Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:12]=1>>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[C:13]([NH:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1)[N:12]=[C:11]2[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3c(C)cccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [5-methyl-1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[N:12](=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])\[NH2:13].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:13]/[N:12]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: N/N=C/c1ccccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Cc1cccc(Cl)c1)N/N=C/c1ccccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A flask is charged with (3-chlorophenyl)acetic acid (0.34 mmol), 4-dimethylaminopyridine (0.66 mmol), a solution of N-{2-[(E)-hydrazonomethyl]phenyl}-4-(trifluoromethyl)benzenesulfonamide (0.33 mmol) in N,N-dimethylacetamide (1 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 mmol). The reaction is stirred at room temperature for 18 hours. The reaction is worked up either by adding water and obtaining a solid precipitate, or by evaporating the reaction mixture. The product is purified on silica gel with ethyl acetate-methylene chloride mixtures. Obtained a 60% yield of N-[2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl]-4-(trifluoromethyl)benzenesulfonamide. 1H NMR (400 MHz, CDCl3)(mixture of geometric isomers) d 3.73&4.17(2s, 2H); 7.16 (m); 7.36 (m); 7.47 (s); 7.60m; 7.66 (m); 7.75 (m); 7.89 (s); 7.96 (m); 8.06 (m); 9.62 (bs); 10.80 (bs). ESI− for C22H17ClF3N3O3S: m/z =494 (M−H)−.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].CC(C)([O-])C.[K+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: BrCCCCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCCCBr)c2ccccc21
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
To a solution of isatin (7.35 g) in N,N-dimethylformamide (70 ml) was added potassium tert-butoxide (6.98 g) under cooling at 5° C., and the reaction mixture was stirred for 10 minutes at the same temperature. To the mixture was added dropwise a solution of 1,4-dibromobutane (54 g) in N,N-dimethylformamide (25 ml), and stirred for an hour at 18° C. The reaction mixture was poured into ice-water, and extracted with chloroform. The extracts were combined, washed with water and evaporated. After addition of n-hexane (200 ml) to the residue, the solvent was decanted and then to the residue was added chloroform (20 ml). The mixture was filtered to remove insoluble substances and the filtrate was subjected to column chromatography on silica gel (50 g), eluted with chloroform. The fractions containing the object compound were collected, and concentrated to give dark red oil of 1-(4-bromobutyl)isatin (7.52 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O[N:29]1C2C=CC=CC=2N=N1.CN1CCOCC1.COC1C=CC(CON)=CC=1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH:14]([CH:18]([CH3:19])[CH3:20])[C:15]([NH2:29])=[O:17])[CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: COc1ccc(CON)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)C(C(N)=O)C(C)C)cc1
Reaction time: 8 h

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride (2.41 g, 5.82 mmol), 1-hydroxybenzotriazole (0.786 g, 5.82 mmol), 4-methyl-morpholine (1.9 mL, 17.46 mmol), and O-(4-methoxybenzyl)hydroxylamine (1.78 g, 11.63 mmol) (prepared according to Pol. J. Chem. 55, 1163°-1167 (1981 )) are dissolved in methylene chloride (55 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.45 g, 7.57 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (ethyl acetate followed by 5% methanol/ethyl acetate) to give N-(4-methoxybenzyloxy)-2CR)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanamide, m.p. 45°-53° C.
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:16])[O:7][CH2:8][CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:16])[O:7][CH2:8][CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: ClSCl
Reactant: CCCCC(CC)COC(=O)NC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)N(C)SCl
Temperature: 5 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
To a solution of 62 g (0.6 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to 0° C. under a nitrogen atmosphere was added a solution of 75 g (0.4 mole) of 2-ethylhexyl N-methylcarbamate and 44.5 g (0.44 mole) of triethylamine in 100 ml of methylene chloride at -10° to 3° C. The addition took 2 hr. After stirring for 1 hr at 5° C., the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. The product was extracted into 200 ml of hexanes and the solid triethylamine hydrochloride was filtered. The filtrate was concentrated to give 105.4 g of 2-ethylhexyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:16]1[C:17]2[C:22]([N:23]=[C:24]3[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2>CN(C=O)C>[CH:18]1[C:17]2[C:22](=[N:23][C:24]3[C:29]([C:16]=2[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: Clc1c2ccccc2nc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Cl)cc1)c1c2ccccc2nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After a mixture of DMF (250 ml), methyl p-chlorophenylacetate (25.9 g, 140 mmol) and NaH (211 mmol) was stirred at room temperature for 1 hour, 9-chloroacridine (15.0 g, 70.2 mmol) dissolved in 250 ml of DMF was added slowly. The resultant reaction mixture was stirred at room temperature for 18 hours. This reaction mixture was then poured onto 1.5 l. of an ice/H2O mixture and extracted with CHCl3 (500 ml). The CHCl3 extract was washed with H2O (3×500 ml) and dried over MgSO4. Evaporation of the CHCl3 extract gave a crude residual solid which was recrystallized from cyclohexane; yield, 20.2 g (79.4%), mp 192°-193°.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH3:12]>[Fe]>[Br:1][C:8]1[C:7]([CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH3:3])[CH:9]=1
Reactant: BrBr
Reactant: COc1cc(C)ccc1C
Agent: [Fe]
Product: COc1cc(C)c(Br)cc1C

Procedure:
Bromine (291.5 g, 1835 mmol) was added dropwise to a mixture of 2,5-dimethylanisole (250 g, 1835 mmol) and Fe powder (3.25 g) while stirring. The commencement of the reaction could be observed by means of the evolution of gas. The remaining bromine was then added dropwise over a period of 30-40 minutes at room temperature while cooling on a water bath. The reaction mixture was stirred further for about 4 hours. The solution was subsequently separated from the Fe powder, a little chloroform was added and the mixture was shaken with water, leading to the solution becoming lighter in color. After shaking with 50 ml of saturated aqueous Na2SO3 solution, the solution had become completely decolorized. It was shaken once more with dilute aqueous NaOH and twice with H2O and, after drying, the solvent was taken off. The crude product was fractionally distilled under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[ClH:10].[CH2:11]([Cl:13])[CH3:12].[OH-].[Na+]>O>[ClH:13].[ClH:10].[ClH:13].[CH2:3]([N:4]([CH2:11][CH3:12])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCN1CCN(CCO)CC1
Reaction time: 18 h
Yield: 51 %

Procedure:
To a stirred solution of 76.0 g (0.58 mol) of 1-(2-hydroxyethyl)piperazine in 200 ml of water was added dropwise 201.0 g (0.58 mol) of a 50% aqueous solution of 2-diethylamino)ethyl chloride hydrochloride. The pH was maintained at 10 by addition of 25% NaOH while the solution was stirred for 18 hours. Water was removed to give a thick oil which was extracted with ethanol. The ethanolic solution was filtered, then the ethanol was removed. The resulting liquid was distilled to give 67.7 g (51%) (b.p. 110°-112° C./0.1 Torr) of the alcohol as a light brown liquid. The trihydrochloride salt was prepared by acidifying the free base to a pH of 1 and removing the water.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:8][N:7]=1)=[O:5])[CH3:2]>C1COCC1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c(C=C(C)C)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)c(CC(C)C)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.7 %

Procedure:
To a solution of 4-methyl-5-(2-methyl-propenyl)-pyridine-2-carboxylic acid ethyl ester (1.33 g, 6.06 mmol) in THF (10 mL) and ethanol (10 mL), Pd/C (300 mg, 10% Pd) is carefully added. The slurry is stirred at rt for 15 h under 2 bar of H2. The catalyst is filtered off and the filtrate is concentrated and dried to give 5-isobutyl-4-methyl-pyridine-2-carboxylic acid ethyl ester (1.27 g) as a colourless oil; LC-MS: tR=0.86 min, [M+1]+=222.10.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:31]1([F:35])[CH2:34][N:33]([C:2]2[C:3]([F:28])=[C:4]([N:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]4[N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:20]=[CH:19][CH:18]=4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:32]1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: FC1(F)CNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2cccc(N3CC(F)(F)C3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 32.4 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (177 mg, 0.4 mmol), 3,3-difluoroazetidine hydrochloride (62.2 mg, 0.48 mmol), NaOt-Bu (99.9 mg, 1.04 mmol), Xantphos (99.9 mg, 0.173 mmol) and Pd2(dba)3 (39.7 mg, 0.043 mmol) in 1,4-dioxane (2 mL) was heated to 90° C. for 16 h under N2. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) to yield the title compound (58.8 mg, 32% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.77 (3H, s), 4.42 (4H, t, J=12.6 Hz), 6.43-6.82 (1H, m), 6.90-7.49 (8H, m), 7.79 (1H, s), 8.39-8.60 (1H, m).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:11]([Cl:17])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24]CCCC)=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>Br>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:11]([Cl:17])[N:10]=[C:9]1[C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1ccc(-c2nc(Cl)c(CC(=O)O)n2Cc2ccccc2)cc1
Agent: Br
Solvent: O
Product: O=C(O)Cc1c(Cl)nc(-c2ccc(O)cc2)n1Cc1ccccc1
Yield: 58.2 %

Procedure:
1 g of 1-benzyl-4-chloro-2-(4-n-butoxyphenyl)imidazole-5-acetic acid was boiled in 14 ml of 48% hydrobromic acid for 2 hours, and addition of 15 ml of water, followed by allowing the solution to stand, resulted in crystals deposited. Recrystallization of the crystals from aqueous ethanol yielded 0.5 g of 1-benzyl-4-chloro-2-(4-hydroxyphenyl)imidazole-5-acetic acid as colorless, prism-formed crystals, m.p. 140°-145° C.
Reaction SMILES: C[C:2]1([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]1[C:14]([O:16]C)=[O:15].[CH3:23][Si](C)(C)[O-].[K+:28].C(OCC)C>O1CCCC1>[CH3:23][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[C:3]([C:14]([O-:16])=[O:15])[C:2]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[CH:7][N:6]=2)[CH:9]=[N:10][CH:11]=1.[K+:28]
Reactant: COC(=O)C1C=C(c2cccnc2)N=CC1(C)c1nccs1
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cncc(-c2cc(C(=O)[O-])c(-c3nccs3)cn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxylate (7-3, 890 mg, 2.9 mmol, 1 equiv) in tetrahydrofuran (14.3 mL) was added potassium trimethylsilanolate (640 mg, 5.0 mmol, 1.75 equiv). The reaction mixture was stirred at room temperature for 1 hour. Ethyl ether (15 mL) was added and the precipitate was filtered to afford the title compound (7-4) as a white solid. ESI+MS[M+H]+C15H12N3O2S=298.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[CH2:22]([O:19][C:18](=[O:20])[C@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A suspension of crude (S)-2-(4-chlorophenyl)-αmethyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.0 g, 0.00663 mole) in absolute ethanol was stirred at room temperature while 4 drops of concentrated sulfuric acid was added. The reaction mixture was refluxed for three days. Approximately 1/2 to 2/3 of the solvent was removed under reduced pressure. Saturated sodium bicarbonate solution (20 ml) was added to the remaining solution. The product was extracted into two portions of ethyl acetate and the combined organic layers were washed twice with water, dried over sodium sulfate, filtered and evaporated to an oil which was dissolved in hot absolute ethanol. Water was added to the cloud point and upon cooling to room temperature, a solid precipitated. The solid was collected by filtration, rinsed with water and dried under high vacuum at 50° C. to give 1.48 g (68%) of title compound, mp 103°-106° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[NH4+].[Cl-]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)NCCCCCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)NCCCCCCOS(C)(=O)=O
Temperature: 0 °C

Procedure:
A solution of N-(6-hydroxyhexyl)prop-2-enyloxycarboxamide (2.55 g, 12.7 mmol; Charreyre, M. T.; Boullanger, P.; Pichot, C.; Delair, T.; Mandrand, B.; Llauro, M. F. Mak. Chem. 1993, 194(1), 117-35.) in dry CH2Cl2 (30.0 mL) was treated with Et3N (4.06 mL, 29.1 mmol) then cooled to 0° C. To this solution was transferred MsCl (15.2 mmol; 20.0 mL of a 0.76 M solution in CH2Cl2) using a cannula; full conversion coincided with completion of the transfer. The resulting solution was warmed to 22° C., then treated with 2 M NH4Cl (50 mL) and transferred to a separatory funnel. The layers separated and the aqueous layer washed with CH2Cl2 (3×50 mL). The combined washes were washed with 20% aqueous NaCl then dried over MgSO4, filtered and concentrated in vacuo to a pale yellow oil (3.2 g) that was used without further purification in the subsequent alkylation step. 1H NMR (CDCl3, 300 MHz): δ 5.90 (1H, ddt, J=17.2, 10.4, 5.6 Hz), 5.29 (1H, dq, J=17.2, 1.6 Hz), 5.19 (1H, dq, J=10.4, 1.3 Hz), 4.71 (1H, brs), 4.54 (2H, brd, J=5.5 Hz), 4.20 (2H, t, J=6.5 Hz), 3.17 (2H, brs), 2.98 (3H, s), 1.79-1.69 (2H, m), 1.55-1.29 (6H, m).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16]2[CH:21]=[C:20]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)[N:19]=[CH:18][N:17]=2)[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)C)=O>C(Cl)Cl>[CH3:34][S:31]([C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C:20]1[N:19]=[CH:18][N:17]=[C:16]([N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH3:15])[CH:21]=1)[CH2:23][CH2:24]2)(=[O:33])=[O:32]
Reactant: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 15 %

Procedure:
7c was taken up in DCM (2 mL). Diisopropylethylamine (0.6 mL, 11 eq) and 1-chloroethyl chloroformate (0.2 mL, 5.7 eq) were added. The reaction mixture was stirred at room temperature for 22 h. The solvent was then evaporated under a stream of nitrogen and the residue was dissolved in methanol and heated at 50° C. for 3 h. The solvent was removed under a stream of nitrogen and the residue was purified by preparative HPLC to give 25 mg (15%) of 7d.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1.Cl[C:29]([O:31][CH3:32])=[O:30].CCCC(C)C>C(OCC)C>[CH3:32][O:31][C:29]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1)=[O:30]
Reactant: COC(=O)Cl
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Agent: Cl
Solvent: CCCC(C)C
Solvent: CCOCC
Product: COC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the technique of Example 113, starting from 3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one hydrochloride salt (170 mg, 0.43 mmol) and methyl chloroformate gave the desired product (114 mg) after trituration with diethyl ether and isohexane.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]2)[CH2:9][CH2:8]1>ClCCl>[CH3:1][S:2]([O:6][C@H:7]1[CH2:8][CH2:9][C@@H:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]2)[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CN1CCN([C@H]2CC[C@@H](O)CC2)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)CC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.24 ml methanesulphonic acid chloride are added dropwise at 0° C. to 500 mg (cis)-1-hydroxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane and 0.52 ml N,N-isopropyl-ethylamine in 10 ml dichloromethane and stirred for 1.5 hours at ambient temperature. The product is purified by column chromatography.
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1>[C:1]1([NH:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a 0° C. suspension of 21.0 g of product from Example 144 in 200 ml of dry tetrahydrofuran is added, dropwise over 30 minutes, 51.27 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. The reaction is stirred at room temperature for 1 hour, heated at reflux temperature for 2 hours and stirred overnight at room temperature. Ethyl acetate is added followed by concentrated sodium hydroxide. The reaction is filtered, concentrated in vacuo and the residue is recrystallized from hexane to give 16.9 g of the desired product.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:19]1[CH:20]=[CH:21][C:22]([O:29][CH3:30])=[C:23]([CH:28]=1)[C:24](OC)=[O:25])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1.Cl.OC(C1C=CC(OC)=C(C=1)C(OC)=O)C[N:35]1CCN(C2C=CC=CC=2C)CC1.COC(=O)C1C=C(C(O)CN2CCN(C3C=CC=CC=3)CC2)C=CC=1OC>>[ClH:1].[OH:2][CH:3]([C:19]1[CH:20]=[CH:21][C:22]([O:29][CH3:30])=[C:23]([CH:28]=1)[C:24]([NH2:35])=[O:25])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1
Reactant: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3C)CC2)ccc1OC
Reactant: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3OC)CC2)ccc1OC
Agent: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3)CC2)ccc1OC
Agent: Cl
Product: COc1ccc(C(O)CN2CCN(c3ccccc3OC)CC2)cc1C(N)=O

Procedure:
Following essentially the same procedure but substituting methyl 5-[1-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-methoxybenzoate hydrochloride and methyl 5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-methoxybenzoate hydrochloride for the methyl-5-[1-hydroxy-2-(4-phenyl-1-piperazinyl)ethyl]-2-methoxybenzoate above results in the preparation of 5-[1-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-methoxybenzamide hydrochloride, having a m.pt. of 247°-8° C. (dec.) and 5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-methoxybenzamide hydrochloride, having a m.pt. of 214°-6° C. (dec.), respectively.