Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[C:10]([CH:15]=[CH2:16])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([CH2:15][CH3:16])=[N:9][CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cnc1C=C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC(C)(C)C)cnc1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of 5,6-divinyl-nicotinic acid tert-butyl ester (890 mg, 3.8 mmol) in THF (20 mL) containing some methanol, Pd/C (100 mg, 10% Pd) is added and the mixture is stirred under 1 atm of H2 at rt for 3 h. The catalyst is filtered off and the filtrate is evaporated. The remaining residue is purified by FC (SiO2, EA-heptane) to give 5,6-diethyl-nicotinic acid tert-butyl ester (860 mg) as an oil; LC-MS: tR=0.79 min, [M+1]+=236.14.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([F:18])[CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]=1[CH:34]=[O:35]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[C:21]=2[CH:34]=[O:35])=[C:4]([F:18])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Reactant: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1nccc(-c2cc(F)c(Cl)cc2F)c1C=O
Yield: 76 %

Procedure:
Prepared as described in Example 17, Part C by Suzuki coupling between 2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) preparation described in Example 14, Part A) and tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (Preparation described in Example 17, Part B) to afford tert-butyl 4-(4-chloro-2,5-difluorophenyl)-3-formylpyridin-2-ylcarbamate (3.7 g, 8.91 mmol, 76% yield) as a yellow solid. LC/MS (ESI) m/e 367.1 [(m)−, calcd for C17H16ClF2N2O3 367.1] LC/MS retention time (method E): tR=1.07 min.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH3:13].[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH2:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:13]
Reactant: CCN1CCCCC1CCc1ccccc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCN1CCCCC1CCc1ccccc1NC(=O)c1ccc(OC)cc1

Procedure:
Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with anisoyl chloride according to the procudure of Example 25 provides 2'-[2-(1-ethyl-2-piperidyl)ethyl]-p-anisanilide, m.p. 136.5°-137.5° C. (corr.), from ethyl acetate.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([I:15])=[C:9]([CH2:11][C:12](Cl)=[O:13])[CH:10]=1.CCOC(C)=O>CCOCC>[CH3:1][N:2]([CH3:3])[C:12](=[O:13])[CH2:11][C:9]1[CH:10]=[C:5]([Br:4])[CH:6]=[CH:7][C:8]=1[I:15]
Reactant: O=C(Cl)Cc1cc(Br)ccc1I
Reactant: CNC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cc1cc(Br)ccc1I

Procedure:
Dimethylamine (200 mL of 2 M in THF) is added dropwise to a solution of the above 5-bromo-2-iodophenylacetyl chloride in Et2O (500 mL), cooled in an ice bath. After the addition is complete, EtOAc (350 mL) is added and the solution washed with water (350 mL), brine (250 mL) and dried (MgSO4). Evaporation by rotary evaporator and trituration with 1:1 Et2O/hexanes gives N,N-dimethyl-5-bromo-2-iodophenylacetamide (m.p. 127–129° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH3:34])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH3:34])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: CCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under argon and at −78° C., 14.0 ml (1.0M in THF, 14.0 mmol, 1.05 eq.) of bis(trimethylsilyl)lithium amide were added dropwise to a solution of 5.0 g (13.3 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 100 ml of tetrahydrofuran, and the mixture was stirred at −78° C. for 15 min. 2.6 g (14.7 mmol, 1.1 eq.) of neat ethyl trifluoromethanesulphonate were then added dropwise. The cooling bath was removed and the reaction mixture was stirred at RT for another 1 h. The reaction mixture was cooled to 0° C., and saturated aqueous ammonium chloride solution was added. After phase separation, the aqueous phase was extracted twice with methyl tert-butyl ether. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by flash chromatography (340 g of silica gel, mobile phase: cyclohexane/ethyl acetate mixtures 8:1, 4:1). The product-containing fractions were combined and concentrated under reduced pressure. The residue was dissolved in hot methyl tert-butyl ether and the solution was left to stand without any cover, and after 10 min the mixture had crystallized almost completely. The crystals were filtered off and washed twice with methyl tert-butyl ether. The combined filtrates were concentrated under reduced pressure and the residue was re-crystallized as described. The two crystal batches were combined and dried under reduced pressure. Yield: 4.2 g (78% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C(Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (451 mg, 1.34 mmol, Intermediate 1) in DCM (12 ml) was treated with TEA (0.42 ml, 3 mmol) and benzyl bromide (0.54 ml, 4.5 mmol), and stirred at RT for 5 h. The mixture was washed with water, the pH value was adjusted to 5 with a 0.5 M HCl, then dried and concentrated. The crude residue was purified by column chromatography (eluent:DCM/MeOH 95:5) to give (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (440 mg) as a light yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:19][CH:18]=1.[OH-].[Na+]>ClCCl>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6](=[O:14])[CH2:5]3)[CH2:31][CH2:32]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2cccc(N3CCNCC3)c2c1
Reactant: O=C1CC(CCCl)c2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2cccc(N3CCN(CCC4CC(=O)Nc5ccccc54)CC3)c2c1
Temperature: 130 °C
Yield: 87.5 %

Procedure:
1.5 g (7.15 mmol) of (±)-4-(2-chloroethyl)-3,4-dihydro-2(1H)-quinolinone are mixed intimately with 3.65 g (15 mmol) of 1-(7-methoxy-1-naphthyl)piperazine and the mixture is heated to 130° C. for 1 h while stirring. The cooled residue is taken up between 25 ml of 2N sodium hydroxide and twice 50 ml of dichloromethane. The organic extract is washed with water, dried over magnesium sulphate and concentrated. The residue is purified by elution with a dichloromethane/methanol (95:5) mixture on a silica column. The purified fraction is crystallized in ether and this solid is drained and dried. 2.6 g (87.5%) of (±)-4-{2-[4-(7-methoxy-1-naphthyl)-1-piperazinyl]ethyl}-3,4-dihydro-2(1H)-quinolinone, melting point 177°-178° C., are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH2:18][OH:19])[CH:16]=2)[C@H:11]([N:22]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:10][C@@H:9]1[CH3:42])=[O:7])[CH3:4].I[CH3:44].O>CN(C)C=O>[CH2:3]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH2:18][O:19][CH3:44])[CH:16]=2)[C@H:11]([N:22]([CH2:27][C:28]2[CH:29]=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:10][C@@H:9]1[CH3:42])=[O:7])[CH3:4]
Reactant: CCOC(=O)N1c2cc(CO)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1c2cc(COC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a suspension of sodium hydride (4.2 mg, 60% dispersion in mineral oil, 0.10 mmol) in N,N-dimethylformamide (2.5 mL) was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-hydroxymethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic add ethyl ester (Example 85) (50 mg, 0.087 mmol). After the reaction was stirred at room temperature for 30 min, iodomethane (60 μL, 0.96 mmol) was added, and the reaction was stirred for 18 h. The reaction mixture was then poured into water and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The excess N,N-dimethylformamide was azeotroped off with heptanes. Purification by silica gel chromatography using 15-25% ethyl acetate/hexanes as eluent afforded the title product (30 mg, 59%): 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.3 (t, 3H), 3.4 (s, 3H), 3.75 (s, 3H), 3.8 (s, 3H), 6.4 (s, 1H), 7.4 (s, 1H), 7.75 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[N:8]([CH2:13][C:14]#[CH:15])[Si](C)(C)C.[CH3:18][N:19]1[C:27]2[N:26]=[CH:25][N:24]([CH2:28][CH2:29][CH3:30])[C:23]=2[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:38])[CH3:37])[C:20]1=[O:39]>CCCCCC.O1CCCC1>[NH2:8][CH2:13][C:14]#[C:15][C:36]([OH:38])([CH3:37])[CH2:35][CH2:34][CH2:33][CH2:32][N:21]1[C:22](=[O:31])[C:23]2[N:24]([CH2:28][CH2:29][CH3:30])[CH:25]=[N:26][C:27]=2[N:19]([CH3:18])[C:20]1=[O:39]
Reactant: C#CCN([Si](C)(C)C)[Si](C)(C)C
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
29 ml (46.5 mmol) of a 15% strength butyllithium solution in n-hexane were slowly added dropwise to a stirred solution of 9.26 g (46.5 mmol) of N,N-bis(trimethylsilyl)-2-propynylamine from stage C1 in 50 ml of tetrahydrofuran at -40° C. under argon. The mixture was then warmed to room temperature and again cooled to -40° C., and a solution of 14.25 g (46.5 mmol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 40 ml of tetrahydrofuran was slowly added. After removal of the cooling bath, the mixture was stirred at room temperature for 6 hours. The reaction mixture was then added to saturated ammonium chloride solution at 0° C., the aqueous phase was extracted with ether, the organic phase was dried over sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure. The crude product was subjected to flash chromatography first with the mobile phase mixture dichloromethane/methanol/saturated ammonia solution=19/1.5/2.5 and then with 9/1/2.5. Yield: 9.79 g (58% of theory); yellowish oil
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[C:8](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9].O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]([NH:9][CH:2]([OH:3])[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(O)NC(=O)OCc1ccccc1
Yield: 64.9 %

Procedure:
A solution of 17.3 g (0.169 mole) of ethyl glyoxylate and 23.0 g (0.152 mole) of benzyl carbamate in 250 ml of toluene was heated under reflux for 6 hours, with removal of water using a Dean-Stark trap. The resulting reaction mixture was concentrated in vacuo, and diethyl ether was added to the residue. The mixture was filtered, and the diethyl ether solution was evaporated in vacuo to give 25.0 g of ethyl 2-(benzyloxycarbonylamino)-2-(hydroxy)acetate as a sticky solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH3:34])([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])[O:11][C:10]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=1)([CH3:34])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2

Procedure:
Using Paar's hydrogenation apparatus, a mixture of 9.1 g of 6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)-2H-chromene (prepared as described in Preparation 21), 2g of 10% w/w palladium-on-carbon and 150 ml of methanol was stirred for 10 hours under 3-5 atmospheres (about 3-5-bars) pressure of hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 10:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]=2[O:4][N:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(Cl)(Cl)Cl>[C:18]([N:3]1[C:2](=[O:1])[C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]=2[O:4]1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)noc2C1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1oc2c(c1=O)CCN(C(=O)OC(C)(C)C)C2

Procedure:
t-BOC THIP (7.2 g) was refluxed with acetic acid anhydride (5.0 g) in 50 ml of CHCl3 for 2 hours. 2-Acetyl-6-(t-butyloxycarbonyl)-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-one was isolated as an oil in 6.4 g (76%) yield by column chromatography (Silicagel 60 "Merck") (eluted with ether/CH2Cl2 (1:3)). The t-BOC group was split off as above, yielding 73% of the oxalate. M.P. 177°-178° C. (dec.) (Found: C 44.32; H 4.70; N (10.58); C10H12N2O7 requires C 44.12; H 4.45; N 10.29%).
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[CH:6]([O:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:8])[CH3:7].[Cl-].[NH4+]>O1CCCC1>[CH:2]1([C:12]([OH:14])([CH2:11][CH2:10][O:9][CH:6]([CH3:8])[CH3:7])[CH3:13])[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: CC(=O)CCOC(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)OCCC(C)(O)C1CC1

Procedure:
To the Grignard reagent [production according to E. Renk et al. J. Am. Chem. Soc. 83, 1987 (1961)], from 9.06 g (0.37 mol) of magnesium and 42.8 g (0.35 mol) of cyclopropyl bromide in 460 cc of absolute tetrahydrofurane, is added dropwise at 5°C over the course of 10 minutes, in an atomosphere of nitrogen and while stirring, a solution of 46 g (0.35 mol) of 4-isopropoxy-2-butanone in 100 cc of absolute tetrahydrofurane. After stirring the reaction mixture at room temperature for 20 hours, saturated ammonium chloride solution and ice are added and the mixture is extracted with ether. The ether extract is washed with saturated salt solution, dried over sodium sulphate and the ether evaporated off. The resulting 2-cyclopropyl-4-isopropoxy-2-butanol is obtained after distillation at 75°-79°/12 mm as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14](OC)=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[NH2:21][NH2:22]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:21][NH2:22])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCN(C)CC2)c1
Reactant: NN
Solvent: CO
Product: CN1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Temperature: 65 °C
Yield: 60.6 %

Procedure:
Methyl 3-((4-methylpiperazin-1-yl)sulfonyl)benzoate (200 mg, 0.670 mmol) was added to the hydrazine (43.0 mg, 1.341 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography (3% methanol/DCM) to yield the 3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide (125 mg, 0.406 mmol, 60.6% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.08 (s, 1H), 8.12 (m, 2H), 7.84 (d, 1H, J=7.6 Hz), 7.72 (t, 1H, J=7.6 Hz), 4.57 (m, 1H), 2.88 (m, 4H), 2.32 (m, 4H), 2.10 (s, 3H). Mass [M+H]+:298.9
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:16][CH3:17])[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:8][C:7]1=O)([O:3][CH3:4])=[O:2].[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26]N)[CH3:19].C(Cl)(C)=O>CO>[CH3:4][O:3][C:1](=[O:2])[CH2:5][C:6]1([CH2:16][CH3:17])[C:7]2[NH:26][C:21]3[C:22](=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:18][CH3:19])[C:8]=2[CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH2:11]1
Reactant: CCc1ccccc1NN
Reactant: CCC1(CC(=O)OC)CCC(C2CC2)CC1=O
Solvent: CO
Solvent: CC(=O)Cl
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)CCC3C1CC1
Temperature: 0 °C
Yield: 33.8 %

Procedure:
The mixture of diastereomeric ketones (40 mmol, 9.52 g) prepared in Step (d) and 2-ethylphenylhydrazine (40 mmol, 5.45 g) were heated at reflux in 172 ml of MeOH for 60 hours, cooled to 0° C. and treated with 80 mmol (6.28 g, 5.7 ml) of AcCl. The reaction was refluxed an additional 45 minutes followed by removal of solvent in vacuo. Flash chromatography afforded 4.58 g (13.5 mmol, 34%) of orange oil containing a mixture of diastereomers.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(3-chloro-phenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.20 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.13 (d, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.58 (m, 2H), 7.95 (s, 1H), 8.12 (d, J=5 Hz, 1H), 9.95 (s, 1H); MS (ESI/APCI+) m/e 331 (M+H)+.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:13]([O:20][C@H:21]1[CH2:30][C@H:29](O)[C@H:28]2[C:23]([CH:24]=[CH:25][C@H:26]([CH3:49])[C@@H:27]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:35]2)=[CH:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Si:13]([O:20][C@H:21]1[CH2:30][C@H:29]([O:10][C:9](=[O:11])[CH:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:12])[C@H:28]2[C:23]([CH:24]=[CH:25][C@H:26]([CH3:49])[C@@H:27]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:44])[CH2:35]2)=[CH:22]1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(Oc1ccccc1)C(=O)O
Product: CC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 74.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 598 mg of (2RS)-2-phenoxypropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 944 mg of the title compound as a colorless foam.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=O.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C.[Pd]>[N:24]1([CH2:1][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[O:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reactant: C1CCNCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCCCOc1cccc(CN2CCCCC2)c1
Yield: 77.3 %

Procedure:
2-[3-[3-Formylphenoxy]propyl]-1H-isoindole-1,3-dione (50 g) and piperidine (20.7 g) in ethyl acetate (750 ml) were hydrogenated over 10% palladium/carbon catalyst. The catalyst was removed by filtration and the solvent evaporated and hydrazine hydrate (40 ml) was added to an ethanolic solution of the residue at 25°. After 67 hr the reaction mixture was diluted with ether, filtered and the filtrate was distilled to give the title compound as a colourless oil (31.05 g) b.p. 154°-8°/0.15 mm. TLC silica, methanol/0.88 ammonia 80:1, Rf 0.2.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH2:10]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:6][CH2:5][CH2:9][CH2:10][CH2:2][CH:3]=[CH2:4]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Product: C=CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
The procedures of Preparation Examples 18-20 were repeated except that 6 g 4-hydroxyl benzoic acid was replaced by 9.3 g 4-hydroxybiphenyl-4'-carboxylic acid, Yield: I-25: 67%; I-26: 89.8%; I-27: 80.6%. 1H-NMR:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([N:19]2[C:23]3[CH:24]=[C:25]([CH3:29])[C:26]([CH3:28])=[CH:27][C:22]=3[N:21]=[CH:20]2)[N:11]=1>>[CH3:28][C:26]1[C:25]([CH3:29])=[CH:24][C:23]2[N:19]([C:12]3[N:11]=[C:10]([NH:1][C@H:2]4[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]4)[N:18]=[C:17]4[C:13]=3[N:14]=[CH:15][NH:16]4)[CH:20]=[N:21][C:22]=2[CH:27]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Cc1cc2ncn(-c3nc(Cl)nc4[nH]cnc34)c2cc1C
Product: Cc1cc2ncn(-c3nc(N[C@H]4CC[C@H](N)CC4)nc4[nH]cnc34)c2cc1C
Temperature: 140 °C

Procedure:
570 mg of trans-1,4-diaminocyclohexane are brought to its melting temperature (70° C.), 149 mg of product obtained in stage 1 above are added in a single step, and the mixture is then heated at 140° C. for approximately 18 hours.