Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Cl:33])=[CH:11][C:10](=[O:34])[CH2:9][CH2:8]1)(=O)C.[OH-].[K+]>O1CCCC1.CO.C(OCC)(=O)C>[Cl:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@@H:14]1[CH2:13][C:12]2[C@H:7]([CH2:8][CH2:9][C:10](=[O:34])[CH:11]=2)[C@@H:6]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][C@H:5]2[OH:4])([CH3:21])[C:19](=[O:23])[CH2:18][CH2:17]1
Reactant: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCCl)CC3=CC(=O)CC[C@@H]3[C@H]21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]12C[C@@H](O)[C@H]3[C@@H]([C@H](CCCCCCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 3 h
Yield: 58.3 %

Procedure:
6.0 g of 11α-acetoxy-7α-(9-chlorononyl)-estr-4-ene-3,17-dione is saponified at 60° C. in a mixture of 12 ml of tetrahydrofuran and 12 ml of methanol with 17 ml of a 1N potassium hydroxide solution. After 3 hours, it is diluted with ethyl acetate, washed neutral with saturated sodium chloride solution and water and dried. The chromatography of the crude product on silica gel with a methylene chloride-acetone gradient yields 3.2 g of 7α-(9-chlorononyl)-11α-hydroxy-estr-4-ene-3,17-dione as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[K+].Cl.[CH3:24][N:25]([CH2:27][CH2:28]Cl)[CH3:26].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>O.O1CCCC1>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[CH3:24][N:25]([CH3:26])[CH2:27][CH2:28][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CN(C)CCCl
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.2 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 17 ml of a 10% aqueous potassium hydroxide solution and 1.2 ml of tetrahydrofuran is added at room temperature with stirring 2.16 g of N,N-dimethyl-2-chloroethylamine hydrochloride in its powdery form. The resulting mixture is stirred at room temperature for 3 hours and, thereafter, the reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried and then distilled under reduced pressure to remove the solvent, whereby an oily 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is obtained. The oily product thus obtained is treated, according to usual procedure, with maleic acid and recrystallized from an isopropyl alcohol-acetone mixture to obtain 4.50 g of 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine maleate, m.p. 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:26][C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1

Procedure:
The product from Example 4a (5.00 g, 17.53 mmol) was reacted with 4-methylthiophenol (2.17 g, 17.53 mmol) in place of thiophenol following the procedure from Example 1e for 18 h giving the crude title compound which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane providing a solid (3.53 g, 78%).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[C@@H:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C@@H:19]1[CH3:25].[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][N:21]1[CH2:22][CH2:23][C@@H:18]([C:3]2[CH:4]=[C:5]3[C:14](=[CH:15][C:2]=2[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:27]=2[F:26])[O:13][CH2:12][C:11]2[N:6]3[C@H:7]([CH3:17])[C:8](=[O:16])[NH:9][N:10]=2)[C@@H:19]([CH3:25])[CH2:20]1
Reactant: COc1cccc(B(O)O)c1F
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@@H]4CCN(C)C[C@@H]4C)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(-c2cc3c(cc2[C@@H]2CCN(C)C[C@@H]2C)N2C(=NNC(=O)[C@H]2C)CO3)c1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A mixture of (R)-7-bromo-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.050 g, 0.123 mmol), (2-fluoro-3-methoxyphenyl)boronic acid (0.025 g, 0.147 mmol), K2CO3 (0.034 g, 0.246 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.020 g, 0.025 mmol) in dioxane (3 mL) and water (0.5 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by preparative TLC (eluting with 17% MeOH in EtOAc) to give (R)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-3-methoxy-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.0248 g, 45%) as a solid. 1H NMR (400 MHz, CD3OD): δ 7.14 (m, 2H), 6.96-6.90 (m, 1H), 6.81-6.72 (m, 2H), 4.95-4.91 (m, 1H), 4.60 (d, J=13.2 Hz, 2H), 3.90 (s, 3H), 3.13 (m, 1H), 3.00-2.74 (m, 2H), 2.34 (m, 3H), 2.19 (m, 2H), 2.14 (m, 1H), 1.67 (m, 2H), 1.48 (m, 3H), 0.89-0.79 (m, 3H). LC/MS (Table 1, Method 4) Rt=2.075 min.; MS m/z: 453 [M+H]+. SFC (Table 2, Method 27), Rt=3.239 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=O)[CH:3]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][N:13]=3)[CH:14]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])[CH:3]=1
Reactant: Cc1cc(Nc2ncccc2C=O)no1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cccnc2n(-c2cc(C)on2)c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
3.3 g (16 mmol) of (2-(5-methyl-3-isoxazolyl)amino)nicotinaldehyde was dissolved in ethanol (60 mL), and 3.9 g (24 mmol) of diethyl malonate and 0.56 g (6.5 mmol) of piperidine were added thereto. The resulting mixture was stirred overnight at 90° C. The reaction mixture was cooled, and then the solvent was distilled off. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 7:3), and thus 2.7 g of the title compound was obtained as pale yellow crystals (yield: 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)cc1C1OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A mixture of 5-bromo-2-fluoro-benzaldehyde (24.92 g, 123.2 mmol), ethylene glycol (21.0 mL, 369.6 mmol), toluene (650 mL), and TsOH (2.49 g, 12.4 mmol) were heated at reflux under a N2 atmosphere in a flask fitted with a Dean Stark trap and condenser. After 18 h, the mixture was cooled to rt, washed with a satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by FCC (EtOAc/hexanes) gave the desired product (28.74 g, 95%) as an oil. 1H NMR (CDCl3): 7.68-7.63 (m, 1H), 7.45-7.39 (m, 1H), 6.98-6.91 (m, 1H), 6.05-6.00 (m, 1H), 4.12 (br s, 2H), 4.02 (br s, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[F:20][C:21]1[C:31](I)=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([OH:33])[CH:22]=1.C(N(CC)CC)C.CN(C)C(=O)C>C(Cl)(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:20][C:21]1[C:31]([CH:2]=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)(=[O:10])=[O:11])=[CH:7][CH:8]=2)=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([OH:33])[CH:22]=1
Reactant: CCOC(=O)c1cc(I)c(F)cc1O
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)c(F)cc1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-Ethenyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (2.7 g, 10 mmol), ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (3.6 g, 80%, 10 mmol), triethylamine (5 ml) and N,N-dimethylacetamide (5 ml) were mixed and heated to 50° C. Palladium acetate (40 mg) was added and the solution kept at 50° C. for 18 h. The solution was poured into water and the precipitate dissolved in chloroform. The solution was dried, applied on top of a short silica gel column and eluted with 30% isobutylmethylketone in toluene. The pure fractions were collected and evaporated to dryness. After trituration with acetonitrile the product crystallized. Yield 1.1 g.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:18])[CH2:9]P(OCC)(OCC)=O)([CH3:6])([CH3:5])[CH3:4].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].O>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:9]/[C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:18])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.19 g (29.64 mmol, 60% pure) of sodium hydride were suspended in 25 ml of toluene and 25 ml of THF, and the suspension was cooled to 0° C. 7.28 ml (30.99 mmol) of tert-butyl(diethoxyphosphoryl)acetate were then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min. 5 g (26.94 mmol) of 4-chloro-3-nitrobenzaldehyde were then added to the reaction mixture, and the reaction mixture was then warmed to room temperature. The mixture was stirred at room temperature for 2 hours, and 50 ml of water were then added. After removal of the organic phase, the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 9:1). This gave 6.77 g (23.86 mmol, 77% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][NH:20][CH2:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:24]3[CH2:25][CH2:26][CH:22]([CH2:21][NH:20][CH3:19])[CH2:23]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC)C3)nc21
Yield: 44.4 %

Procedure:
1.00 g (3.69 mmole) 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-napthyridine-3-carboxylic acid, 40 ml acetonitrile, and 1.27 g (11.08 mmole) N-methyl-3-pyrrolidinemethanamine are stirred at room temperature for three days. The reaction was filtered and the precipitate dissolved in aqueous ammonium hydroxide at pH 11. The solution was filtered and the solvent removed at reduced pressure. The product was washed with 5 ml of water, 10 ml ethanol/ether (1:1), and finally witn ether until dry to give 0.571 g of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 251°-253° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35].CCOCC.CCCCCC>C(#N)C.C(Cl)Cl>[C:34]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH2:19]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])(=[O:36])[CH3:35]
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CC#N
Solvent: CCCCCC
Product: CCOc1cc([C@@H](CC(=O)NOC(C)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 63 %

Procedure:
A solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide and acetic anhydride (0.09 mL, 1 mmol) in acetonitrile/methylene chloride (6 mL each) was stirred at room temperature for 21 hrs. Ether (10 mL) and hexane (10 mL) was added to give a suspension. The suspension was filtered to give (1R)-cyclopropanecarboxylic acid {2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (270 mg, 63% yield): mp, 140-142° C.; 1H NMR (DMSO-d6) δ 0.88-0.92 (m, 4H, 2CH2), 1.30 (t, J=7 Hz, 3H, CH3), 1.75-1.81 (m, 1H, CH), 2.09 (s, 3H, CH3), 3.02-3.07 (m, 2H, CH2), 3.73 (s, 3H, CH3), 4.01 (q, J=7 Hz, 2H, CH2), 4.18 (d, J=18 Hz, 1H, NCHH), 4.60 (d, J=1.8 Hz, 1H, NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86-6.95 (m, 3H, Ar), 7.18 (d, J-=8 Hz, 1H, Ar) 7.49 (t, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH), 11.86 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.79, 14.70, 15.46, 17.95, 17.95, 34.55, 46.53, 51.06, 55.44, 63.76, 111.87, 111.99, 116.77, 117.29, 117.47, 119.23, 131.17, 132.74, 136.94, 142.25, 147.92, 148.52, 166.48, 168.02, 168.32, 171.70; Anal Calcd for C26H29N3O7+0.1H2O: C, 62.79; H. 5.92; N. 8.45, H2O, 0.36. Found: C, 62.44; H. 5.82; N. 8.37, H2O, 0.30.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6](F)[NH:5][C:4]=2[CH:3]=1.Cl.[CH3:15][C:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.C>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:22][C:16]3([CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:5][C:4]=2[CH:3]=1
Reactant: CC1(N)CCCCC1
Reactant: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CCCCC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 7.9 %

Procedure:
A mixture of 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 2.08 mmol), 1-methylcyclohexylamine hydrochloride (373 mg, 2.49 mmol) and triethylamine (0.58 ml, 4.16 mmol) in ethanol (3 ml) was stirred for 20 h at 50° C. and then for 22 h at 100° C. in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was triturated with water followed by adjustment to pH <2 with 4M hydrochloric acid. The crude product was isolated by filtration and dissolved in 1 N sodium hydroxide followed by treatment with decolourising charcoal. After filtration, the solution was acidified to pH <2 with 4M hydrochloric acid and the precipitate was filtered off and purified by chromatography (dichloromethane/methanol (19:1)). Recrystallisation from ethanol afforded 55 mg (8%) of the pure title compound; mp 218-219° C.; 1H-NMR (DMSO-d6): δ1.18-1.54 (m, 11H), 1.97-2.12 (m, 2H), 6.55 (br s, 1H), 7.12 (s, 1H), 10.60 (br s, 1H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:14](#[N:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[K+]>C(O)CO.CCCCCC>[C:7]1(=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]#[N:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCCCCCC#N
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCCC
Product: CCCCCC(C#N)=C1CCCCC1

Procedure:
Into a 25 ml. flask, equipped with magnetic stirrer, heating mantle, condensor, calcium sulfate drying tube, constant temperature controller and thermometer, was charged 0.98 g. of cyclohexanone (0.01 M), 11.1 g. of heptanonitrile (0.10 M) and 0.66 g. of 85% potassium hydroxide flakes. The mixture was heated cooled, 30 ml. of hexane was added, and the mixture washed six times with 30 ml. portions of water and once with saturated brine. The washes were each in succession, cross-extracted with two 15 ml. portions of hexane. The combined organic and hexane phases were dried over anhydrous sodium sulfate and solvent evaporated on a rotary evaporator at ~30 mm. Hg to give 6.7 g. of oil. Gas chromatographic analysis (6' × 1/4" column, 20% Carbowax 20 m. on Chromasorb W, programmed 135° C. to 220° C. at 4°/minute, He flow ~60 ml./minute) showed product nitrile peaks at 17.8 minutes (10.3%) and 20.1 minutes (4.1%) with heptanonitrile at 4.3 minutes (85.5%). The product peaks which eluted together at 17.6 minutes on a 20% SE30 column (6' × 1/4") under the same operating parameters were trapped out for odor evaluation. An IR spectrum on the trapping of combined isomers showed a nitrile band at 4.5 microns and an olefin band at 6.27 microns. The product was described by perfumers as having an interesting, fruity, floral, salicylate quality.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[CH:51][C:52]([N:55]3[CH:59]=[N:58][CH:57]=[N:56]3)=[N:53][CH:54]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[N:55]1([C:52]2[N:53]=[CH:54][C:49]([C:16]3[CH:15]=[N:14][N:13]4[C:8]([N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:40])([CH3:39])[CH3:1])=[CH:9][C:10]([CH:18]5[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]5)=[N:11][C:12]=34)=[CH:50][CH:51]=2)[CH:59]=[N:58][CH:57]=[N:56]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CC1(C)OB(c2ccc(-n3cncn3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-n5cncn5)nc4)c3n2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a pressure tube were charged tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (563 mg, 0.8 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(1H-1,2,4-triazol-1-yl)pyridine (287 mg, 1.1 mmol), PdCl2(dppf)2.CH2Cl2 (29 mg, 0.04 mmol), DME (6 mL) and 2M Na2CO3 (2 mL). The resulting mixture was briefly degassed with Argon; the tube was capped, and heated with stirring under 80° C. overnight. After cooling, solvent was removed. The residue was diluted with EtOAc (20 ml), and organic layer was isolated, washed with brine and dried (MgSO4). After concentration under reduced pressure, the residue was purified on silica gel eluting with EtOAc/Hexanes (0-50%) to provide the title compound (370 mg, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7](CC2C=CC(OC)=CC=2OC)[CH2:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=2)=[O:5])[CH3:2].S(Cl)(Cl)=O.C(O)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(O)c2ccc(Oc3ccccc3)cc2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 78.9 %

Procedure:
365 mg of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-7-phenoxy-1,2-dihydro-isoquinoline-3-carboxylic acid ethyl ester was dissolved in 7.9 ml of dichloromethane. To the solution was added 92 μL of thionyl chloride. The reaction was stirred at room temperature for 6.5 h, and then 500 μL of ethanol was added and the reaction stirred for an additional 10 min. The mixture was partitioned between ethyl acetate and sodium bicarbonate. The organic fraction was successively washed with 0.5 M HCl, water, brine; dried over anhydrous sodium sulfate, and concentrated to 468 mg of a yellow oil. The oil was purified by flash chromatography on silica gel, eluting with a gradient of 15-50% ethyl acetate in hexanes, to produce 232 mg of crude product, which was crystallized from ether and hexanes to give 193 mg of off-white solid; MS (+) m/z 310.08 (m+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:27])=[C:15]([CH:26]=1)[C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH3:25])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:27][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:26][C:15]=1[C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH3:25])=[O:17]
Reactant: CC1CCCCC1OC(=O)c1cc(N)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCCC1OC(=O)c1cc(NC(=O)c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.3 %

Procedure:
Benzoyl chloride (5.2 g, 0.037 mole) was added slowly at room temperature to a stirred mixture of 2-methylcyclohexyl 5-amino-2-chlorobenzoate (10 g, 0.037 mole), triethylamine (4.0 g, 0.04 mole) dissolved in methylene chloride (100 ml). This reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then washed with water (200 ml), 3% HCl solution (100 ml), 2% NaOH solution (100 ml) and water (100 ml), dried (magnesium sulfate) and filtered. The solvent was evaporated off to give a brown oil which was crystallized with ethyl/hexane to give 2-methylcyclohexyl 2-chloro-5-(benzoylamino)benzoate as a white solid (5 g, m.p. 121°-122° C.)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(C)c(C)cc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate(5.422 g, 0.02 mol) and 1-phenylpiperazine(3.44 g, 0.02 mol) were dissolved in tetrahydrofuran(10 ml). After DBU(3.04 g, 0.02 mol) was added, the resulting solution was stirred at room temperature for 2 hrs, concentrated and purified by column chromatography to obtain the titled compound.