Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC([N:31]1[CH2:35][CH2:34][C@H:33]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:32]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([C@H:33]4[CH2:34][CH2:35][NH:31][CH2:32]4)[CH:40]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn([C@H]4CCNC4)c3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (20 mg, 0.048 mmol), (S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (26 mg, 0.071 mmol) and potassium carbonate (20 mg, 0.10 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was stirred at 100° C. for 30 min in the microwave reactor. Then, the mixture was passed through PL-Thiol MP SPE+ resin and concentrated in vacuo. The resulting solid was left to stir in DCM (0.2 mL) and TFA (0.2 mL) at rt for 30 min. Purification via MDP afforded the title compound as a white solid. MS (ES+): m/z: 475.96/477.94 (70/50) [MH+]. HPLC: tR=2.35 min (ZQ3, polar—5 min). 1H NMR (400 MHz, CD3OD): δ 1.89 (d, J=6.6 Hz, 3H), 2.40 (ddd, J=13.9, 7.6, 3.3 Hz, 1H), 2.50-2.62 (m, 1H), 3.50 (ddd, J=11.5, 8.8, 4.4 Hz, 1H), 3.63-3.73 (m, 2H), 3.75-3.82 (m, 1H), 5.28 (q, J=6.4 Hz, 1H), 6.53 (q, J=6.8 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H), 7.39 (dd, J=8.9, 4.9 Hz, 1H), 7.79 (s, 1H), 7.89 (s, 1H), 8.14 (d, J=4.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:22](N1C=CN=C1)(N1C=CN=C1)=[S:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[C:12]4[N:11]([C:22](=[S:23])[NH:19][C:17](=[O:18])[C:16]=4[CH:15]=[N:14]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(F)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(F)c1)=CC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 63.0 g of 7-(3-fluorophenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 6) and 2.5 liters of dry tetrahydrofuran was stirred and cooled to -78° C. in a dry-ice-acetone bath, then 18.0 g of sodium hydride (60% dispersion in mineral oil) was added in one portion. This mixture was stirred at -78° C. for 11/2 hours then 40.0 g of 1,1'-thiocarbonyldiimidazole was added and stirring was continued at -78° C. for 2 hours. The mixture was allowed to warm to room temperature and was stirred for 48 hours, and then the reaction was quenched with 2.5 liters of water, neutralized with 5% aqueous hydrochloric acid. The crystalline solid that formed was collected, washed with ether and dried to give 54.6 g of the desired product as cream-colored crystals, m.p. 298°-300° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH2:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH:51][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
Under an nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e), 2.59 g (13.5 mmol) of EDC and 1.22 g (9.0 mmol) of HOBT are dissolved in 20 ml of DMF. After 15 min, 3.79 ml (27 mmol) of TEA are added and then a solution of 2.11 g (4.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 41 ml of DMF is added dropwise. After 3 hours the reaction mixture is concentrated by evaporation. The resulting oil is dissolved in ethyl acetate and a small amount of THF and washed with 2×water, sat. NaHCO3 solution, 2×water and brine. The aqueous phases are extracted with ethyl acetate; the combined organic phases are dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; methylene chloride/THF 5:1) and crystallisation from ethyl acetate/DIPE yield the title compound: HPLC20-100: tRet=16.0; FAB MS (M+H)+=640.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1(=O)[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.CCOC(C)=O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: O=C1C=CC(=O)C=C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of zinc chloride (8.39 g, 1.14 mmol, 1 eq) in toluene at ambient temperature, ethyl 3-(4-fluorophenyl)-3-oxopropanoate (13 g, 2.74 mmol, 1 eq) was added and stirred at 70° C. for 15 min. Benzoquinone (6.66 g, 0.72 mmol, 1 eq) was added portion wise into the reaction mixture and stirred at the same temperature for 15-20 min. Dean-stark apparatus was assembled and the reaction mixture was heated at 140° C. for 12 h and cooled to ambient temperature. Reaction completion was judged by TLC. EtOAc was added to the reaction mass and filtered through the filter paper, to remove the inorganic material. Brine was added to the reaction mixture (filtrate) and extracted, dried over sodium sulphate and concentrated to get the crude material. Further it was purified by column chromatography using 10% EtOAc/Hexane system. Yield: 8.0 g (43%). 1H NMR (400 MHz, CDCl3): δ 1.38-1.42 (t, 3H, J=7.14 Hz), 4.37-4.42 (q, 2H, J=7.13 Hz), 5.2 (br s, 1H), 6.87-6.9 (q, 1H, J=3.81 Hz), 7.14-7.18 (q, 2H, J=5.82 Hz), 7.36-7.39 (d, 1H, J=8.80 Hz), 7.50-7.51 (d, 1H, J=2.56 Hz), 8.00-8.03 (m, 2H). LCMS: (ES+) m/z=301 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)C>[CH3:12][NH:13][C:14]([NH:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1)=[S:15]
Reactant: NCCSCc1ccsn1
Reactant: CN=C=S
Agent: Cl
Solvent: CCO
Product: CNC(=S)NCCSCc1ccsn1

Procedure:
A solution was prepared by the gradual addition of cysteamine hydrochloride (2.03 g.) to sodium (0.83 g.) dissolved in ethanol (50 ml.) with stirring at 0° under a nitrogen atmosphere. After starting for 2 hours at 0°, 3-bromoethylisothiazole (3.2 g.) was added dropwise over 15 minutes at 0°, the reaction mixture subsequently being set aside overnight at room temperature. Following acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to yield 3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g.). This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulphate, filtered and concentrated to yield the amine base as an oil (1.56 g.). The amine was dissolved in ethanol (10 ml.), methyl isothiocyanate (0.66 g.) added, and the solution heated under reflux for 30 minutes. Concentration, followed by purification of the crude product by chromatography on a column of silica gel with ethyl acetate as eluant followed by chromatography on a column of alumina with benzene/ethyl acetate as eluant gave N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. (Found: C, 38.9; H, 5.4; N, 16.5; S, 38.3. C8H13N3S3 requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=O)[CH3:11])=[CH:4][C:3]=1[CH3:14].Cl.[NH2:16]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][N:16]=[C:10]([CH3:11])[CH:9]=2)=[CH:4][C:3]=1[CH3:14]
Reactant: NO
Reactant: CC(=O)CC(=O)c1ccc(Br)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2ccc(Br)c(C)c2)on1

Procedure:
A solution of 1-(4-bromo-3-methylphenyl)butane-1,3-dione (D77) (615 mg; 0.0024 ml) in ethanol (15 ml) was treated with hydroxylamine hydrochloride (170 mg; 0.0024 mol) and potassium carbonate (336 mg; 0.0024 mol), and the mixture heated at reflux for 2.5 hours, then overnight at room temperature. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo to leave the crude isoxazole, which was purified by chromatography on silica gel, eluting with pentane, 60-80 petroleum-ether and ethyl acetate, to afford the title compound as a yellow crystalline material (477 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1.[H][H]>[Pt](=O)=O.C(O)C>[NH2:3][C:2]([CH3:1])=[CH:6][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2)on1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(N)=CC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
3-Methyl-5-[4-(tert-butyl)phenyl]isoxazole (900 mg, 4.18 mmol) is introduced into 20 ml of ethanol, platinum(IV) oxide catalyst (90 mg) is added and the mixture is then hydrogenated under atmospheric pressure hydrogen for 12 h. The catalyst is filtered off and the filtrate is concentrated. 897 mg (99% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1Cl.[F:22][C:23]([F:31])([F:30])[CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([C:23]([F:31])([F:30])[F:22])[CH2:25]1
Reactant: CNc1cc(Cl)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(3,3,3-trifluoro-propyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (80 mg, 0.246 mmol), 3-trifluormethyl-piperidine (150 mg, 0.98 mmol), DIPEA (0.34 mL, 2.0 mmol) and dioxane (5 mL).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7]2>C1COCC1.[Ni]>[Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7]2
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCc1ccccc1)CC2
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(Br)c2c(c1N)CN(CCc1ccccc1)CC2
Yield: 98 %

Procedure:
A solution of the product from Example 9 (0.6 g, 1. mmol) in THF (50 mL) was stirred over RaNi under a hydrogen balloon for 40 mins. The catalyst was filtered off and concentrated under vacuum to give the title compound (0.54 y, 98% yield) as a pink solid.
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.O[CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:28]=[C:22]3[C:21]2=[O:37])[CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:10][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:28]=[C:22]3[C:21]2=[O:37])[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(CO)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(CCl)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 27.1 %

Procedure:
Toluene-4-sulfonyl chloride (73 mg, 0.38 mmol) was added to a solution of 5-(6-hydroxymethyl-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (67 mg, 0.19 mmol) and TEA (0.06 mL, 0.478 mmol) in DCM (1 mL) at 0° C. The reaction was stirred for 10 minutes at 100° C. under microwave irradiation. The mixture was basified with a saturated solution of NaHCO3, the organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash column chromatography (silica, AcOEt in DCM 0/100 to 10/90). Desired fractions were collected and the solvent evaporated in vacuo. The residue was triturated with DIPE to yield 5-(6-chloromethyl-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (19 mg, 27% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.47-4.56 (m, 2H), 4.62 (s, 2H), 4.62-4.67 (m, 2H), 5.13 (s, 2H), 6.94-7.00 (m, 1H), 7.00-7.05 (m, 2H), 7.08 (s, 1H), 7.27-7.35 (m, 3H), 7.77 (dd, J=8.3, 7.6 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O.[Cl-].[Na+].O>[OH:1][N:2]=[C:3]([C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1)[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COCCNc1nonc1C(Cl)=NO
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
N-Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride (1.3 g, 5.0 mmol) [made according to Example 1, steps A through E] was stirred in water (10 mL) and warmed to 60° C. for 5 minutes. 3-(trifluoromethyl)aniline [Aldrich, product #A41801] (880 mg, 5.5 mmol) was added in one portion and the reaction stirred for 15 minutes. While remaining at 60° C., a solution of sodium bicarbonate (630 mg, 7.5 mmol) in water (10 mL) was added dropwise over 5 minutes. The reaction was stirred at 60° C. for an additional 50 minutes, and then allowed to cool to room temperature. Ethyl acetate (20 mL) and brine (30 mL) were added to the flask and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organics were dried over sodium sulfate. The solvent was removed in vacuo to give the desired product as an orange solid (1.4 g, 80%). LCMS calculated for C13H15F3N5O3 (M+H)+: m/z=346.1. 1H NMR (400 MHz, CD3OD): δ 7.36 (t, J=8.2 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 3.60 (t, J=5.2 Hz, 2H), 3.46 (t, J=5.2 Hz, 2H), 3.38 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([Cl:15])[C:8]=1[Cl:16])(=O)=O.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:9]1[C:8]([Cl:16])=[C:7]([C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)[CH:12]=[CH:11][C:10]=1[CH:13]=[O:14]
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccc3ccccc23)c(Cl)c1Cl
Reaction time: 16 h

Procedure:
A mixture of Example 5A (0.20 g, 0.62 mmol), 1-naphthylboronic acid (0.13 g, 0.74 mmol), Pd(PPh3)4 (20 mg), and 2M Na2CO3 (0.62 mL) in toluene (2.0 mL) was heated to 100° C., stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes to 5:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15]CC)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH:33][CH3:34])=[CH:28][CH:27]=1)#[N:25].C(N(C(C)C)CC)(C)C>C(O)CC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:33]([CH3:34])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=3)[C:13](=[O:15])[C:12]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccc(C(C)(C)C)cc1
Reactant: CNNc1ccc(C#N)cc1
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Yield: 40 %

Procedure:
A mixture of 73.19 g of ethyl 3-(4-t-butylphenyl)-3-chloro-2-ethoxycarbonyl-acrylate, 33.6 g of 1-(4-cyanophenyl)-2-methyl-hydrazine, 44.3 g of diisopropylethylamine and 500 ml of 1-propanol was refluxed under heating for 7 days. The reaction mixture was evaporated under reduced pressure. After addition of 1N hydrochloric acid, the resulting residue was extracted with chloroform. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized in ethyl acetate to give 34.9 g of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C[Sn](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[BH4-].[Na+]>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: Brc1ccc2ccncc2c1
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(-c2ccc3c(c2)CNCC3)nc1

Procedure:
In close analogy to the procedure described above, 7-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]=O>C(O)(=O)C.C(Cl)Cl>[CH2:10]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][O:9]1
Reactant: OCCc1ccccc1
Reactant: C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc2c(c1)CCOC2
Yield: 40.2 %

Procedure:
To a solution of phenethyl alcohol (122 mg, 1.0 mmol) in glacial acetic acid (2 mL) was added formaldehyde (40% in water, 100 μl, 1.5 mmol) and Yb(CNf3)3 (276 mg, 0.1 mmol, 10 mol %). The mixture was stirred at reflux for 18 hours. The mixture was allowed to cool, diluted with CH2Cl2, washed with water, aqueous sodium hydrogen carbonate solution, and brine, dried over MgSO4, filtered and evaporated. Chromatography (3:1 PE:Et2O) gave isochroman (54 mg, 40%) as a colourless oil: IR (thin film; NaCl plate) 2929, 2851, 1605, 1585 cm−1; δH (300 MHz, CDCl3) 7.23-7.14 (3H, m, Ar—H×3), 7.04-7.00 (1H, m, Ar—H), 4.82 (2H, s, ArCH2O), 4.04 (2H, t, J=5.7 Hz, ArCH2OCH2), 2.90 (2H, t, J=5.7 Hz, ArCH2CH2); δC (75 MHz, CDCl3) 135.0, 133.3, 129.0, 126.4, 126.0, 124.4, 68.0, 65.4, 28.4; MS 134 (M+), 104, 77, 51.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CO>[F:1][C:2]1[CH:9]=[C:8]([N:16]2[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: OC1CCNCC1
Reactant: N#Cc1c(F)cc(F)cc1F
Solvent: CO
Product: N#Cc1c(F)cc(N2CCC(O)CC2)cc1F
Temperature: 65 °C
Yield: 21.3 %

Procedure:
To a solution of 1.0 g (6.4 mmol) of 2,4,6-trifluorobenzonitrile in MeOH (35 mL) was added 0.65 g (6.4 mmol) of 4-hydroxypiperidine and 1.2 mL (6.7 mmol) of N,N-diiisopropylethylamine. The mixture was heated to 65° C. for 4 h then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.325 g (21%) of 2,6-difluoro-4-(4-hydroxy-piperidin-1-yl)-benzonitrile as a white solid.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:54])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:55]([N:27]1[C@H:26]([C:24]([NH:23][C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=3[CH3:22])=[CH:10][CH:9]=2)[C:5]([OH:54])=[O:4])=[O:25])[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28]1)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (19 mg) was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and benzoyl chloride (3 eq.) added. After stirring at room temperature for 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 797.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]=[C:19]=[S:20].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:18]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[C:19]1=[S:20])[CH3:2]
Reactant: S=C=Nc1ccc2ccccc2c1
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2ccc3ccccc3c2)C1=S
Yield: 34.6 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 9.3 g of 2-naphthyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (4.7 g) was obtained as a light pink solid, m.p. 156°-159° C. Anal. Calcd. for. C15H14N2O S: C, 66.64; H, 5.22; N, 10.36 Found: C, 66.69; H,5.24; N, 10.42. Mass spectrum (EI, M.+) m/z 270.