Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=1[CH:12]=O)([O-:3])=[O:2].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[CH:19]=[CH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:12]=[CH:19][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:18]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(C=O)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(C=CC(=O)OCC)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
The 2-nitro-1,3-benzenedialdehyde (3.4 g, 0.019 mole) is dissolved in toluene (60 ml) and carbethoxymethylene triphenylphosphorane (19.2 g, 0.06 mole) is added. The mixture is heated at 60° C. for eight hours, cooled, and concentrated at reduced pressure. Diethyl ether (100 ml) is added and the mixture is filtered. The filtrate is concentrated and purified by flash chromatography over silica (elution with 4:1 hexane:ethyl acetate) to afford after concentration pure 2-nitro-1,3-benzenediacrylic acid diethyl ester, mp 114°-115° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:24][NH:25][CH3:26].C[Si](Cl)(C)C.O>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH3:26])[CH3:24])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(C)C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of dichloromethane. 1.63 g of dimethylamine HCl (0.02 mol, 1 eq) is added and the reaction mixture is cooled to 0° C. 0.43 g TMSCl (0.004 mol, 0.2 eq) is added in 5 min. The reaction mixture is heated to room temperature and stirred for 5 hours. 50 mL of water is added to the mixture, it is stirred for 15 min and the phases are separated. The organic phase is washed with 30 mL of water then it is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 4.68 g of the title compound (VIb) (70%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[F:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23].O>CN(C)C=O>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH:14]2[CH2:15][CH2:16][CH2:17][CH:13]2[F:12])[CH:20]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1F
Reaction time: 0.67 h

Procedure:
A suspension of sodium hydride (0.3; 60% oil dispersion) in dimethylformamide (5 mL) is treated with 4-amino-3,5-dichloropyridine (0.62 g) and the mixture is stirred for 40 minutes. A solution of 3-(2-fluoro-cyclopentyloxy)-4-methoxybenzoyl chloride in dimethylformamide (12 mL) is added, and the mixture is stirred at 80-90° C. for 1 day. The solution is cooled, poured into water (75 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried over magnesium sulfate and concentrated. The residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and petroleum ether (1:3 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-(2-fluorocyclopentyloxy)-4-methoxybenzamide (0.26 g), m.p. 167-169° C. [Elemental analysis: C,53.8; H,4.2; N,6.75; Cl,17.8%; calculated: C,54.15; H,4.3; N,7.0; Cl,17.8%].
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].Cl[O-].[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1OC
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1OC
Reaction time: 2 h
Yield: 88 %

Procedure:
3-butyryl-4-(2-methoxyphenylamino)-8-(2-methylthioethoxy)quinoline (0.35 g, 0.85 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.42 ml) were added and the mixture was stirred for 2 h. Another portion of sodium hypochlorite (0.5 ml) was added and the stirring was continued for 2 h. The organic layer was dried over sodium sulfate and evaporated. The residue crystallized from a mixture of ethyl acetate and isopropyl ether and 0.32 g (88%) of the title compound was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: OCCCCl
Product: O=C1CCN(CCCO)CC1

Procedure:
1-(3-Hydroxypropyl)-4-piperidone is prepared from 4-piperidone and 3-chloro-1-propanol essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[O:9]C(=O)[NH:7][C:6]=2[CH:13]=1.[Br:14][C:15]1[C:16]([CH3:22])=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C1(C)C(C)=CC=CC=1>[NH2:7][C:6]1[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:10]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[C:16]=1[CH3:22])=[O:9]
Reactant: Cc1c(N)cccc1Br
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Solvent: Cc1ccccc1C
Product: Cc1c(Br)cccc1NC(=O)c1ccc(F)cc1N
Yield: 40.9 %

Procedure:
A mixture of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (5.00 g, 27.6 mmol) and 3-bromo-2-methylaniline (5.14 g, 27.6 mmol) in xylene (50 mL) was heated at reflux for 8 h. The cooled mixture was filtered. The collected solid was washed with 3 times with DCM and the combined filtrates were concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-45%), to give 2-amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide (3.65 g, 41% yield). Mass spectrum m/z 323, 325 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.65 (1 H, d, J=8.14 Hz), 7.45-7.57 (3 H, m), 7.14 (1 H, t, J=8.03 Hz), 6.39-6.50 (2 H, m), 5.80 (2 H, br. s.), 2.43 (3 H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1.[CH2:25]([Mg]Br)[CH3:26]>C1COCC1.CN1C(=O)CCC1>[CH2:25]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1)[CH3:26]
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(Cl)n1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCc1nc(SC)ncc1-c1ccnc(Nc2ccc(C#N)cc2)n1
Yield: 26.7 %

Procedure:
4-(4′-Chloro-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile (35) (205 mg, 0.526 mmol) and ferric acetylacetonate (18.57 mg, 0.053 mmol) were dissolved in THF (3305 μl) and NMP (248 μl), then ethylmagnesium bromide (789 μl, 0.789 mmol) was added dropwise under nitrogen. The reaction was quenched with 1N HCl, then was extract with EtOAc. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was dry-loaded onto silica gel and purified by Biotage™ silica gel chromatography [25 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] to obtain 49 mg of the desired product (21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.58 Hz, 3H) 2.59 (s, 3H) 2.95 (q, J=7.58 Hz, 2H) 7.25 (d, J=5.05 Hz, 1H) 7.68-7.78 (m, 2H) 7.95-8.03 (m, 2H) 8.67-8.75 (m, 2H) 10.33 (s, 1H). MS (ES+): m/z=349.5 [M+1] (100). HPLC: tR=1.57 minutes over 3 minutes. Purity: 93% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O)C.C(OC([N:35]=[C:36]=[S:37])=O)C>>[Si:23]([O:22][CH:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:12][N:11]1[C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4](=[O:3])[NH:35][C:36]1=[S:37])([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1[nH]ccc1NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Reactant: CCOC(=O)N=C=S
Product: COc1ccc(C(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)O[Si](C)(C)C(C)(C)C)cc1
Yield: 52.3 %

Procedure:
The title compound (0.07 g, 90%) was prepared in accordance with general method B using 3-{[2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methoxyphenyl)ethyl]amino}-1H-pyrrole-2-carboxylic acid ethyl ester (0.13 g, 0.31 mmol) and ethoxycarbonyl isothiocyanate (0.042 mL, 0.37 mmol).
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][CH2:10]O.[BrH:12]>>[BrH:12].[BrH:12].[NH2:7][CH2:8][CH2:9][CH2:10][S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1
Reactant: NCCCO
Reactant: Sc1ncc[nH]1
Agent: Br
Product: NCCCSc1ncc[nH]1

Procedure:
A solution of 2-mercaptoimidazole (2 g.) and 3-aminopropanol (1.14 ml.) in hydrobromic acid (48%, 25 ml.) was heated under reflux for 25 hours. The reaction mixture was evaporated to dryness and the oily residual solid recrystallised twice from ethanol/ether to give 2-(3-aminopropylmercapto)imidazole dihydrobromide (3.55 g.) m.p. 160°-162°.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]2[C:8]([CH3:17])([CH3:16])[CH2:7][CH2:6][C:5]([CH3:19])([CH3:18])[C:4]=2[CH:3]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:10][C:9]2[C:8]([CH3:17])([CH3:16])[CH2:7][CH2:6][C:5]([CH3:19])([CH3:18])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO)c(Br)cc21
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(Br)cc21
Yield: 66.1 %

Procedure:
To a solution of 10.2 g (31.55 mmol) of 2-bromo-3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 80 mL of dimethlformamide was added 9.46 g (138.8 mmol) of imidazole and 10.46 g (69.4 mmol) of tert-butyldimethylsilyl chloride. After 4 hours the reaction mixture was diluted with diethyl ether and washed with 1 N aqueous ammonium chloride and brine. The organic fraction was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 1-2% ethyl acetate/hexane) to afford 9.17 g (66%) of 2-bromo-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>N1C=CC=CC=1.O1CCCC1>[N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:19](=[O:22])[CH2:20][CH3:21])[CH3:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(c1cccc(OCCCN)c1)N1CCCC1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(=O)NCCCOc1cccc(C(C)N2CCCC2)c1
Yield: 71.3 %

Procedure:
211.8 mg of 3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine was dissolved in 2 ml of dry pyridine, and the solution was stirred under ice cooling. A solution of 87 mg of propionyl chloride in 2 ml of dry tetrahydrofuran was added dropwise in small portions. After the addition, the reaction temperature was adjusted to room temperature, and the mixturwe was stirred for 2 hours. The solvent was distilled off, and 10 ml of water was added. Furthermore, 300 mg of potassium carbonate was added. The precipitated oily product was extracted with 30 ml of chloroform. The extract was dried over anhydrous potassium carbonate, and the solvent was distilled off. The residue was purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 185 mg of N-[3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propyl] propionamide as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:23][Li]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [Li]C
Reactant: CSc1ccc2cnnc(-c3ccc(NC(C)=O)cc3)c2c1
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(c1ccc(NC(C)=O)cc1)=NNC2C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the phthalazine 7 (1.2 g, 3.88 mmol) in THF (150 mL) was added methyl lithium (1.4 M, 11 mL) at 0° C. The resulting dark brown solution was stirred 2 hours. Ice water was added to quench the reaction. The aqueous phase was extracted with DCM three times. The combined organic phase was dried over Na2SO4. Removal of the solvent afforded the crude product, which was used directly for the next step.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([NH:25][C@@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[N:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:12][C:5]=2[N:4]=[CH:3]1.[O:31]([C:33]#[N:34])[K].Cl>CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([NH:25][C@@H:26]3[CH2:30][CH2:29][N:28]([C:33]([NH2:34])=[O:31])[CH2:27]3)=[N:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:12][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(N[C@@H]3CCNC3)c2c1=O
Reactant: N#CO[K]
Agent: Cl
Solvent: CO
Product: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(N[C@@H]3CCN(C(N)=O)C3)c2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-methyl-7-(4-morpholinophenyl)-5-(pyrrolidin-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one (8.0 mg, 0.0197 mmol) in methanol (0.2 mL) were added KOCN (2.9 mg, 0.0354 mmol) and 1N aqueous HCl solution (19.7 μL, 0.0197 mmol). The reaction mixture was stirred at room temperature overnight, evaporated under vacuo, and purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C23H27N7O3 (M+H+) 450.2, found 450.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:19]([CH3:22])([O-:21])=[O:20].Cl.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@H:10]([OH:11])[CH2:22][N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@H](O)C[N+](=O)[O-]
Yield: 60.6 %

Procedure:
To a stirred solution of 62.3 mg (0.25 mmol) of (R)-2-t-butoxycarbonylamino-3-phenylpropanal [synthesized by the method described in Journal of Medicinal Chemistry, 130, 1162 (1987)] in 1.0 ml of THF was added at 0° C., 0.27 ml (5 mmol) of nitromethane, followed by dropwise addition of 0.5 ml (0.025 mmol) of the lanthanum/(R)-1,1'-bi-2-naphthol complex solution (Reference Example 1, 0.05 mol/l). The resultant mixture was stirred at 0° C. for 2 hours. To this solution were added 0.5 ml of 1N hydrochloric acid and 3 ml of water. The mixture was extracted with diethylether, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent; n-hexane-ethyl acetate 8:2) to give 47 mg of ⟦(2S,3R)⟧ (2R,3R)-3-t-butoxycarbonylamino-1-nitro-4-phenyl-2-butanol. Yield 60%. ⟦(2S,3R)⟧ (2R,3R)-3-t-Butoxycarbonylamino-1-nitro-4-phenyl-2-butanol:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](Br)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:12].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([C:8]2[CH:9]=[CH:10][C:5]3[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:6]=3[CH:7]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1c(=O)[nH]c2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)c1
Product: Cn1c(=O)[nH]c2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared from 1-methyl-6-bromo-1,3-dihydro-benzoimidazol-2-one and 3-chloro-phenyl boronic acid in the same fashion as that of Example 5. mp 219-220° C.; 1H-NMR (DMSO-d6) δ11.0 (s, 1H), 7.75 (bs, 1H), 7.65 (dd, 1H, J=7.5, 1.76 Hz), 7.49-7.44 (m, 2H), 7.39-7.32 (m, 2H), 7.06 (d, 1H, J=7.94 Hz), 3.35 (s, 3H); MS (ES) m/z 259([M+H]+, 100%); Anal. Calc. For C14H11ClN2O: C, 65; H, 4.29; N, 10.83. Found: C, 64.44; H, 4.36; N, 10.6.
Reaction SMILES: [NH2:1][C:2]([C:27]#[N:28])([CH3:26])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[Cl:25])[C:8]#[N:9].C(NC(C)C)(C)C.[F:36][C:37]([F:49])([F:48])[S:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>ClCCl>[C:27]([C:2]([NH:1][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([S:38][C:37]([F:49])([F:36])[F:48])=[CH:40][CH:41]=1)([CH3:26])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][C:15]=1[Cl:25])#[N:28]
Reactant: O=C(Cl)c1ccc(SC(F)(F)F)cc1
Reactant: CC(N)(C#N)COc1cc(C#N)ccc1Oc1ccc(OC(F)(F)F)cc1Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(C#N)(COc1cc(C#N)ccc1Oc1ccc(OC(F)(F)F)cc1Cl)NC(=O)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
21.5 g of 3-(2-amino-2-cyano-2-methyl-ethoxy)-4-(2-chloro-4-trifluoromethoxy-phenoxy)-benzonitrile (described in example 1 step d)) and 11.4 ml of N, N-diisopropylamine are dissolved in 250 ml of dichloromethane and 14.5 g of 4-(trifluoromethylthio)-benzoylchloride are slowly added. The reaction mixture is stirred at room temperature for 20 hours and washed with water, a saturated aqueous solution of sodium bicarbonate and water. The organic phase is dried with magnesium sulfate and evaporated under vacuum. The residue is purified by recrystallization from diethylether/hexanes to yield N-[1-cyano-1-methyl-2-(5-cyano-2-{2-chloro-4-trifluoromethoxy-phenoxy}-phenoxy)-ethyl]-4-trifluoromethylsulfanyl-benzamide as a colorless solid.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10](Cl)=[CH:11][C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]>CN1CCCC1=O>[Cl:9][CH:10]=[C:11]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]
Reactant: [O-]c1ccccc1
Reactant: C=CC(C)(C)C=C(Cl)Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=CC(C)(C)C(=CCl)Oc1ccccc1
Yield: 92 %

Procedure:
23.2 g (0.2 mol) of sodium phenolate and 16.5 g (0.1 mol) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene are heated to 180° C. in 100 ml of N-methylpyrrolidone, during the course of 10 hours. The working-up corresponding to Example A1(a) yields 20.5 g (92% of theory) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.6 %

Procedure:
To a solution of 2.00 g (0.013 mol) of methyl anthranilate dissolved in 20 mL of chloroform was added 3.2 mL (0.039 mol) of pyridine followed by 2.733 g (0.013 mol) of p-methoxybenzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 5 h and then washed with 3N HCl and water. The organics were then dried over Na2SO4, filtered and concentrated in vacuo. The resulting white solid was washed with ether and dried in vacuo to provide 3.7 g (87%) of the desired sulfonamide. CI Mass Spec: 322 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][C:28]([OH:30])=O)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:32])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]4[O:25][C:28](=[O:30])[CH2:27][N:26]=4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: ClCCl
Product: O=C1CN=C(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of N-[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine (510 mg) and PS (polymer supported)-carbodiimide (1.69 g, 123 mmol/g) in dichloromethane (25 mL) was stirred at room temperature overnight. The reaction mixture was filtered through a short pad of Celite® diatomaceous filter aid and rinsed with dichloromethane. The filtrate was concentrated to provide the title compound (400 mg, 81% yield) as a pale yellow solid used directly for next step.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[N:31]=[C:30]([CH3:32])[N:29]([CH3:33])[C:17]2=[N:18][C:19]=1[N:20]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].CI.[C:47](OCC)(=O)C>CN(C=O)C>[F:42][C:2]([F:41])([F:1])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[N:31]=[C:30]([CH3:32])[N:29]([CH3:33])[C:17]2=[N:18][C:19]=1[N:20]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:8]1[N:12]=[N:11][N:10]([CH3:47])[N:9]=1
Reactant: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc2n1C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c(N(CC3CC3)CC3CC3)nc2n1C
Reaction time: 0.25 h
Yield: 4.4 %

Procedure:
To a solution of (6-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-cyclopropylmethyl-amine (0.220 g, 3.7 mmol.) in DMF (8 mL) was added 60% sodium hydride (0.017 g, 0.741 mmol.) at 0° C. and the resulting reaction mixture was stirred at the same temperature for 15 min. and then methyl iodide (0.046 mL, 0.0741 mmol.) was added and continued to stir for 30 min. The crude product was extracted with ethyl acetate (250 mL), washed with water (250 mL×2) and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography using 230-400 mesh silica gel eluting with 1:1 hexane: ethyl acetate yielded 0.010 gm (yield: 4.4%) of pure colorless gummy compound.