:51])=[O:45])[CH:39]=1)=[O:12])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCOc1ccc(C(=O)O)cc1OCCC(C)C
Reactant: CC(C)CCOC(=O)Cc1ccccc1OCCC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)CCOC(=O)Cc1cc(C(=O)c2ccc(OCCC(C)C)c(OCCC(C)C)c2)ccc1OCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
In 8 ml of methylene chloride is dissolved 0.80 g of 3,4-diisopentyloxybenzoic acid. Then, 20 μl of N,N-dimethylformamide is added, and the mixture thus obtained is stirred at ambient temperature for one hour. To the mixture thus obtained are successively added 1.10 g of aluminum chloride and 0.95 g of isopentyl 2-(2-isopentyloxyphenyl)acetate at 5-10° C., and the mixture thus obtained is stirred at 5-10° C. for 10 minutes. The reaction mixture is added to a mixture of chloroform and ice water, and the organic layer is separated. After washing the organic layer with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to obtain 1.20 g of isopentyl 2-[5-(3,4-diisopentyloxybenzoyl)-2-isopentyloxyphenyl]-acetate as a yellow oily product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:9]([CH3:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[ClH:12].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16]([NH:1][CH2:2][C:3]1([N:9]([CH3:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:17]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN(C)C1(CN)CCCCC1
Solvent: c1ccncc1
Product: CN(C)C1(CNC(=O)c2ccc(Cl)c(Cl)c2)CCCCC1
Product: Cl
Reaction time: 1 h

Procedure:
A mixture of 1-aminomethylcyclohexyl dimethylamine (1.0 g.), 3,4-dichlorobenzoyl chloride (2 ml) and pyridine (10 ml) was allowed to stand at room temp. for 1 hr. The pale yellow solid produced was filtered and recrystallised from ethanol/ether to give a colourless microneedles of 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine hydrochloride m.p. 215°-16° .
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[N:10]2[CH2:29][C@@H:30]2[CH2:32][O:31]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(n1)NC(=O)CC2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 7-(methyloxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (4.974 g, 27.9 mmol) in DMF (100 ml) at 0° C. under argon was treated with sodium hydride (60%, 1.340 g, 33.5 mmol) and allowed to stir at 0° C. for 20 min. The reaction mixture was then treated with (2S)-2-oxiranylmethyl 3-nitrobenzenesulfonate (7.60 g, 29.3 mmol) and then then allowed warm slowly to rt and stirred at rt for 1 h. Water (5 ml) was then added. Reaction was evaporated, saturated aqueous NaHCO3 (500 ml) was then added and the mixture was extracted with DCM (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:27])[O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:2]2.[Br:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][CH2:37][CH2:36][C:35]=2[CH:39]=1>C(OCC)(=O)C>[Br-:28].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:10]([NH:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N+:1]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]5[O:38][CH2:37][CH2:36][C:35]=5[CH:39]=4)([CH2:6][CH2:5]3)[CH2:2]2)=[O:27])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Reactant: BrCCc1ccc2c(c1)CCO2
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[N+]2(CCc3ccc4c(c3)CCO4)CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (53 mg, 0.14 mmol, prepared as in example 1) in ethyl acetate (2 ml), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (32.3 mg, 0.14 mmol) was added. The resulting mixture was stirred at room temperature for 8 days, and then the solvent was evaporated, and the crude was purified by flash chromatography (DCM/MeOH=95/5) to collect (R)-3-((bis(3-fluorophenyl)-methoxy)carbonylamino)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide (22.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)n1ccc2ccccc21
Yield: 81 %

Procedure:
The title compound was prepared from 4-fluoro-benzene sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 81%; mp 135-137° C.; 1H NMR (CDCl3) δ 7.86-7.99 (m, 3H), 7.51-7.54 (m, 2H), 7.19-7.35 (m, 2H), 7.05-7.12 (m, 2H), 6.66-6.68 (dd, J=4 Hz, 1H); 13C NMR (CDCl3) δ 168.1, 164.0, 135.2, 134.7, 134.6, 131.2, 130.1, 129.9, 126.6, 125.2, 123.9, 121.9, 117.2, 116.9, 113.9, 110.0; MS (ES+) m/z 275.99 (M++1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=2)[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>[OH-].[Na+].CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 55.3 %

Procedure:
In a mixture of 1N NaOH solution (4.5 ml) and methanol (10 ml), methyl 2-[4-(2-butylbenzimidazol-1-yl)methylphenyl]benzoate (1.2 g) was heated for 3 hours under reflux. The reaction mixture was concentrated, and the concentrate was dissolved in water, washed with ether, then acidified with 1N-HCl to afford crystals. The crystals were collected by filtration and recrystallized from ethyl acetate-methanol to afford colorless crystals (0.64 g, 53%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N+:3]=1[O-].[CH2:17]=O.[CH3:19][NH:20][CH3:21]>O>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:19][N:20]([CH3:17])[CH3:21])[CH:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: C=O
Reactant: Cc1c(O)ccc(Cc2ccccc2)[n+]1[O-]
Reactant: CNC
Solvent: O
Product: Cc1nc(Cc2ccccc2)cc(CN(C)C)c1O
Temperature: 80 °C

Procedure:
A mixture of 8.6 g (40 millimoles) of 2-methyl-6-benzyl-pyridin-3-ol N-oxide, 5 g of 30% strength aqueous formaldehyde solution, 5.5 g of 40% strength aqueous dimethylamine solution and 9 ml of water is heated for 2 hours at 80° C. It is then evaporated to dryness, the residue is taken up in chloroform, this solution is shaken with active charcoal and filtered, and the solvent is distilled off. 10.2 g of 2-methyl-4-dimethylaminomethyl-6-benzyl-3-pyridin-3-ol N-oxide remain.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH:25]([OH:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO.C(Cl)Cl.C(#N)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[CH3:34][O:27][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CCN(c2ccc(F)cc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: COC1c2ccccc2C(=O)N1CCCN1CCN(c2ccc(F)cc2)CC1
Reaction time: 5 h
Yield: 141.7 %

Procedure:
The same procedure is followed as in Example 2, starting from an agitated solution of 2-[3-(4-(4-fluorophenyl)-1-piperazinyl)propyl]-3-hydroxy-1 -isoindolinone (6.8 g) in methanol (170 cc) to which 33.5 cc of concentrated sulphuric acid is added at a temperature close to 20° C. in the course of 15 minutes. Agitation is continued for 5 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 83 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and a 33% aqueous solution of ammonia (50 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (20 cc) and the solution is poured onto silica (500 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (99-1 by volume). The first 300 cc are eliminated and the next 3500 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetonitrile (50 cc). A solution of oxalic acid (1.1 g) in acetonitrile (25 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 4.1 g of 3-methoxy-2-[3-(4-(4-fluorophenyl)-1-piperazinyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 177° C.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@H:13]3[C:8]3[C:9]2=C([CH:5]=[CH:6][CH:7]=3)N1.[H-].[Na+].CI.[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>O>[CH3:2][CH:11]1[N:10]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:8]3[C:9]2=[C:27]([CH:5]=[CH:6][CH:7]=3)[N:28]([CH3:29])[C:30]1=[O:31]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)C(=O)N4C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of ethyl 2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (from Example 211, Step A) (500 mg, 1.6 mmol) in DMF (20 mL) at rt was added NaH (147 mg, 3.6 mmol), MeI (0.25 mL, 4.0 mmol) and stirred at 25° C. for 3 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 1,3-dimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (350 mg, 64%) as an oil. MS [M+H]+ 328. 1H NMR (CDCl3, 300 MHz): δ 7.18 (d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.63 (d, 1H, J=7.7 Hz), 4.90 (m, 1H), 4.51 (m, 1H), 3.20 (m, 5H), 3.49 (m, 1H), 3.42 (s, 3H), 2.91 (m, 1H), 2.80 (m, 1H), 1.61 (d, 3H, J=7.0), 1.28 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(COC)OC.CCOCC>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOC
Product: COC(=O)COc1ccc(CCNCc2ccccc2)cc1
Reaction time: 8 h
Yield: 125.4 %

Procedure:
The starting material was obtained as follows: N-Benzyltyramine (9.08 g) was added to a stirred solution of potassium t-butoxide (4.5 g) in dimethoxyethane (80 ml). To the clear solution was added methyl bromoacetate (6.2 g) and the mixture was stirred overnight. The mixture was diluted with ether (250 ml) and washed with water (2×25 ml). The ethereal solution was dried (MgSO4) and evaporated, to give methyl 4-[2-(benzylamino)ethyl]phenoxyacetate (15.0 g) as an oil, which was dissolved in isopropanol and teated with phenylglycidyl ether (7.5 g). The solution was heated to reflux for 1 hour, and then evaporated. The residue was dissolved in toluene and volatile material evaporated before being purified by chromatography on K60 silica (220 g) using 1% methanol in dichloromethane. Methyl 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetate was obtained as an oil (9.5 g), NMR: 2.55-2.85[m,6H, CH2NHCH2CH2 ]; 3.65-4.05[m,8H, PhOCH2CHOH and PhCH2 and OCH3 ]; 4.67]s, 2H, OCH2CO]; 6.73-7.40[m, 14H, aromatic H].
Reaction SMILES: [C:1](#N)[CH2:2][CH3:3].[Ca:5].[OH-:6].[Ca+2].[OH-:8].[O-2].[Ca+2]>O>[C:1]([O-:8])(=[O:6])[CH2:2][CH3:3].[Ca+2:5].[C:1]([O-:8])(=[O:6])[CH2:2][CH3:3]
Reactant: CCC#N
Reactant: [Ca]
Reactant: [OH-]
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: CCC(=O)[O-]

Procedure:
A process for producing a calcium propionate comprising contacting propionitrile, a calcium compound selected from calcium hydroxide, calcium oxide or mixtures thereof, and water at a temperature of about 90° C. to about 250° C. at a sufficient pressure to achieve the desired temperature and for a sufficient time to produce a reaction mixture comprising calcium propionate;
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:28]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: COc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2c1CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 61.1 %

Procedure:
4.16 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 2.5 g of 4-methoxyisoindoline, 6.4 g of DBU, and 28 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 3.64 g of the target compound.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22].[CH:25]1([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[CH:25]1([C:28]2[CH:34]=[CH:33][C:31]([N:32]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([S:21]([C:17]5[S:16][CH:20]=[CH:19][CH:18]=5)(=[O:23])=[O:22])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(S(=O)(=O)c1cccs1)CC2

Procedure:
Light brown solid. MS (ESI): 417.13 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), thiophene-2-sulfonyl chloride and 4-cyclopropyl-aniline.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20](N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[Cl:45][C:46]1[CH:47]=[C:48]([C:53]2[CH:54]=[N:55][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[N:57][CH:58]=2)[CH:49]=[CH:50][C:51]=1[Cl:52].C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:62]1[CH2:61][CH2:60][N:59]([C:56]2[N:57]=[CH:58][C:53]([C:48]3[CH:49]=[CH:50][C:51]([Cl:52])=[C:46]([Cl:45])[CH:47]=3)=[CH:54][N:55]=2)[CH2:64][CH2:63]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Clc1ccc(-c2cnc(N3CCNCC3)nc2)cc1Cl
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 39 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 5-(3,4-dichlorophenyl)-2-piperazine-1-yl-pyrimidine, dihydrochloride (0.52 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0 67 g), to yield the title compound as a white solid (0.51 g, 39%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:29])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=3)[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:37][CH2:38][C@H:39]1[CH2:43][O:42][C:41]([CH3:45])([CH3:44])[O:40]1>CN(C=O)C>[CH3:44][C:41]1([CH3:45])[O:40][C@@H:39]([CH2:38][CH2:37][O:13]/[N:12]=[C:11]2\[NH:10][C@@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=3)[CH2:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:29])[C:5]\2=3)[CH2:43][O:42]1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O)N2)n1
Reactant: CC1(C)OC[C@H](CCI)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC[C@H]3COC(C)(C)O3)N2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (86 g or Compound 61, 10.0 mg, 0.025 mmol) in dry DMF (1 mL) was added Cs2CO3 (12.2 mg, 0.0375 mmol) and the reaction mixture stirred at ambient temperature for 30 minutes. Then, (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (86d, 7.68 mg, 0.03 mmol) was added and the reaction mixture stirred overnight. LCMS showed complete consumption of starting material. The reaction mixture was poured onto crushed ice and the resulting solid was filtered, rinsed with cold water, and dried to afford (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (86 h, 8.2 mg, 63%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 3H) 1.39 (s, 3H) 1.91-2.01 (m, 4H) 2.72 (s, 3H) 3.07 (dd, J=16.55, 10.48 Hz, 1H) 3.26 (dd, J=17.05, 4.93 Hz, 1H) 3.55 (dd, J=7.96, 7.20 Hz, 1H) 3.90 (s, 3H) 4.05 (dd, J=7.96, 5.94 Hz, 1H) 4.10-4.21 (m, 3H) 4.89 (dd, J=10.61, 3.79 Hz, 1H) 6.74 (d, J=8.84 Hz, 1H) 7.01 (d, J=8.08 Hz, 1H) 7.11-7.22 (m, 2H) 7.61-7.69 (m, 2H)MS (ES) [M+H] calculated for C27H32FN6O4, 523.24. found 523.50.