Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([C:29]#[N:30])[CH:19]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:18]2)=[O:16])=[N:10]1)(C)(C)C.C(O)(=O)C.O>CCOC(C)=O>[OH:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:20]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)([C:29]#[N:30])[CH:19]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:18]2)=[O:16])=[N:10]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.2 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide (65.2 mg, 0.0995 mmol), acetic acid (2.0 mL, 31 mmol), water (1 mL) and stirred at RT over the weekend (48 h). Reaction complete by 50%. The mixture was then diluted with EtOAc and washed with NaHCO3(s). The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated under reduced vacuum and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-amide (21.6 mg, 40.22%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[C:46](B(O)O)=[CH:45][C:44]([CH3:50])=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>O1CCOCC1.O>[C:35]([O:39][C:40]([N:42]1[C:46]([C:23]2[CH:24]=[CH:25][C:20]3[N:21]([C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)[N:19]=3)[CH:22]=2)=[CH:45][C:44]([CH3:50])=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Br)cn4c3-c3ccccc3)cc2)CCC1
Reactant: Cc1cc(B(O)O)n(C(=O)OC(C)(C)C)n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)n3c2)n(C(=O)OC(C)(C)C)n1
Temperature: 110 °C

Procedure:
A mixture of {1-[4-(6-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg) and 1-tert-butoxycarbonyl-3-methylpyrazole-5-boronic acid (44 mg) in dioxane (1 mL) and water (0.43 mL) was placed under argon and [1,1-bis-(diphenylphosphino)-ferrocene]-dichloropalladium-dichlormethane-complex (7.9 mg) added. The mixture was heated at 110° C. under microwave irradiation for 60 minutes. On cooling the mixture was partitioned between DCM and water and extracted. The organic portion was dried and concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O.[NH4+].[N:11]#[C:12][S-:13]>Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12]([NH2:11])=[S:13]
Reactant: N#C[S-]
Reactant: Nc1ccccc1Cl
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: NC(=S)Nc1ccccc1Cl
Temperature: 25 °C

Procedure:
2-Chloroaniline (23, 10.52 mL, 100 mmol) was dissolved in conc. HCl (9 mL) followed by H2O (25 mL). The mixture was heated at reflux for 30 minutes then allowed to cool to rom temperature. To this solution was added NH4SCN (7.61 g, 100 mmol) and the mixture was heated at reflux overnight. The reaction was allowed to cool to room temperature and a solid formed. The water layer was decanted off and the solid was dissolved in CH2Cl2 and the organic layer was washed in brine. The organic layer was dried over MgSO4, filtered and evaporated to give a residue, which was purified by flash silica gel chromatography.
Reaction SMILES: [OH: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+].[CH3:15]I>O1CCCC1>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC)cc1
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
A solution of methyl 4-hydroxyphenylacetate (25.0 g, 0.147 mol) in tetrahydrofuran (50 ml) was added dropwise to a stirred suspension of sodium hydride (4.45 g of an 80% dispersion in oil, 0.147 mol) in tetrahydrofuran (150 ml) and the mixture was stirred for 90 minutes. A solution of methyl iodide (20.9 g, 0.47 mol) in tetrahydrofuran (50 ml) was added dropwise and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate:hexane 1:9, to give methyl 4-methoxyphenylacetate (22.0 g) as a colourless oil.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)=[CH2:20])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:21]2[C:22]([O:33][CH3:34])=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2ccccc2)c1OC)c1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(-c2ccccc2)cccc1C(C)c1cccc(C(C)(C)C)c1O
Temperature: 65 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
A solution of 12 (1.05 g, 2.34 mmol) in methanol (30 mL) and ethyl acetate (60 mL) was treated with 20% palladium on activated carbon (50% wet, 0.10 g) and was hydrogenated at 30 psi in a Parr shaker for 16 hr. The catalyst was filtered out and washed with ethyl acetate. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (80 g) with 1% ethyl acetate in hexane (3 L). The relevant fractions were stripped and the residue was taken up in ethanol (10 mL) and stirred at 65° C. for 30 min. The resulting slurry was allowed to cool overnight. The crystals were collected by filtration, washed with cold ethanol and dried in a vacuum oven at 65° C. to produce pure B3 (0.29 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:12]([S:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33](Cl)=[CH:32][C:31]=1[CH:37]1[CH2:39][CH2:38]1)[C:25](=[O:40])[CH:24]=[CH:23]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O1CCOCC1>[CH2:12]([S:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)=[CH:32][C:31]=1[CH:37]1[CH2:39][CH2:38]1)[C:25](=[O:40])[CH:24]=[CH:23]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1ccc(Cl)cc1C1CC1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1ccc(-c2cc(F)cc(F)c2)cc1C1CC1
Temperature: 150 °C

Procedure:
A microwave vial charged with 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.254 g, 0.359 mmol), (3,5-difluorophenyl)boronic acid (1.133 g, 7.18 mmol), 6-(benzylthio)-1-(4-chloro-2-cyclopropylphenyl)quinolin-2(1H)-one (1.500 g, 3.59 mmol), potassium phosphate (2.285 g, 10.77 mmol) and 10 ml and dioxane 3 ml water was heated to 150° C. in a Biotage Initiator microwave reactor for 30 minutes. The organic layer was removed and concentrated. The crude residue was used in the following step without purification. m/z (ESI) 496.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[CH2:12][CH:11]([CH3:16])[CH2:10][CH2:9][C:8]=2[N:7]([C:17]2[C:18]([CH3:32])=[C:19](C([O-])=O)[C:20](C3C=CC=CC=3)=[CH:21][CH:22]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:33]([OH:36])(=[O:35])[CH3:34]>[OH-].[Na+]>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[CH2:12][CH:11]([CH3:16])[CH2:10][CH2:9][C:8]=2[N:7]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:6]3[C:34]([C:33]([OH:36])=[O:35])=[CH:3][CH:2]=[CH:1][CH:5]=3)=[CH:22][CH:32]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(-c2ccc(-c3ccccc3)c(C(=O)[O-])c2C)c2c(c1=O)CC(C)CC2
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2c(c1=O)CC(C)CC2
Temperature: 60 °C

Procedure:
Using the procedure of Example 31, 0.4 g of product A of Example 32 in 10 ml of 2N sodium hydroxide were reacted. The mixture was stirred over-night at about 60° C. and the medium was cooled to ambient temperature, acidified with glacial acetic acid, decanted, impasted in a solution of 2N hydrochloric acid, separated, dried and crystallized from 50 ml of an ethanol-water 49-1 mixture to obtain 0.220 g of the expected product melting at 255° C.
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C)=[CH:25][CH:24]=2)=[N:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(OC1C=NC(C2C=CC(CCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCCCC>>[CH2:1]([O:16][C:17]1[CH:22]=[N:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=2)=[N:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCC)cc2)nc1
Product: CCCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1

Procedure:
5-pentadecyloxy-2-(4-hexylphenyl)pyrimidine ##STR40## 5-pentadecyloxy-2-(4-heptylphenyl)pyrimidine 5-pentadecyloxy-2-(4-octylphenyl)pyrimidine ##STR41## 5-pentadecyloxy-2-(4-nonylphenyl)pyrimidine 5-pentadecyloxy-2-(4-decylphenyl)pyrimidine
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=O)[CH3:4].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[NH2:16][C:17]1[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][C:2]1[C:3]([CH3:4])=[N:16][C:17]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=[CH:26][C:27]=2[N:28]=1
Reactant: CCOC(=O)c1cccc(N)c1N
Reactant: CC(=O)C(C)=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cccc2nc(C)c(C)nc12
Temperature: 70 °C
Reaction time: 12 h
Yield: 67.2 %

Procedure:
2,3-Butanedione (0.0776 mol) was added at room temperature to a solution of sodium pyrosulfite (0.1 mol) in water (75 ml). The mixture was heated to 70° C. and then added to a solution of ethyl 2,3-diaminobenzoate (0.0776 mol) in water (75 ml). The mixture was stirred at 100° C. for 12 hours, cooled, basified with K2CO3 10% and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (17.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 93/7; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 12 g (67%) of ethyl 2,3-dimethyl-5-quinoxalinecarboxylate (interm. 6).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[CH2:3].[NH3:11]>>[NH2:11][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: N
Product: CC(C)(N)c1ccc(O)cc1

Procedure:
A 0.10-g sample of 4-(1-methylethenyl)phenol is exposed to excess, gaseous ammonia for about one day at 50° C. After excess ammonia is purged, a quantitative yield of 2-amino-2-(4-hydroxyphenyl)propane is obtained. No 1-amino-2-(4-hydroxyphenyl)propane is detectable by 60 MHz proton NMR.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].B(F)(F)F.CO.[CH:17]1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O.CCOC(C)=O.CO.C(Cl)Cl>[CH3:1][Si:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([O:8][CH3:17])=[O:7])[NH2:5]
Reactant: C[Si](C)(C)C[C@H](N)C(=O)O
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H](N)C[Si](C)(C)C
Temperature: 70 °C
Yield: 92 %

Procedure:
3-Trimethylsilyl alanine (J. Organomet. Chem., 628, (2001), 183–194; 19 mg, 0.118 mmol) was mixed with 3 ml BF3-MeOH (14%, 3.7 mmol) in a sealed tube and heated to 70° C. Analysis was performed using TLC (MeOH:DCM 1:9, stained w. ninhydrine in ethanol). The mixture was heated for 3 h and was then cooled to ambient temperature. The mixture was poured into a mixture of 3 ml EtOAc and 2 ml water containing Na2CO3. More Na2CO3 (5%-aq) was added until pH ca 7. The aqueous phase was washed with EtOAc (2×3 ml). The combined organic layers were washed with brine (1 ml), dried with Na2SO4 and evaporated. The product was obtained as a white film. Mass: 19 mg (92% yield). NMR (CDCl3): 0.1 (s, 9H), 1.2–1.4 (m, 2H), 3.8 (s, 3H), 4.2 (brs, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]([CH:10]([CH2:15][CH2:16][CH3:17])[C:11]([O:13]C)=[O:12])=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:7]=[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26]2)[N:5]=1>CO>[CH3:3][C:4]1[C:9]([CH:10]([CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=[O:12])=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:7]=[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26]2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(Oc3ccccc3)C2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCC(Oc3ccccc3)C2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of sodium hydroxide 5N (1 mL) was added to a mixture of methyl 2-(4-methyl-2-(3-phenoxypiperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.050 g; 0.053 mmol) in methanol (1 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N. The aqueous layer was extracted with ethyl acetate, dried and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 4) furnished 0.013 g (26%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([F:17])=[C:6](/[C:8](=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])[CH:7]=1.Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21](=[O:22])[C:20]([F:27])([F:26])[C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:18])=[CH:4][C:5]=1[F:17])([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH3:25]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(5-bromo-2,4-difluoro-phenyl)-eth-(E)-ylidene]-amide (intermediate A2E) and ethyl 2-bromo-2,2-difluoroacetate, the product (R)-3-(5-bromo-2,4-difluoro-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester was obtained as an orange oil. MS (ISP): m/z=462.1 [M+H]+ and 464.1 [M+2+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:3]=[N:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[CH2:28][CH2:27]2)[CH2:20]1
Reactant: CN1CCCC(CN2CCNCC2)C1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Product: CN1CCCC(CN2CCN(c3ccc(-c4ccc(C(F)(F)F)cc4)nn3)CC2)C1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (1-methylpiperidin-3-ylmethyl)piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[H-]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(N)=O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCCN)cc1OC
Temperature: 0 °C

Procedure:
A solution of 3-(3,4-dimethoxy-phenyl)-propionamide (11.1 g, 53.0 mmol) in anhydrous THF (400 ml) is slowly added to a stirred, ice-cooled suspension of LiAlH4 (4.02 g, 106 mmol) in anhydrous THF (170 mL). Upon completion of the addition, the mixture is stirred at reflux for 2 h. After cooling to 0° C., H2O (5 mL) and NaOH 1N (5 mL) are added dropwise to decompose the excess of hydride. The suspension is filtered and evaporated. The residue is partitioned between H2O (40 mL) and CH2Cl2 (100 mL). The organic layer is washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the title compound as a yellow oil.
Reaction SMILES: C([N:3](CC)[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH:9](C(C3C=CC=CC=3)C3C=CC=CC=3)[C:10]32[O:17][CH2:16][CH2:15][O:14]3)[CH2:7]1)=[O:5])C>C[O-].[Na+]>[CH2:15]1[CH2:16][O:17][C:10]2([CH2:9][N:8]3[CH2:13][CH2:12][CH:11]2[CH:6]([C:4]([NH2:3])=[O:5])[CH2:7]3)[O:14]1
Reactant: CCN(CC)C(=O)C1CN2CCC1C1(OCCO1)C2C(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)C1CN2CCC1C1(C2)OCCO1
Yield: 86.4 %

Procedure:
A suspension of 21 (9.8 g, 22 mmol) in sodium methoxide (28% in MeOH; 400 g) was heated at reflux temperature for 9 hours. The resulting solution was poured on ice (300 ml) and extracted with CH2Cl2 (150 ml) three times. The combined extracts were dried over sodium sulfate (Na2SO4) and concentrated. The clude was purified by recrystallization from ethanol (EtOH) to give 22 (1:4 mixture at 6-position ; 8.4 9, 19 mmol, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:18]=1[C:29]([F:32])([F:31])[F:30].Cl>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:17]2[C:18]([C:29]([F:31])([F:32])[F:30])=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[C:9](=[O:13])[O:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)Nc1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)N(c1cccc(Cl)c1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.3 %

Procedure:
Ethyl 3-chlorophenylcarbamate (1.0256 g) was dissolved in diglyme (3 ml), and to the solution were added sodium hydride (205.5 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (1.1583 g). The reaction mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=5:1) and recrystallized from hexane-ethyl acetate to give the title compound (0.7854 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.OC1C=CC(C2C=CC(Cl)=CC=2)=CC=1C=O.[CH2:31]([C:33](CC)([C:37]([O-])=[O:38])[C:34]([O-:36])=[O:35])C.N1CCCCC1.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]3[C:11](=[CH:10][CH:9]=2)[O:14][C:37](=[O:38])[C:33]([C:34]([OH:36])=[O:35])=[CH:31]3)=[CH:6][CH:7]=1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=Cc1cc(-c2ccc(Cl)cc2)ccc1O
Solvent: C1CCNCC1
Product: O=C(O)c1cc2cc(-c3ccc(Cl)cc3)ccc2oc1=O
Reaction time: 2 h

Procedure:
4-(p-Chlorophenyl)phenol is converted via the Duff reaction [J. Chem. Soc., 547 (1941)] to 2-hydroxy-5-(p-chlorophenyl)benzaldehyde, mp. 74°-78° C. i.r. 6.02μ. A solution of 2]3 mg. (1 mmole) of this aldehyde, 0.4 ml. (2.63 mmole) of diethylmalonate and 0.2 ml. (2 mmole) of piperidine is heated for 10 minutes and kept at 25° C. for 2 hours. Then 5 ml. of 9 N HCl is added and the mixture stirred at reflux overnight. The mixture is cooled in an ice bath and filtered to yield 238 mg. of the desired compound, i.r. 5.74, 5.9μ.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:21]([NH:37][CH2:38][CH2:39][C:40](Cl)=[O:41])([C:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:29]([N:30]([CH3:32])[CH3:31])[C:28]=2[CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22]>CN(C)C=O>[S:21]([NH:37][CH2:38][CH2:39][C:40]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[O:41])([C:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:29]([N:30]([CH3:32])[CH3:31])[C:28]=2[CH:27]=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)Cl)cccc12
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)c3ccccc3S(=O)(=O)N=[N+]=[N-])cccc12
Reaction time: 24 h

Procedure:
To 152 mg (0.8 mmol) of para-amino-benzenesulfonyl azide dissolved in 5 mL dimethylformamide was added 0.11 mL (6 mmol) triethylamine, then 0.5 mmol N-Dansyl 3 aminopropanoyl chloride dissolved in 10 mL dimethylformamide was added dropwise. The mixture was stirred under argon for 24 hrs. The solvent was evaporated, the remaining oil was purified by chromatography on silica (Eluent Toluol/Aceticacidethylester 1:1). The fractions containing the product were collected and the solution was evaporated.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[CH2:25][CH2:24]3)O1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C(O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:10]1[CH:11]=[CH:12][C:7]([C:3]2[O:4][CH:5]=[CH:6][C:2]=2[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[CH2:25][CH2:24]3)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Reactant: Brc1ccoc1-c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=C1CCc2cc(-c3ccoc3-c3ccncc3)ccc21
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A solution of the product of Example 5 Step 5 (0.22 g, 1 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)indanone (0.25 g, 1 mmol) (WO98/45265) and potassium acetate (294 mg, 3 mmol) in dimethylformamide (2 ml), ethanol (2 ml) and water (2 ml) was treated with palladium (II) acetate (12 mg, 0.05 mmol) and triphenylphosphine (26.2 mg, 0.1 mmol) and heated under reflux for 5 hours. The reaction mixture was cooled to room temperature filtered through celite and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate (1:1) and methanol/ethyl acetate (1:9) to afford the title compound (0.17 g, 62%); MS(ES+) m/e 276 [M+H]+.