Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].S1[C:18]2[N+:9](=[CH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]=2)C=C1.O1C=CC(C(C2C=COC=2)=C)=C1>[N+](C)([O-])=O>[Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][N:9]=1
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: c1ccc2c[n+]3ccsc3cc2c1
Agent: C=C(c1ccoc1)c1ccoc1
Solvent: C[N+](=O)[O-]
Product: [O-][Cl+3]([O-])([O-])O
Product: c1ccc2cnccc2c1

Procedure:
A mixture of 1.5 g (0.01 mol)) of thiazolo[3,2-b]isoquinolinium perchlorate and 1.3 g (8 mmol) of 1,1-di-(3-furyl)ethylene in 50 ml of nitromethane was heated to reflux under nitrogen for 3 h. The mixture was cooled and concentrated in vacuo. The residue was triturated with ether/ethyl acetate (75 ml), filtered to yield a crude product. This solid was triturated in 50 ml of methylene chloride and the solid was collected by filtration. The solid product was washed with ether, isopropanol, methylene chloride, and dried to afford 1.7 g of 11,11-di(3-furyl)-5,10-ethano-5,10-dihydrothiazolo-3,2-b]isoquinolin perchlorate (Formula I: A=thiazolo;R1 =R2 =R3 =R6 =H; R4 =R5 =3-furanyl;X- =ClO4-).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][CH2:6]2.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]=[C:24]=S)[CH:19]=[C:20]([Cl:22])[CH:21]=1.C[Si](C)(C)[Si](C)(C)C.[Li].[NH2:35][NH2:36]>C(OCC)(=O)C.C(O)(=O)C.C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[NH:36][N:35]=[C:8]3[C:9]4[C:5]([CH2:6][C:7]=23)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: NN
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)-c1n[nH]c(Nc3cc(Cl)cc(Cl)c3)c1C2
Reaction time: 8 h

Procedure:
A mixture of 5,6-dimethoxyindan-1-one, Compound 3a, (4 g, 0.021 mole), 3,5-dichlorophenyl isothiocyanate, Compound 3b, (4.45 g, 0.022 mole) and THF (30 mL) was added to lithium hexamethyldisilane (26.9 mL, 0.269 mole) dropwise at room temperature with stirring. Hydrazine (1.04 mL, 0.032 mole) and acetic acid (1.65 mL) were added to the reaction mixture, which was then stirred at room temperature for 12 hrs. The reaction continued at 75° C. overnight. The resulting organics were first diluted with ethyl acetate (100 mL), then washed with water and brine solution, dried (Na2SO4), and solvent was removed in vacuo. The chemical residues were recrystallized from ethanol. The first and second crops of solid were combined and dissolved in hot CH3CN, to which an equal volume of HCl-ether solution was added to precipitate the title compound (Compound 19), which was collected and dried under vacuum at 60° C. mp>270° C.; MS m/z 376 and 378 (M+H)+; 1HNMR (DMSO-d6): 3.44(s,2H), 3.83(s,3H), 3.82(s,3H), 6.93(s,1H), 7.19 (s,1H), 7.21(s, 1H), 7.35(s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:9]2=[O:13])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 58B (0.82 g, 3.00 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 4.5 mL, 4.5 mmol) via syringe under nitrogen followed by ethyl 2-bromoacetate (0.33 mL, 3.00 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated and then diluted with ethyl acetate. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography eluting with ethyl acetate/hexane (20:80) gave the title compound. MS (APCI+) m/z 359.9 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CN(C)CCN(C)C.[C:21](=O)=[O:22].CC(C)=O.C([Li])(C)(C)C>CCCCC.CN(C)C=O>[CH:21]([C:5]1[S:1][C:2]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:3][CH:4]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)c1cccs1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: CC(C)=O
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C=O)s1
Reaction time: 0.83 h

Procedure:
A solution of t-butyl 2-thiophenecarboxylate (1.84 g, 10 mmol) and N,N,N',N'-tetramethylethylenediamine (1.74 g, 15 mmol) in anhydrous tatrahydrofuran was stirred in a nitrogen stream under cooling with dry ice/acetone, followed by the dropwise addition of a 1.7M solution (8.0 ml) of t-butyllithium (13.6 mmol) in pentane. The obtained mixture was stirred as such for about 50 minutes. Anhydrous dimethylformamide (15 ml) was gradually dropped into the resulting mixture to conduct a reaction. The dry ice/acetone was removed to raise the temperature of the mixture to room one. The resulting mixture was stirred for 40 minutes and poured into 300 ml of a diethyl ether/0.3N HCl (3:1) mixture. The obtained mixture was stirred for a while. The organic layer was recovered, washed with a phosphate buffer solution having a pH of 7 and an aqueous solution of common salt, dehydrated and distilled to remove the solvent. The residue was purified by silica gel column chromatography (developer: n-hexane/ethyl acetate=8:1) to give t-butyl 5-formyl-2-thiophenecarboxylate. yield: 1.7 g
Reaction SMILES: C(C1C=C([CH2+]=NC2C=CC(OC3C=CN=C(C(NC)=O)C=3)=CC=2F)N(C2C=[CH:34][CH:33]=[C:32]([CH2:36][OH:37])C=2)N=1)(C)(C)C.[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48]([NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62]([NH:64][CH3:65])=[O:63])[CH:57]=3)=[CH:53][C:52]=2[F:68])=[O:49])[N:44]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][OH:76])[CH:70]=2)[N:43]=1)([CH3:41])([CH3:40])[CH3:39].N1C=CC=C[CH:78]=1.CC(C)C(=O)CCl>ClCCl.CCOC(C)=O>[CH3:78][CH:33]([CH3:34])[CH2:32][C:36]([O:76][CH2:75][C:71]1[CH:72]=[CH:73][CH:74]=[C:69]([N:44]2[C:45]([NH:47][C:48](=[O:49])[NH:50][C:51]3[CH:67]=[CH:66][C:54]([O:55][C:56]4[CH:61]=[CH:60][N:59]=[C:58]([C:62](=[O:63])[NH:64][CH3:65])[CH:57]=4)=[CH:53][C:52]=3[F:68])=[CH:46][C:42]([C:38]([CH3:41])([CH3:39])[CH3:40])=[N:43]2)[CH:70]=1)=[O:37]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Reactant: CNC(=O)c1cc(Oc2ccc(N=[CH2+]c3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Reactant: c1ccncc1
Agent: CC(C)C(=O)CCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COC(=O)CC(C)C)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 18 %

Procedure:
To a 0° C. solution of example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (0.10 g, 0.19 mmol) in dichloromethane (1.0 mL)/pyridine (0.3 mL) was added dropwise 3-methylbutanonyl chloride (0.02 mL, 0.23 mmol). The reaction mixture was allowed to warm to room temperature and stir for 72 h. The reaction mixture was diluted with EtOAc and washed with sat. aqueous NaHCO3. The combined organic layer was washed with brine, dried and concentrated. The crude material was purified via column chromatography (CH2Cl2: MeOH, 100% CH2Cl2 to 98.5:1.5) to afford 0.02 g (18%) of the desired product as a white solid. MS m/z 617.3 (M+H)+; Retention time (LC-MS): 3.89 min.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Reaction time: 12 h
Yield: 89 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (prepared as for CT13430) (12.25 g, 50.0 mmol) and potassium carbonate (6.91 g, 50.0 mmol) in dimethylformamide (400 ml) was added benzyl bromide (9.24 g, 54.0 mmol). After stirring for 12 hours, the mixture was poured into cold water (680 ml). The precipitate was filtered, washed with water (3×50 ml), ether (3×50 ml) and dried under vacuum to provide 7-benzyl-8-bromo-3-methylxanthine (14.92 g, 89% yield) as a white powder.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>>[C:8]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])#[N:9]
Reactant: C=CC(=O)OCC
Reactant: N#CCc1ccccc1
Product: CCOC(=O)CCC(C#N)(CCC(=O)OCC)c1ccccc1

Procedure:
The required diethyl γ-cyano-γ-phenylpimelate was prepared by reacting phenylacetonitrile with ethyl acrylate according to the general method of Koelsch, J. Am. Chem. Soc., 65, 437 (1943). This product, boiling point 148°-151° C. at 0.04 mm [Branchini et al., Ann. Chim. (Rome) 51, 1382 (1961) report 170°-172° C. at 0.2 mm] was obtained in addition to the mono-Michael addition product reported by Koelsch.
Reaction SMILES: [SH2:1].Br[C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2>C1C2C(CCCC2)CCC1>[CH:15]1[C:16]2[C:11](=[CH:10][C:9]3[C:4]([C:3]=2[S:1][C:3]2[C:16]4[C:11]([CH:10]=[C:9]5[C:4]=2[CH:5]=[CH:6][CH:7]=[CH:8]5)=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:12]=[CH:13][CH:14]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: S
Solvent: C1CCC2CCCCC2C1
Product: c1ccc2c(Sc3c4ccccc4cc4ccccc34)c3ccccc3cc2c1

Procedure:
Hydrogen sulphide is passed into a solution of 20 g (0.08 mole) of 9-bromoanthracene in decahydronaphthalene at a temperature of 180° C for 14 hours, the solvent is separated by filtration, the residue is recrystallized from toluene to obtain 8.5 g (63.3 percent by weight) of di(9-anthryl) sulphide. This is a yellow crystalline substance melting at 257° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:29]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccccc1N1CCc2ccccc21
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1N1CCc2ccccc21)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture, under N2, of 9.86 g of 1-(2-aminophenyl)indoline hydrochloride and 100 ml of dry methylene chloride is treated with 8.09 g of triethylamine. The mixture is cooled to 0°-5° C., and a solution of 6.34 g of o-fluorobenzoyl chloride in 25 ml of CH2Cl2 is added over 1 hour at such a rate as to keep the temperature below 5° C. The mixture is then stirred overnight at ambient temperature. Water is added, the organic layer is separated, washed with 3 N--HCl, with 3 N--NaOH, with H2O, dried and concentrated to a crystalline solid of 1-[2-(2-fluorobenzamido)phenyl]indoline, m.p. 139°-141° C.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH:8]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH:8]1[S:4][CH2:1][CH2:2][S:3]1
Reactant: SCCS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(C2SCCS2)c1
Yield: 97.2 %

Procedure:
9.9 g of ethane 1,2-dithiol are added to 18.6 g of 2-chloro-5-nitrobenzaldehyde and 0.5 g of p-toluenesulfonic acid in 250 ml of toluene and the mixture is refluxed for 5 hours under a water separator. After the mixture has been cooled, the solvent is removed, the residue is stirred with petroleum ether and the product is filtered off and dried. 25.5 g of 4-chloro-3-(1,3-dithio-lan-2-yl)-nitrobenzene (mp. 130-131° C.) are obtained.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20]O>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH3:17][O:18][CH2:19][CH2:20][O:16][CH2:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: COCCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COCCOCc1c2ccccc2cc2ccccc12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-methoxyethanol (1 l) in benzene (1.5 l), conc. sulfuric acid (3 ml) was added and the mixture was heated to 80° C. A solution of 9-anthracenemethanol (45 g, 0.22 mole) in 2-methoxyethanol (450 ml) was added to the mixture under reflux and stirring was continued for 1.5 hours under reflux. After standing at room temperature overnight, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous MgSO4 and evaporated. The residual crude oil (63 g) was chromatographed on silica gel (Wakogel C-200, manufactured by Wako Pure Chemical Industries, Ltd.) with n-hexane/ethyl acetate [50/1→25/1→8/1 (V/V)] as eluent to give 47.6 g of 9-(2-methoxyethoxy)methylanthracene as orange yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])[CH2:5][CH2:4]1.C(N(CC)CC)C.O>CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[C:17]([F:20])([F:18])[F:19])[CH2:5][CH2:4]1)=[O:1]
Reactant: N#Cc1ccc(N2CCC(CO)CC2)c(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(N2CCC(C=O)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 4-[4-(hydroxymethyl)piperidin-1-yl]-3-(trifluoromethyl)benzonitrile (3.55 g) in DMSO (50 mL) were added triethylamine (10.6 mL) and sulfur trioxide pyridine complex (6.63 g). The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.06 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH:11]([CH3:20])[CH:12](OS(C)(=O)=O)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:21][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.CCOC(C)=O>[N:28]([CH:12]1[CH:11]([CH3:20])[N:9]2[C:10]3[C:6]([C:7]([CH2:21][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23])=[C:8]2[CH2:14][CH2:13]1)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[N+:29]=[N-:30]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(OS(C)(=O)=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(N=[N+]=[N-])CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Propyl {4-fluoro-6-methyl-7-[(methylsulfonyl)oxy]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate was dissolved in DMF (1 M) and treated with NaN3 (2.0 eq.), warmed to 80° C. and stirred overnight. The reaction mixture was diluted with EtOAc and extracted with sat'd NH4Cl, water, dried (Na2SO4) and concentrated. Chromatography on SiO2 (0-100% EtOAc/hexanes) gave propyl (7-azido-4-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate: 1H NMR (600 MHz, CDCl3) δ 7.30 (d, J=7.9 Hz, 1H), 6.96-6.99 (m, 1H), 6.80 (dd, J=12.6, 7.6 Hz, 1H), 4.87 (dd, J=13.2, 6.5 Hz, 1H), 4.10 (d, J=7.0 Hz, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.61 (m, 2H), 3.01 (m, 2H), 2.10-2.20 (m, 2H), 1.57-1.63 (m, 2H), 1.43 (d, J=6.8 Hz, 3H), 0.87 (t, J=7.3 Hz, 3H); MS (EI) calc'd for C18H22FN4O2 [M+1]+345.2. found 345.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[C:5]([CH3:21])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reaction time: 20 h
Yield: 89.3 %

Procedure:
2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (830 mg, 2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and then stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to produce 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester colorless oil (563 mg, 89%) 1H NMR (300 MHz, CDCl3): δ 7.23 (t, 2H), 7.13 (d, 2H), 6.96 (t, 1H), 6.83 (d, 2H), 6.76 (d, 2H), 4.19 (q, 1H, J=7.1), 3.23 (d, 1H, J=12.4), 3.08 (d, 1H, J=12.4), 1.39 (s, 3H), 1.22 (t, J=7.1). MS [EI+] 318 (M+H)+, [EI−] 359 (M+OAc−).
Reaction SMILES: [Mg].II.Br[C:5]([CH3:7])=[CH2:6].[CH3:8][C:9]1[CH2:10][CH2:11][CH:12]2[C:18]=1[CH2:17][CH2:16][C:15](=[O:19])[CH2:14][C:13]2=[CH2:20]>O1CCCC1>[OH:19][C:15]1([C:5]([CH3:7])=[CH2:6])[CH2:16][CH2:17][C:18]2[CH:12]([CH2:11][CH2:10][C:9]=2[CH3:8])[C:13](=[CH2:20])[CH2:14]1
Reactant: C=C(C)Br
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C1CC(O)(C(=C)C)CCC2=C(C)CCC12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a Grignard solution, prepared from 1 g of magnesium chips activated with 1 g of iodine, 5 ml of 2-bromopropene and about 100 ml of tetrahydrofuran, were added over 10 minutes 1.76 g of 1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene. The mixture was stirred vigorously for 30 minutes, cooled to 0° and treated with excess ice-cold ammonium chloride solution. The mixture was then extracted with ether, the organic extract washed with carbonate solution and water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product (2.6 g), which was obtained in the form of a yellow oil, was distilled under high vacuum and yielded 1.6 g (yield 76%) of pure 6-hydroxy-6-isopropenyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.1 ca 100° IR(film):νmax = 3550, 3090, 1640, 1450/40, 1378, 1330, 1220, 1165, 1105, 1065, 1038, 900/895, 780 cm-1. The compound has a woody, slightly camphorous, somewhat spicy odour.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][C:37](O)=[O:38])[CH:30]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:37](=[O:38])[CH2:36][CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Reactant: O=C(O)CCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)CCc2cccnc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
Piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) is dissolved in methylene chloride (10 mL) at ambient temperature. 3-Pyridinepropionic acid (60.0 mg; 0.4 mmol), triethylamine (0.111 mL; 0.4 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0836 g; 0.4 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then diluted with methylene chloride (90 mL) and washed successively with water (40 mL), saturated aqueous sodium bicarbonate (40 mL), and saturated brine (25 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (1%→20% methanol in methylene chloride) affording the desired product (138.4 mg) as an oil. ESMS:MH+ 512.4 (base).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O.[CH2:22]=[C:23]([CH3:25])[CH3:24].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:16]([C:15]1[CH:18]=[CH:19][C:20]([F:21])=[C:13]([Cl:12])[CH:14]=1)[CH2:22][C:23]2([CH3:25])[CH3:24])=[O:11]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: C=C(C)C
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccc(F)c(Cl)c1)N2
Temperature: 85 °C
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and 3-chloro-4-fluoro-benzaldehyde (12.3 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL), and washed with water (100 mL×2) and brine (100 mL×2), and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (8.4 g, 31.0%) as a light yellow solid: MS (ESI) M+1=348.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:15][C:16]([F:19])([F:18])[F:17])=[C:12]([NH2:14])[CH:13]=2)[CH2:4][CH2:3]1.[N:20]#[C:21][NH2:22]>Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:15][C:16]([F:19])([F:17])[F:18])=[C:12]([NH:14][C:21]([NH2:22])=[NH:20])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(N)c2)CC1
Reactant: N#CN
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(OC(F)(F)F)c(NC(=N)N)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (275 mg, 1 mmol) in HCl 6N (1 mL), cyanamide (336 mg, 8.0 mmol) was added and the reaction was stirred at 60° C. for 1 h. The mixture was cooled down to room temperature, diluted with water (3 mL), extracted with DCM (10 mL). NaOH 2N was added to pH>11. The aqueous phase was extracted with Et2O (3×10 mL), dried over sodium sulfate and concentrated. The residue was crystallized from diethyl ether to give the title compound (240 mg, 76% yield) as a white solid.