Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[Na+].O>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:2]2[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][N:1]2[CH2:6][CH2:5]3)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C(=Cc2ccc(Cl)cc2)N2CCC1CC2
Reaction time: 48 h
Yield: 79.9 %

Procedure:
A solution of 3-quinuclidinone (54.5 g), 4-chlorobenzaldehyde (84.0 g) and sodium hydroxide (3.50 g) in absolute ethanol (400 cm3) was heated at reflux for 2.5 hours. The mixture was cooled and addition of water (100 cm3) caused the product to precipitate as an orange solid. The precipitate was collected and washed with 1:1 ethanol-water (400 cm3). The mother-liquors were stood for 2 days, after which time further precipitated material was collected. The orange solid was redissolved in dichloromethane (800 cm3) and washed with water (200 cm3). The organic phase was dried (MgSO4), filtered and evaporated to dryness to give the title compound as a bright yellow powder (86.2 g, 76%), mp. 108°-110° C.; δH (360 MHz; CDCl3) 1.99-2.05 (4H, m, 2×NCH2CH2), 2.63 [(1H, quintet, J=2.9, (CH2)2CH], 2.92-3.01 (2H, m, 2×NCH), 3.11-3.19 (2H, m, 2×NCH), 6.95 (1H, s, C=CH), 7.33 (2H, d, J=8.6, 2×ArH o to Cl) and 7.98 (2H, d, J=8.6, 2×ArH m to Cl); m/z (CI+ ; NH3) 248 (M+ +H, 100%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[ClH:11].[CH3:12][CH2:13][CH:14]([N:16]1[N:21]=[CH:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][C@@H:42]5[O:46][C@:45]([C:53]6[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][C:54]=6[Cl:60])([CH2:47][N:48]6[N:52]=[CH:51][N:50]=[CH:49]6)[O:44][CH2:43]5)=[CH:36][CH:35]=4)[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[C:17]1=[O:18])[CH3:15].COC(C)(C)C>O1CCOCC1>[CH3:12][CH2:13][CH:14]([N:16]1[N:21]=[CH:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][C@@H:42]5[O:46][C@:45]([C:53]6[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][C:54]=6[Cl:60])([CH2:47][N:48]6[N:52]=[CH:51][N:50]=[CH:49]6)[O:44][CH2:43]5)=[CH:36][CH:35]=4)[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[C:17]1=[O:18])[CH3:15].[ClH:11].[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@H]5CO[C@](Cn6cncn6)(c6ccc(Cl)cc6Cl)O5)cc4)CC3)cc2)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C

Procedure:
Co-crystals of itraconazole HCl and tartaric acid were prepared. Approximately 212.7 mg of L-tartaric acid and 118 microL of 37% HCl were dissolved in 25 mL of hot dioxane. This solution was added to 1.0 g of cis-itraconazole dissolved in 50 mL of hot dioxane with stirring. The mixture was heated until a clear solution formed and was then allowed to cool to room temperature. Upon cooling, 50 mL tert-butyl methyl ether was added and the crystals were harvested by vacuum filtration on a Buchner funnel with #4 Whatman filter paper. The crystals were washed 3 times with 5 mL aliquots of cold tert-butyl methyl ether and left to air dry. Approximately 573 mg of a crystalline form of cis-itraconazole HCl-tartaric acid (1:1:0.5) co-crystal were obtained. (See FIGS. 20 and 21)
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[O:22][CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:40][NH:41]2)C1C=CC=CC=1)C>>[CH3:23][O:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][C:4]([NH:41][CH3:40])=[O:3])[CH:14]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(OC)c2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(OC)c2c1

Procedure:
The amide compound CCXII was prepared from 3-(3-methoxy-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH:15]1([CH2:21]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH:15]1([CH2:21][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1oc(=O)n(CC2CCCCC2)c2ccccc12
Temperature: 60 °C
Yield: 23.1 %

Procedure:
815 mg (5 mmol) of isatoic acid anhydride is dissolved in 15 ml of N,N-dimethylacetamide and mixed under cover gas and in a moisture-free environment with 220 mg (5.5 mmol) of sodium hydride (60% dispersion in mineral oil). It is heated for 1 hour to 60° C. After cooling, 885 mg (5 mmol) of cyclohexylmethyl bromide is added, and the batch is heated to 60° C. for 4 hours. It is then diluted with water to 60 ml and shaken out three times with ethyl acetate. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 300 mg of N-cyclohexylmethylisatoic acid anhydride is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][NH:13][CH3:14])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:20]([Si:23]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])Cl)([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][CH2:10][O:11][Si:23]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:20]([CH3:22])[CH3:21])[CH2:12][NH:13][CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CNCC(CCO)c1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CNCC(CCO[Si](C(C)C)(C(C)C)C(C)C)c1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
3-(4-Bromophenyl)-4-(methylamino)butan-1-ol (see Chem. Pharm. Bull. 46, 1998, 242; 1.77 g, 6.86 mmol) was dissolved in CH2Cl2 (100 mL) at 0° C. under argon. Imidazole (1.22 g, 17.9 mmol) was added, the mixture stirred for 10 min and then triisopropylchlorosilan (3.16 g, 16.4 mmol) was added with cooling. The mixture was stirred at room temperature for 48 h and then washed twice with water (100 mL) and brine. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (CH2Cl2-Methanol-NH4OH, 15:1:0.1). There was obtained 2.17 g (75%) of {2-(4-bromophenyl)-4-[(triisopropylsilyl)oxy]butyl}methylamine as an oil. 1H NMR (300 MHz, CDCl3): 0.9-1.1 (m, 21H), 1.6-1.9 (m, 2H), 2.4 (s, 3H), 2.7-2.8 (m, 2H), 3.0-3.1 (m, 1H), 3.4-3.6 (m, 2H), 7.1 (d, 2H), 7.4 (d, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][CH:19](OC)OC>CN(C)C=O.C(OC(=O)C)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17][O:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)OC
Reactant: CC(C)(C)c1ccc2c(c1)CC(=O)NC2=O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Temperature: 120 °C

Procedure:
6-tert-Butyl-4H-isoquinoline-1,3-dione (45 mg, 0.21 mmol) is dissolved in N,N-dimethylformamide (1 mL) and acetic anhydride (2 mL). Trimethylorthoformate (0.2 mL) is added and the mixture is heated to 120° C. for 1 hour. The volatiles were removed under vacuum and the residue passed through a column to afford the crude product, is used directly in the next step. MS (ESI): 258.3 (M−1)−1.
Reaction SMILES: C(=[N:14][C:15]1([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:19][CH2:18][O:17][C:16]1=[O:20])(C1C=CC=CC=1)C1C=CC=CC=1>Cl.C1COCC1>[NH2:14][C:15]1([CH2:21][C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH2:19][CH2:18][O:17][C:16]1=[O:20]
Reactant: O=C1OCCC1(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: NC1(Cc2ccncc2)CCOC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
3-(Benzhydrylidene-amino)-3-pyridin-4-ylmethyl-dihydro-furan-2-one (1.67 g, 4.69 mMol) was dissolved in a solution of 1 N HCl (20 mL) in THF (50 mL). The mixture was stirred for 1 hour at ambient temperature after which time it was partitioned between ethyl ether (Et2O) and water. The water layer was washed again with Et2O and then adjusted to pH 8 with NaHCO3. The aqueous layer was then extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated under vacuum to give 630 mg of the titled compound as an oil
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccn1
Yield: 24.4 %

Procedure:
By the method of Example 20, 10 g (0.09 mole) of 2-fluoro-4-methylpyridine and 16 g (0.09 mole) of N-bromosuccinimide were reacted in 90 ml of carbon tetrachloride to produce 4.18 g 4-bromomethyl-2-fluoropyridine. The ir, proton nmr, and 19F nmr spectra were all consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][OH:19]>C(#N)C>[OH:19][CH2:18][CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OCCBr
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CCc2ccccc21

Procedure:
To a stirred mixture of 24 parts of indoline and 83 parts of powdered anhydrous potassium carbonate in 150 parts of acetonitrile was added 50 parts of 2-bromoethanol. The mixture was gradually warmed to reflux and kept at reflux temperature for 8 hours. The mixture was filtered and the solvent was removed. The product was purified by column chromatography on a silica gel column. The eluents were 1:1 mixture of hexane with methylene chloride and then ethyl acetate. The product was 29 parts with a boiling point of 118° C. at 0.5 torr. Proton and carbon-13 NMR spectra were consistent with structure.
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:3].[C:10](#[N:14])/[CH:11]=[CH:12]/[CH3:13]>C(O)C>[NH2:14][C:10]1[CH2:11][CH:12]([CH3:13])[N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:3]=1
Reactant: NNc1ccccn1
Reactant: C/C=C/C#N
Agent: [Na]
Solvent: CCO
Product: CC1CC(N)=NN1c1ccccn1

Procedure:
A 0.3 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 5.45 g. of 2-hydrazinopyridine is added, followed by 3.35 g. of crotononitrile (mixture of cis or trans isomers). The reaction mixture is refluxed for 3 hours, then the solvent is removed in vacuo. Water is added and the solid is collected by filtration. The solid is recrystallized from dichloromethane-hexane, then acetone-hexane to give 3.1 g. of the product of the Example as yellow crystals, m.p. 154°-157° C.
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].C(O[C:20]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)(C)(C)C>[OH-].[K+].C(O)C>[C:26]([O:25][C:23]([O:22][C:20]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 28 °C
Yield: 63 %

Procedure:
A solution comprising 0.49 grams potassium hydroxide, 40 grams of 4-acetoxystyrene, and 100 grams of absolute ethanol was refluxed for 4 hours. The reaction solution was cooled to 28° C. and 13 grams of potassium hydroxide pellets were added over a period of 10 minutes. After an additional 30 minutes of reaction, 64 grams di-tertiary-butyl-dicarbonate was charged portionwise over 20 minutes and the reaction was stirred for an additional hour at 28° C. After aqueous washing, the reaction product was extracted with ethyl acetate. The ethyl acetate was stripped from the extraction mixture on a rotary evaporator and the residual oil was charged with 0.07 grams phenothiazine. Distillation at 0.1 mm Hg gave 34.2 grams (64%) 4-tertiary-butoxycarbonyloxystyrene.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([CH2:27][C:28]([OH:30])=O)[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:28](=[O:30])[CH2:27][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:26])=[CH:21][CH:22]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)Cc1ccc(CC(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Yield: 91.8 %

Procedure:
Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzyl ester hydrochloride and 400 mg (2.1 mmol) 1,4-phenylenediacetic acid afforded, after flash chromatography (EtOAc), 1.07 g (91%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:22]([CH2:31][CH3:32])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:22]([CH2:31][CH3:32])=[CH:21][C:20]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCC#N
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCC#N
Reaction time: 24 h
Yield: 70.5 %

Procedure:
4-fluorobenzene boronic acid (1.14 g) was dissolved in ethanol (7 mL). To this was added 1-(benzyloxy)-2-bromo-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene (1.5 g), toluene (20 mL), tetrakis-triphenylphosphine palladium (470 mg), and 2M sodium carbonate solution (6.1 mL). The resulting mixture was heated to reflux and held there for 24 hours. The solution was cooled, diluted with ethyl acetate, and the layers separated. The organic layer was washed with saturated ammonium chloride, dried over magnesium sulfate, filtered, and concentrated to afford a green oil. This was purified by flash chromatography on silica using hexane/ethyl acetate (9:1). The resulting fractions were concentrated under vacuum to afford 1-Benzyloxy-2-(4-fluorophenyl)-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene (1.1 g) as a clear oil. NMR (CDCl3): 1.18, t (3H); 2.15, m (2H); 2.59, m (4H); 4.06, t (2H); 5.00, s (2H); 6.53, s (1H); 7.06, t (2H); 7.09, s (1H); 7.30, m (5H); 7.49, d of d (2H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:14])=[CH:6][C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[CH3:15][CH2:16][CH:17]([OH:20])[CH2:18][CH3:19]>CN(C=O)C>[CH2:16]([CH:17]([O:20][C:4]1[C:5]([CH3:14])=[CH:6][C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)[CH2:18][CH3:19])[CH3:15]
Reactant: Cc1cc2nnc(N)n2nc1Cl
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn2c(N)nnc2cc1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Pentanol (30 ml) was initially charged under argon, admixed with sodium hydride (1.48 g) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.005, 1.88 g), dissolved in 3-pentanol (130 ml) and DMF (60 ml), was slowly added dropwise within 1 h. After stirring for 1 h, the mixture was concentrated, and the residue was admixed with water and extracted four times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using an 80 g silica gel cartridge (0-10% dichloromethane-methanol gradient in 40 min). The clean product fractions were combined and dried. 1.25 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)CCC1(c2ccc(F)c(F)c2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC1(c2ccc(F)c(F)c2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)propanoate (Int. 3-D, 540 mg, 1.822 mmol) in MeOH (15 mL) was added 1N NaOH (3.64 mL, 3.64 mmol), and the mixture was stirred at room temperature for 20 hrs. Since the reaction was not complete on TLC, an additional 1.82 mL of 1N NaOH was added, and it was continued to stir for 3 hrs. TLC showed that the reaction was complete. Next, the reaction mixture was acidified with the addition of 6 mL of 1N HCl, and the product was extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4, and evaporated to give 3-(1-(3,4-difluorophenyl)cyclohexyl)propanoic acid (Int. 3, 489 mg, 1.822 mmol, 100% yield) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+]>CO>[C:12]1([S:9]([CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][C:3]([OH:18])=[O:2])(=[O:11])=[O:10])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C=CC=CCS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=CC=CCS(=O)(=O)c1ccccc1
Temperature: 20 °C
Yield: 88.4 %

Procedure:
To a solution of the 6-benzenesulfonyl-hexa-2,4-dienoic acid methyl ester (0.70 g, 2.60 mmol) in methanol (8 mL) were added a aqueous sodium hydroxide 1M, 6.0 mL, 6 mmol) and distilled water (20 mL). After stirring at reflux for 1 hour, the mixture was allowed to cool to 20° C. and was concentrated under reduced pressure. The aqueous solution was washed with diethyl ether (50 mL) and then poured onto a mixture of ethyl acetate (50 mL) and hydrochloric acid (2M, 5 mL) at 0° C. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate (20 mL), distilled water (20 mL), and brine (20 mL), then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a pale yellow solid that was recrystallised from ethyl acetate to give the title compound (0.58 g, 87%) as a white solid, mp 148-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl.[OH2:25].[OH-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:22]([NH2:23])=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: O
Reactant: COc1ccc(-c2nc(C#N)c(N)nc2-c2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile (500 mg) was dissolved in dioxane (10 ml) and conc. HCl (5 ml). The solution was stirred at 80° C. for 5 hours. The reaction mixture was cooled to 25-30° C. and concentrated in vacuo to give a residue. To the residue was added water and 1N NaOH to adjust the pH of the aqueous mixture to 6-7. The precipitated crystals were collected by filtration dried in vacuo to give 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (390 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17](=[O:37])[C@@H:18]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C@H:25]([OH:28])[CH2:26][Cl:27])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:12]([O:16][C:17](=[O:37])[C@@H:18]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[CH2:24][C@H:25]([OH:28])[CH2:26][Cl:27])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCl)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@H](O)CCl)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93.1 %

Procedure:
A solution of benzyl chloroformate (1.21 g, 7.09 mmol) in chloroform (10 mL) was added over a period of 15 min to an ice-cold solution of 12a (2.16 g, 5.46 mmol) in chloroform (40 mL) under an Ar atmosphere. After dropwise addition of triethylamine (1.11 g, 11.0 mmol) in chloroform (10 mL), the reaction mixture was stirred for 4.5 hours at rt. The reaction mixture was extracted with 1 N HCl (60 mL) and water (60 mL), dried, and concentrated. The residue was purified by flash chromatography (33% ethyl acetate/hexane) to give 13a (2.69 g, 93%) as a colorless oil: 1H NMR 61.30-1.83 (m, 6H), 1.44 (s, 9H), 1.45 (s, 9H), 3.20-3.64 (m, 6H), 3.93 (dd, 1H, J=8.2; 5.5), 4.00 (m, 1H), 5.12 (s, 2H), 7.26-7.40 (m, 5H); 13C NMR δ 24.1, 28.3, 28.8, 32.5, 49.4, 51.4, 52.2, 55.7, 68.4, 71.0, 80.4, 82.5, 129.0, 129.1, 129.6, 138.0, 157.5-158.4 (br), 158.1, 173.7; HRMS m/z calcd for C26H42ClN2O7 529.2681, found 529.2694. Anal. calcd. for C26H41ClN2O7: C 59.03, H 7.81, N 5.29. Found: C 59.09, H 7.78, N 5.21. [α]23D−21.8° (c 1.00, CH3OH).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH2:13][CH2:12]2.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCNC2
Temperature: 70 °C

Procedure:
To a suspension of lithium aluminum hydride (10 g, 46 mmol) in tetrahydrofuran (100 mL) at 0° C. under nitrogen was added slowly a solution of the product of Example 53B (4.1 g, 23 mmol) in tetrahydrofuran (50 mL) over 0.5 hours and the mixture was heated at 70° C. for 2 hours. After cooling to 0° C., 15% sodium hydroxide (4.9 mL) was added slowly and the mixture was filtered and washed with ethyl acetate (50 mL). The filtrate was concentrated to give the crude title compound. MS: 164 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[S:21][N:20]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>[Ni].C(N(CC)CC)C>[S:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:18][CH2:17]2)=[N:20]1
Reactant: O=[N+]([O-])c1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1
Yield: 100 %

Procedure:
4-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine was prepared according to the general method as outlined in Preparation 3 starting from 3-{4-[3-(4-nitro-phenyl)-propyl]-piperazin-1-yl}-1,2-benzoisothiazole (0.58 g, 1.52 mmol), 50 mL of THF treated with triethylamine (0.3 mL) and wet Raney nickel (0.56 g). The resultant solid was dried in vacuo (0.535 g, 1.52 mmol). Yield 100%; MS (APCI): 353 [M+H]+.