Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine (diastereomer A) in methanol with 1N sodium hydroxide solution. After the mixture has been neutralised with 1N hydrochloric acid it is extracted by shaking with methylene chloride; the extract is evaporated to dryness, and the remaining residue is triturated with petroleum ether and is filtered off with suction.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33]([OH:36])(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1>C(#N)C.CC(C)=O>[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33]([OH:36])(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:2]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6])=[CH:12][CH:13]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(CCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC(C)=O
Solvent: CC#N
Product: CC(C)(CCl)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
17 g (0.05 mol) of crude 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-4-chloro-butan-2-one were dissolved in 100 ml of absolute acetonitrile. 12 g (0.175 mol) of imidazole were added to this solution and the mixture was heated under reflux for 40 hours. Thereafter, it was concentrated by distilling off the solvent in vacuo and the residue was taken up in 300 ml of methylene chloride. The methylene chloride mixture was washed three times with 100 ml of water each time, dried over sodium sulphate and concentrated again in vacuo. The residue was taken up in 100 ml of acetone, and a solution of 9 g (0.038 mol) of 1,5-naphthalenedisulphonic acid in 50 ml of acetone was added. After 2 hours, the precipitate which had formed was filtered off and dried. 19.8 g (80.7% of theory) of 1-(4-chlorophenoxy)-1-(imidazol-1-yl)-3,3-dimethyl-4-chloro-butan-2-one naphthalene-1,5-disulphonate of melting point 266°- 267° C. were obtained. ##STR14##
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN1C(=O)CCC1>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:31][CH2:30]2)=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])CC1
Yield: 93 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrobenzophenone (1.0 eq), 1-Boc-piperazine (1.1 eq), and TEA (2.0 eq) in NMP yielding tert-butyl 4-(4-benzoyl-2-nitrophenyl)piperazine-1-carboxylate (93%). LCMS (m/z): 412.2 (MH+); LC Rt=3.59 min.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]2=3)=[O:7])=[C:4]([Cl:24])[CH:3]=1.[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28](C(Cl)=O)=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+].[O:51]1CCC[CH2:52]1>ClCCl.CO>[NH:17]1[C:11]2[C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:52]([C:39]4[C:34]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:51])=[CH:3][C:4]=3[Cl:24])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=[N:16]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)c(Cl)c1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.3 g of 6-(4-amino-2-chlorobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]pyrido[3,2-b]azepine, 0.52 g of 4-[1,1'-biphenyl]carbonyl chloride and 0.5 g of N,N-diisopropylethylamine in 10 ml of dichloromethane and 2 ml of tetrahydrofuran is stirred at room temperature for 24 hours. The solvent is removed and to the residue is added 10 ml of methanol and 5 mmol of 1N NaOH. The mixture is stirred overnight, concentrated under vacuum and diluted with water. The mixture is extracted with dichloromethane and the extract washed with 2N NaHCO3, H2O, brine and dried (Na2 SO4). The solvent is removed under vacuum to give the product as a solid (glass), m.p. 181°-192° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 550 mg, 1.63 mmol) was dissolved in 20 mL DMF. To it was added NaH (60% in mineral oil, 98 mg, 2.45 mmol). The mixture was stirred at RT for 30 min, and then iodomethane (305 μL, 4.89 mmol) was added. It was stirred for 1.5 hour, diluted with 120 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to flash column using 0 to 50% EtOAc in hexane to isolate (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl(methyl)carbamate (293). It was treated with 20 mL commercial 4N HCl in dioxane at RT for 1 hour, and the mixture was concentrated in vacuo to dryness. It was dissolved in 5 mL DMF and 15 mL dioxane. To it were added DIEA (1.45 mL, 8.15 mmol) and then dimethylcarbamoyl chloride (300 μL, 3.26 mmol). The mixture was stirred at RT for overnight, diluted with 120 mL EtOAc, washed with water ×2, dried, concentrated, and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea (294, 490 mg, 93% overall) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:52]([CH3:53])=[CH:51][C:39]([O:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:38][C:37]=1[CH3:54].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[C:46]([O:45][C:44]([NH:43][CH2:42][CH2:41][O:40][C:39]1[CH:38]=[C:37]([CH3:54])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:52]([CH3:53])[CH:51]=1)=[O:50])([CH3:49])([CH3:48])[CH3:47]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCNC(=O)OC(C)(C)C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and tert-butyl 2-(4-bromo-3,5-dimethylphenoxy)ethylcarbamate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.92 min; Mass spectrum (ESI+): m/z=606 [M+H]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][C:31]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:32])[CH2:29][CH2:28]1
Reactant: O=C(O)CC1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (75 mg, 69%), MS (ISP) m/z=411.4 [(M+H)+], mp 189° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-cyclopropyl-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:15]Br.O>C(O)(=O)C>[Br:15][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([NH2:8])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: Nc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Br)nc1Cl
Temperature: 25 °C

Procedure:
3-Chloro-pyrazin-2-ylamine (0.750 g, 5.79 mmol) is suspended in acetic acid (7 ml) with stirring at room temperature and sodium carbonate (0.675 g, 6.37 mmol) is added. When all the gas has evolved bromine (0.171 ml, 3.34 mmol) in acetic acid (4 ml) is added dropwise. Sodium carbonate (0.675 g, 6.37 mmol) is added and a gas evolves. Once all gas has evolved bromine (0.171 ml, 3.34 mmol) in acetic acid (4 ml) is added. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is poured onto iced water and left to stir for 30 minutes. A pale yellow suspension has formed. This solid is filtered off and rinsed with cold water to give 5-Bromo-3-chloro-pyrazin-2-ylamine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][C:6]=1[CH3:14].Cl[C:16](OC1C=CC=CC=1)=[O:17].C(N(CC)CC)C.[C:32]([Si:36]([CH3:51])([CH3:50])[O:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[C:45]([S:47][CH3:48])[CH:44]=[C:43]([NH2:49])[N:42]=1)([CH3:35])([CH3:34])[CH3:33]>C(#N)C>[C:32]([Si:36]([CH3:51])([CH3:50])[O:37][CH2:38][CH2:39][NH:40][C:41]1[N:42]=[C:43]([NH:49][C:16]([NH:13][S:10]([C:8]2[S:9][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:14])[CH:7]=2)(=[O:12])=[O:11])=[O:17])[CH:44]=[C:45]([S:47][CH3:48])[CH:46]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CSc1cc(N)nc(NCCO[Si](C)(C)C(C)(C)C)c1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCc1sc(S(N)(=O)=O)cc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCc1sc(S(=O)(=O)NC(=O)Nc2cc(SC)cc(NCCO[Si](C)(C)C(C)(C)C)n2)cc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
5-(2-Methoxy-ethyl)-4-methyl-thiophene-2-sulfonic acid amide (0.082 g, 0.48 mmol) was dissolved in 2.8 mL of abs. acetonitrile and treated successively with phenyl chloroformate (0.075 g, 1.0 eq.) and triethylamine (0.167 mL, 2.5 eq.), and the mixture kept at ambient temperature for 1 h. The above prepared N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-methylsulfanyl-pyridine-2,6-diamine (0.150 g, 1.0 eq.), dissolved in a tiny amount of acetonitrile, was then added, and the mixture heated to 60° C. for 18 h. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=1/1), yielded eventually 0.161 g of the title compound as off-white foam.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O.O>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][N:19]2[C:18](=[O:20])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1-c1ccccc1
Reaction time: 60 h
Yield: 90.6 %

Procedure:
(2-Phenyl)-phenylmethyl bromide (6 g, 0.0243 mol) and potassium phthalimide (5 g, 0.0270 mol) were mixed together in dimethyl formamide at room temperature, stirred for 60 hrs, diluted with cold water, and the solid isolated by filtration. After washing with water, isopropyl alcohol, and hexane the white solid was vacuum dried to yield 6.9 g of the subtitled compound. Mass spectrum: 313
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:15]1([NH:21][C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCCCC1

Procedure:
A solution of 50 g (0.22 mol) of 2-nitro-4-trifluoromethyl-1-chlorobenzene, 22 g (0.22 mol) of cyclohexylamine and 61 g (0.44 mol) of potassium carbonate in 600 ml of ethanol was refluxed for 4 hours. The reaction mixture was concentrated and then the crude product was washed with water and ether. The organic phase was worked up, and the product was purified by column chromatography on silica gel (mobile phase:heptane/ethyl acetate=5/1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])O.[Na+].[Cl:15][C:16]1[C:24]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C(OCC)(=O)C>O1CCCC1.O>[Cl:15][C:16]1[C:24]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:19]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1Cl
Reactant: Nc1cc(O)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(O)ccc2F)c1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
2-Chloro-3-(1-cyano-1-methylethyl)benzoic acid (3.0 g, 13.4 mmol) was dissolved in tetrahydrofuran (67 mL), and oxalyl chloride (1.35 mL, 15.8 mmol) and N,N-dimethylformamide (20 μL) were added. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride. To a solution of 3-amino-4-fluorophenol (1.62 g, 12.8 mmol) in tetrahydrofuran (20 ml) was added a suspension of sodium hydrogen carbonate (3.22 g, 38.3 mmol) in water (40 mL), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise at 0° C. a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride produced above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added ethyl acetate (100 mL), and the aqueous layer was separated. The organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate/n-hexane to give the title compound (4.13 g, 97%) as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2oc(CC3CCCCN3)nc2c1
Yield: 29.3 %

Procedure:
(RS)-2-Benzooxazol-2-ylmethyl-piperidine-1-carboxylic acid tert butyl ester (0.50 g) in dichloromethane (8 ml) was cooled (ice-bath) and trifluoroacetic acid (2 ml) added. The mixture was stirred with ice-cooling for 4 h, poured onto saturated potassium carbonate (20 ml) and extracted with dichloromethane. The combined extracts were dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.10 g)
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH2:17]([NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)C(Cl)=O)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31].[CH3:42][O:43]CCOC>>[CH2:17]([NH:32][C:33]1[CH:41]=[CH:40][C:39]([C:42]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:43])=[CH:35][CH:34]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31]
Reactant: COCCOC
Reactant: C=CCCCCCCCCC=CCCCNc1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCCCCCCCCC=CCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OC(C)(C)C)cc1

Procedure:
A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 3-(1-pentadeca-4,14-dienylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield tert-butyl ethyl 4-(1-pentadeca-4,14-dienylamino)benzoylmalonate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:11]=C/C(Cl)=O)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].[OH:16]C1C=C(C=CC=1)C=O.ICCC>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]=[O:16])[CH2:2][CH3:3]
Reactant: CCCOc1cccc(/C=C/C(=O)Cl)c1
Reactant: O=Cc1cccc(O)c1
Solvent: CCCI
Product: CCCOc1cccc(C=O)c1

Procedure:
For example, (E)-3-(3'-propyloxyphenyl)-2-propenoyl chloride, used in Example 3 (i), can be prepared from commercially available 3-hydroxybenzaldehyde by reacting 3-hydroxybenzaldehyde with 1-iodopropane to give 3-propyloxy benzaldehyde. 3-Propyloxy benzaldehyde is then reacted with malonic acid to give the corresponding propenonic acid which is subsequently converted into (E)-3-(3'-propyloxyphenyl)-2-propenoyl chloride by reaction with oxalyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([NH:13]C(OC(C)(C)C)=O)[CH2:8]2)=[CH:4][CH:3]=1.[ClH:23].CCOCC>CO>[ClH:1].[ClH:23].[NH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1-(4-chlorobenzyl)-3-{(tert-butoxycarbonyl)amino}piperidine (2.55 g, 7.85 mmol) in CH3OH (25 mL) was treated with 1 N HCl-Et2O (50 mL). The reaction mixture was stirred at 25° C. for 15 h. The solvent was removed under reduced pressure to afford 3-amino-1-(4-chlorobenzyl)piperidine dihydrochloride as an amorphous solid (2.49 g, quant). The purity was determined by RPLC/MS (>95%),; ESI/MS m/e 225.2 (M++H, C12H18ClN2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:14])[CH:7]=1.[CH3:17][C@@H:18](O)[CH2:19][CH:20]=[CH2:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([O:15][C@H:20]([CH2:19][CH:18]=[CH2:17])[CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:14])[CH:7]=1
Reactant: C=CC[C@@H](C)O
Reactant: Oc1cccc(Cl)c1-c1cc(Br)ccc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cccc(Cl)c1-c1cc(Br)ccc1F
Reaction time: 8 h
Yield: 41.8 %

Procedure:
5′-Bromo-6-chloro-2′-fluoro-[1,1′-biphenyl]-2-ol (750 mg, 2.49 mmol, 1.0 equiv) were mixed with (R)-pent-4-en-2-ol (428 mg, 4.97 mmol, 2.0 equiv) and PPh3 (1305 mg, 4.97 mmol, 2.0 equiv) in tetrahydrofuran (8 mL). To this solution was added DEAD (2266 μl, 4.97 mmol, 2.0 equiv) dropwise and stirred overnight. The solution was mixed with silica gel and concentrated and purified by 40 g ISCO column with 0-10% EtOAc/hexane to afford 5-bromo-2′-chloro-2-fluoro-6′-((S)-pent-4-en-2-yloxy)-1,1′-biphenyl (385 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 7.49-7.44 (m, 1H), 7.41-7.36 (m, 1H), 7.29 (s, 1H), 7.11-6.99 (m, 2H), 6.87 (dd, J=8.3, 2.0 Hz, 1H), 5.73-5.56 (m, 1H), 5.07-4.93 (m, 2H), 4.36 (dq, J=8.8, 6.0 Hz, 1H), 2.37-2.16 (m, 2H), 1.20 (dd, J=6.0, 3.0 Hz, 3H). LCMS (M+1)=369.0.
Reaction SMILES: [CH:1](=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[Na].C(OC)(=O)[CH2:14][C:15]([CH3:17])=[O:16]>CO>[CH2:2]([CH:1]1[CH:6]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:17][C:15](=[O:16])[CH2:14]1)[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)CC=C1CCCC1=O
Agent: [Na]
Solvent: CO
Product: CC(C)CC1CC(=O)C=C2CCCC21
Yield: 52 %

Procedure:
The procedure of Example 1 is repeated with 85 g (0.56 mol) of isopentylidene cyclopentanone, 1.61 g (0.07 g-atom) of sodium, 76.5 g (0.66 mol) of methyl acetoacetate and 300 ml of methanol. Upon distillation there are obtained 56 g (bp 97°-100° C. at 0.5 mm) of 5-isobutylbicyclo [4.3.0] non-1-en-3-one having the structure: ##STR7##
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][C:14]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=3)[N:21]=2)[CH:17]=[C:16]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH:15]=1.C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:6]([NH:5][S:2]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:22]2[N:21]=[C:20]([C:18]3[CH:17]=[C:16]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[CH:15]=[C:14]([CH3:13])[N:19]=3)[CH:25]=[CH:24][CH:23]=2)[CH:27]=1)(=[O:4])=[O:3])=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c3)n2)n1
Yield: 34.6 %

Procedure:
To a stirred and cooled solution of commercially available chlorosulfonyl isocyanate (0.215 mL, 2.47 mmol) in dichloromethane (5 mL) was added tert-butanol (0.232 mL, 2.47 mmol) and the mixture was stirred at 0° C. for 30 min. Then 3-[6′-methyl-4′-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl-6-yl]-phenylamine (example 327) (0.200 g, 0.494 mmol) and triethyl amine (0.42 mL, 2.96 mmol) were added and the mixture was stirred at 23° C. for 0.5 h. Diluted with DCM, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with heptane/EtOAc/THF, followed by trituration with diethyl ether to give the title compound as an off-white solid (0.100 g, 35%). MS (ISP) 585.3 [(M+H)+].