Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@H:9]1[CH2:21][OH:22])([CH3:4])[CH3:3].O[N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:4][C:2]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@H:9]1[CH2:21][O:22][N:25]1[C:29](=[O:30])[C:28]2[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]1=[O:35])([CH3:1])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a mixture of cis-2-hydroxymethyl-1-(4-methoxyphenyl)-4-oxo-3-azetidinyl-carbamic acid 1,1-dimethylethyl ester (5.8 g, 18 mmol), N-hydroxyphthalimide (3.0 g, 18 mmole) and triphenylphosphine (5.7 g, 22 mmol) was added diethyl azodicarboxylate (3.7 g, 21 mmol). The reaction was allowed to stir at room temperature for 0.5 hours whereby the solvent was removed in vacuo. The reaction mixture was dissolved in methylene chloride and again the solvent evaporated to remove any residual THF. A solid precipitates and is washed with a solution of methylene chloride-diethyl ether (1:1). The filtrate is concentrated and the solid precipitate is again washed with a solution of methylene chloride-diethyl ether (1:1) and combined with the previously recovered material to afford 5.0 g of [cis-2-[[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]methyl]-1-(4-methoxyphenyl)-4-oxo-3-azetidinyl]carbamic acid 1,1-dimethylethyl ester (59%). Another 1.9 g (22.3%) of product could be recovered after concentration of the filtrate followed by flash chromatography (ethyl acetate-hexane, 1:9): mp 188°-189° C.; IR (KBr) 3435, 2980, 1795, 1735, 1710, 1500, 1390, 1370, 1160, and 1130 cm-1 ; NMR(CDCl3) δ 1.48 (9H, s), 3.74 (3H, s), 4.40 (1H, br d, J=12 Hz), 4.52 (1H, m), 4.98 (1H, br d, J=12 Hz), 5.44 (1H, m), 6.22 (1H, d, J-9 Hz, exchangeable), 6.82 (2H, d, J=8 Hz), 7.43 (2H, d, J=8 Hz), 7.78 (4H, m).
Reaction SMILES: [C@H:1]1([NH:10][CH:11]=[CH:12][CH:13]=[C:14]([C:19]([O:21]C)=[O:20])[C:15](OC)=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].O>CO>[C@H:1]1([N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=[O:20])[C:15]2=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C(=CC=CN[C@@H]1CCc2ccccc21)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccn([C@@H]2CCc3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a solution of 11.0 g (1.0 eq) (R)-dimethyl 2-(3-(2,3-dihydro-1H-inden-1-ylamino)allylidene)malonate in 80 ml dry MeOH was slowly added 3.65 g (2.5 eq) NaH (60% dispersion in mineral oil) under N2 protection. The reaction was stirred at room temperature for 10 minutes and was then heated at 60° C. After 20 minutes, to the reaction mixture were added 30 ml water. The resulting mixture was heated at 60° C. for an additional 20 minutes. The solvent was removed in vacuo. The residue was diluted with 50 ml water, and extracted with hexane (2×50 ml) to remove mineral oil. Then the aqueous mixture was acidified with 2N HCl to pH 1-2 and extracted with ethyl acetate (2×100 ml). The combined organic phase was washed with 100 ml brine, dried over sodium sulfate and concentrated in vacuo to afford (R)-1-(2,3-dihydro-1H-inden-1-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid as a white solid (8.7 g, yield 93%) which was used without further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[NH:5][CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:10])[CH:9]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O.O>[N:19]([CH2:3][C:4]1[NH:5][CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:10])[CH:9]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1cc(CCl)[nH]cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
A mixture of 2-(chloromethyl)-5-(phenylmethoxy)-4(1H)-pyridinone, monohydrochloride (3.59 g, 12.54 mmole), sodium azide (4.08 g, 62.7 mmole) and diisopropylethylamine (2.19 ml, 12.54 mmole) in 70 ml of dimethylformamide was stirred at room temperature under argon for 3.5 days. An additional 4.08 g of sodium azide was added and the mixture was heated at 45°-50° C. for 2 hours. After cooling, the reaction mixture was poured into 500 ml of water, producing an insoluble white solid. The pH of the supernatant liquid was lowered from 8.5 to 7.5 with dilute hydrochloric acid, and the white solid was filtered. After washing with water, acetone, and hexane the solid was dried in vacuo. The yield of the title compound was 2.81 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[O:16].C(N(CC)CC)C>ClCCl.CS(C)=O>[CH3:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][CH:8]=[O:7])[C:11]1=[O:16]
Reactant: CN1CCC(CCO)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN1CCC(CC=O)C1=O
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A solution of dimethylsulphoxide (1.7 ml) in dichloromethane (10 ml) was added dropwise over 5 min to a stirred solution of oxalyl chloride (1.0 ml) in dichloromethane (20 ml) at - 72° under nitrogen. The resultant solution was stirred at - 72° for 5 min then a suspension of 3-(2-hydroxyethyl)-1-methyl-2-pyrrolidinone (1.30 g) in dichloromethane (10 ml) and dimethylsulphoxide (1 ml; added to improve dissolution of the alcohol) was added dropwise over 8 min. The resultant cloudy solution was stirred at - 72° for 15 min then treated with triethylamine (7.0 ml). The resultant suspension was warmed to room temperature and stirred at room temperature for 1 h. The suspension was filtered. The residue was washed with ethyl acetate. The combined filtrate and washings were evaporated to give a semi-solid which was chromatographed using a mixture of ethyl acetate and methanol (5:1) as the eluent, to give the title compound (743 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].O1CCOCC1.[OH-].[Na+].Cl>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCCSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1c(SCCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 2-[4-(4-acetyl-3-hydroxy-2-propylphenylthio)butylthio]benzimidazole-5-carboxylate (2.50 g), 1,4-dioxane (30 ml) and sodium hydroxide (1.03 g) in water (30 ml) was stirred at 60 ° C. for 2 hours. This mixture was poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-methanol (10:1), to give the title compound (1.52 g, 64.5 %) as yellow crystals, mp 90-95° C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[N:32][CH:33]=1.N1C=C(CCCCCCO)C=NC=1>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[N:32][CH:31]=[N:30][CH:29]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCCCCc1cncnc1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Agent: OCCCCCCc1cncnc1
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCc2cncnc2)CC1
Yield: 49.3 %

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 23 starting with 7.4 g of 4-(2,2-diphenylethenyl)piperidine and 5.9 g of 5-(6-chlorohexyl)pyrimidine, from 5-pyrimidinehexanol. Chromatography provided 5.9 g (50%) of crude 5-[6-[4-(2,2-diphenylethenyl)-1-piperidinyl]hexyl]pyrimidine. Crystallization from hexane provided the analytically pure 5-[6-[4-(2,2-diphenylethenyl)-1-piperidinyl]hexyl]pyrimidine, mp 88°-90° C. Analysis Calculated for C29H35N3 : C, 81.84; H, 8.29; N, 9.87. Found: C, 81.90; H, 8.31; N, 9.78.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH:20]C(=O)C(Cl)(Cl)[Cl:23])[C:11]=2[N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl>CO.C(O)(C)C>[ClH:23].[CH2:1]([C:8]1[S:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:20])[C:11]=2[N:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1nc2ccccc2c2sc(Cc3ccccc3)nc12)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: Nc1nc2ccccc2c2sc(Cc3ccccc3)nc12
Temperature: 25 °C

Procedure:
Trichloroacetyl isocyanate (1.2 mL, 10.3 mmol) was added to a solution of 2-benzylthiazolo[4,5-c]quinoline-5N-oxide (2.0 g, 6.8 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated to provide crude N-(2-benzylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was dissolved in methanol. Sodium methoxide (1 equivalent) was added. The reaction mixture was heated on a steam bath for 30 minutes and then allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration and then suspended in a mixture of methanol and isopropanol. Hydrochloric acid (1 equivalent) was added and all of the solid dissolved initially. A white solid crystallized out. This material was isolated by filtration, washed with isopropanol and then dried to provide 1.5 g of 2-benzylthiazolo[4,5-c]quinolin-4-amine hydrochloride, m.p. 152-155° C. Analysis: Calculated for: C17H13N3S.HCl: %C, 62.28; %H, 4.30; %N, 12.82; Found: %C, 62.05; %H, 4.23; %N, 12.82.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]1[CH2:18][CH2:17][N:16]([C:19]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)(=O)=O)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.Br[C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1>CN(C)C=O.C(OCC)(=O)C>[F:47][C:46]([F:49])([F:48])[C:43]1[CH:44]=[CH:45][C:40]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:21]3)[CH2:17][CH2:18]2)=[N:41][CH:42]=1
Reactant: COC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)CC1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 1-[4-(2-nitrobenzenesulfonyl)-piperazin-1-yl]-cyclopropanecarboxylate (0.60 g, 1.63 mmol) from Example 16C in anhydrous dimethylformamide (5 mL) was treated with potassium carbonate (0.67 g, 4.88 mmol) and thiophenol (0.21 g, 1.95 mmol) and stirred one hour at room temperature. This reaction mixture was then treated with 2-bromo-5-trifluoromethyl pyridine (0.44 g, 1.95 mmol) and heated overnight at 80° C. Reaction diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 9:1 hexane:ethyl acetate to afford the title compound. MS(ESI) m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].OO.C(=O)([O-])[O-:33].[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1([C:28]([NH2:29])=[O:33])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC1(C(N)=O)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (36 mg) obtained in Example 2 in dimethylsulfoxide (1 mL) were added a solution of 30% aqueous hydrogen peroxide (28 μL) and 2M aqueous potassium carbonate (0.14 mL), and the mixture was stirred overnight at room temperature. Water was added thereto in an ice bath, and the precipitated solid was collected by filtration. The obtained crude crystals were recrystallized (diisopropyl ether/ethanol) to give the title compound (13 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1c(Br)cc(C(=O)O)c(N)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(Br)c(C)c(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 2-amino-5-bromo-3,4-dimethylbenzoic acid (73.9 g) in DMF (750 mL) was added cesium carbonate (148 g), and the mixture was stirred at room temperature for 30 min. To this reaction mixture was added dropwise methyl iodide (22.7 mL) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (56.8 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:18][CH3:19].Cl>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CCI
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Agent: Cl
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)piperidine and iodoethane: m.p. 158° C. (HCl). MS m/z (rel. intensity, 70 eV) 267 (M+, 20), 252 (bp), 130 (10), 115 (12), 84 (20);
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:14]=[C:13]2[C:7]([N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][NH:12]2)=[CH:6][N:5]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1>CC(N(C)C)=O>[Cl:3][C:4]1[N:14]=[C:13]2[C:7]([N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][N:12]2[CH2:18][C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)=[CH:6][N:5]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CN1C(=O)CCNc2nc(Cl)ncc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(CN2CCC(=O)N(C)c3cnc(Cl)nc32)cs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 13 mg, 0.38 mmol) in DMA (0.5 mL) was added a solution of 10-chloro-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 100; 63 mg, 0.30 mmol) in DMA (1 mL). The reaction mixture was allowed to stir, under nitrogen, in ice bath for 10 minutes prior to addition of 4-chloromethyl-2-methylthiazole (ASDI; 75 mg, 0.51 mmol). The reaction mixture was stirred in an ice bath for 20 minutes and then warmed to ambient temperature over 1 hour.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1([NH2+]C2CCCCC2)CCCCC1.C(Cl)(Cl)Cl.[CH3:55][N:56]([CH2:58][CH2:59]Cl)[CH3:57]>O1CCOCC1>[CH3:55][N:56]([CH3:57])[CH:58]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:59]
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Reactant: CN(C)CCCl
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C
Temperature: 70 °C
Yield: 88.4 %

Procedure:
To 1.10 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 1.8 ml chloroform and 1.9 ml solution of dimethylaminoethylchloride in the amount of 0.46 g, which stoichiometrically corresponds to two times molar volume, in dioxane were added to be subjected to reflux in oil bath at 70° C. for 30 hrs. After cooling down to a room temperature, said reaction mixture was similarly treated as in Step Example 1 to obtain N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester in the amount of 766 mg (yield; 88.4%).
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C:5]=2[N:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[N:1]1[C:6]2[CH2:7][CH:8]([CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:9][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1Cc2nccnc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC1Cc2nccnc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 1.3 g (8.7 mmol) of (6,7-dihydro-5H-cyclopentapyrazin-6-yl)-methanol in 15 ml of anhydrous dichloromethane was added at −15° C. 1.33 ml (9.52 mmol) of triethylamine and 0.74 ml (9.52 mmol) of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 1 h. The mixture was then diluted with water and dichloromethane and extracted with dichloromethane. Organic layer was dried and evaporated to give 1.73 g (88%) of methanesulfonic acid 6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: CCOC(=O)C(Cc1ccc(F)cc1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Cc1ccc(F)cc1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate (400 mg, 0.719 mmol) and lithium hydroxide monohydrate (0.306 g, 7.29 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoic acid (0.1 g). 1H-NMR (CDCl3, 400 MHz): 7.55-7.78 (m, 4H); 7.42 (s, 1H), 7.18 (s, 1H); 6.92-7.16 (m, 4H); 3.98 (q, 2H); 3.84 (t, 1H); 3.41 (dd, 1H), 3.02 (dd, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([S:13](=[O:23])(=[O:22])[N:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[NH:24][CH3:25])=[O:5].[NH2:26][C:27]1[CH:32]=[CH:31][NH+:30]=[CH:29][CH:28]=1>CC(C)=O>[Cl-:1].[NH2:26][C:27]1[CH:32]=[CH:31][N+:30]([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:12]=[C:11]([S:13](=[O:23])(=[O:22])[N:14]([CH3:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=[CH:9][C:8]=2[NH:24][CH3:25])=[O:5])=[CH:29][CH:28]=1
Reactant: Nc1cc[nH+]cc1
Reactant: CNc1ccc(S(=O)(=O)N(C)c2ccccc2)cc1NC(=O)CCCl
Solvent: CC(C)=O
Product: CNc1ccc(S(=O)(=O)N(C)c2ccccc2)cc1NC(=O)CC[n+]1ccc(N)cc1
Product: [Cl-]

Procedure:
3-Chloro-N-(5-(N-methyl-N-phenylsulfamoyl)-2-(methylamino)phenyl)propanamide (1 g, 0.0026 mol) and 4-aminopyridinium (0.73 g, 0.0078 mol) were boiled in anhydrous acetone (50 ml) for 50 h. The residue was filtered and subjected to crystallization from a 10:1 mixture of acetonitrile with ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[C:11]([O-:14])(=O)[CH3:12].[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:46]=O)(C)(C)C>C(Cl)(Cl)Cl>[C:11]([N:6]1[C:5]2[C:4](=[CH:3][C:2]([Br:1])=[CH:8][CH:7]=2)[C:9]([CH3:10])=[N:46]1)(=[O:14])[CH3:12]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)[O-]
Reactant: CCc1cc(Br)ccc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1nc(C)c2cc(Br)ccc21

Procedure:
A solution of 4-bromo-2-ethylaniline (1.09 g) in chloroform (20 ml) was stirred at room temp. then treated with potassium acetate (0.49 g) followed by acetic anhydride (0.95 ml). 18-Crown-6 (0.26 g) and t-butylnitrite (1.32 ml) were added after 30 min and the mixture was stirred at reflux for 18 h. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate. The organic phase was separated using a hydrophobic frit and the solvent was evaporated to give the title compound as a brown solid (1.0 g).
Reaction SMILES: CC(S([NH:7][CH:8]([C:14]1[O:15][C:16]([CH3:19])=[N:17][N:18]=1)[C:9]1([CH3:13])[CH2:12][O:11][CH2:10]1)=O)(C)C.Cl.O1CCOCC1>CO>[CH3:19][C:16]1[O:15][C:14]([CH:8]([C:9]2([CH3:13])[CH2:10][O:11][CH2:12]2)[NH2:7])=[N:18][N:17]=1
Reactant: Cc1nnc(C(NS(=O)C(C)(C)C)C2(C)COC2)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nnc(C(N)C2(C)COC2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a solution of 2-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)-(3-methyloxetan-3-yl)methyl]propane-2-sulfinamide (example 245a, 1.23 g, 4.28 mmol) in methanol (20 ml) was added a 4M solution of hydrochloric acid in dioxane (1.61 ml, 6.42 mmol) and the reaction mixture was stirred at room temperature for 2 hours. Reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic phase was extracted with 5 ml of a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (179 mg, 23%). MS (ESI, m/z): 184.5 (M+H+).