Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][S:8]([O:11][CH2:12][C@@H:13]1[C@@H:20]2[C@@H:16]([O:17]C(C)(C)[O:19]2)[CH:15]([NH:23][C:24]2[N:29]3[N:30]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([S:39][C:40]([F:43])([F:42])[F:41])[CH:34]=4)[CH:32]=[C:28]3[N:27]=[CH:26][CH:25]=2)[CH2:14]1)(=[O:10])=[O:9])(C)(C)C.P(=O)(O)(O)O.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[S:8](=[O:10])(=[O:9])([O:11][CH2:12][C@H:13]1[CH2:14][C@@H:15]([NH:23][C:24]2[N:29]3[N:30]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([S:39][C:40]([F:43])([F:42])[F:41])[CH:34]=4)[CH:32]=[C:28]3[N:27]=[CH:26][CH:25]=2)[C@H:16]([OH:17])[C@@H:20]1[OH:19])[NH2:7]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@H]1CC(Nc2ccnc3cc(-c4cccc(SC(F)(F)F)c4)nn23)[C@@H]2OC(C)(C)O[C@H]12
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2ccnc3cc(-c4cccc(SC(F)(F)F)c4)nn23)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl-[({(3aR,4R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methoxy)sulfonyl]carbamate (4.0 g) in acetonitrile (20.0 mL) at 0° C. was added phosphoric acid (20.0 mL) while maintaining the temperature below 10° C. This mixture was warmed to ambient temperature and stirred for 4 hours. At this time HPLC analysis showed that <1% starting material or reaction intermediates remained. To the reaction was added ethyl acetate (20 mL) and water (20 mL). After this addition was complete saturated Na2CO3 (80.0 mL) was added until the pH was between 6-7. After stirring for 10 minutes the phases were separated and the aqueous layer was back extracted with ethyl acetate (20 mL). The organic layers were combined and dried with Na2SO4. The organic layer was then concentrated to 4 vol of ethyl acetate. The solution started to precipitate within 5 minutes. This mixture was stirred for 16 hours. The resulting white solids were collected using a filter over 5 minutes. The solid was dried in a vacuum oven under full vacuum overnight (35° C., 16 hours). This yielded (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate anhydrous Form 1. (2.85 g, 84%). XRPD data is shown in FIG. 1; DSC data is shown in FIG. 2; TGA is shown in FIG. 3; Raman data is shown in FIGS. 4, 5A, 6A and 7A.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH:30]=[CH:31][C:32]1[CH:37]=[C:36]([O:38]CC2C=CC=CC=2)[CH:35]=[C:34]([O:46]CC2C=CC=CC=2)[CH:33]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[C:34]([OH:46])[CH:35]=[C:36]([OH:38])[CH:37]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CC=Cc4cc(OCc5ccccc5)cc(OCc5ccccc5)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCc4cc(O)cc(O)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 43 %

Procedure:
The resulting 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3,5-dibenzyloxyphenyl)-2-propenyl)-5α-androstan-3-one was dissolved in ethyl acetate (3 ml) and stirred in the presence of 10% palladium/carbon (50 mg) at 25° C. for 4 days under hydrogen atmosphere. After the reaction mixture was filtered and evaporated under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3,5-dihydroxyphenyl)propyl)-5α-androstan-3-one (107.5 mg, yield 43%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][C:3]=1[O:19][CH3:20].O>O1CCCC1.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(C=CC(=O)c2ccc(O)cc2)ccc1O
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)c2ccc(O)cc2)ccc1O
Yield: 89.3 %

Procedure:
3-(4-Hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)-2-propene-1-one (10 g) is dissolved in 100 g tetrahydrofuran, 0.2 g of Pd on activated carbon (Pd content: about 5% by weight, water content approx. 50% by weight, based on the total mass of the catalyst) is added and a hydrogenation is carried out at normal pressure and room temperature (approx. 20° C.). After removal of the catalyst and the solvent, 9 g of 3-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)-propane-1-one is obtained. Yield: 89% of the theory.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10](O)=[O:11])[CH:8]=[CH:9][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.Cl>O1CCCC1>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:2]1=2
Reactant: O=C(O)c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)CCO2
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 2,3-dihydrobenzo[b]furan-5-carboxylic acid (1.64 g, 10 mmol) in tetrahydrofuran (10 mL) was added under ice-cooling lithium aluminum hydride (949 mg, 25 mmol) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was stirred under ice-cooling and methanol and 1N hydrochloric acid were added. The precipitate was filtered off and the mother liquor was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.5 g, 100%).
Reaction SMILES: C[C:2](O)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]=[CH2:4].[CH3:12][C:13]([OH:23])(CCC=C(C)C)CCC>>[CH2:13]([OH:23])[CH2:12][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:2][CH2:3][CH3:4]
Reactant: CCCC(C)(O)CCC=C(C)C
Reactant: C=CC(C)(O)CCCCCC
Product: CCCCCCCCCCCO

Procedure:
In "Materials Tested as Insect Attractants" compiled by M. Beroza and N. Green in Agriculture Handbook No. 239 in Table 2 it is stated that 3-methyl-1-nonen-3-ol has, on a scale of 1 to 3, an attractancy of "1" for the Oriental Fruit Fly and an attractancy of "1" for the Mediterrean Fruit Fly and 4,8-dimethyl-7-nonen-4-ol has on a scale of 1 to 3 an attractancy of 37 2" for the Oriental Fruit Fly and an attractancy of "3" for the Mediterrean Fruit Fly and an attractancy of "1" for the Mexican Fruit Fly and an attractancy of "1" for Drosophila.
Reaction SMILES: [K].[CH2:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[N:12][NH:13][C:7]=2[N:6]=[C:5]1[SH:14])[CH3:3].[CH3:15]I>CN(C=O)C>[CH2:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[N:12][NH:13][C:7]=2[N:6]=[C:5]1[S:14][CH3:15])[CH3:3]
Reactant: CI
Reactant: CCn1c(S)nc2[nH]ncc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Product: CCn1c(SC)nc2[nH]ncc2c1=O
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of 5-ethyl-6-mercapto-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium (5.0 g) in DMF (40 ml) was added methyl iodide (3.65 g) and the mixture was stirred for 1 hour. This reaction mixture was concentrated and the residue was diluted with water. The resulting crystals were collected by filtration and rinsed with water to provide 5-ethyl-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one as colorless solid (2.908 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15].CC(N=NC(C#N)(C)C)(C#N)C.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][P:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)([CH3:11])=[O:16])[CH3:15]
Reactant: CCOP(C)OCC
Reactant: O=C(O)c1ccc(Br)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOP(C)(=O)c1ccc(C(=O)O)cn1
Reaction time: 16 h

Procedure:
6-Bromonicotinic acid (150 mg, 0.74 mmol) and diethyl methylphosphonite (1.21 g, 8.91 mmol) were dissolved in toluene and the solution was purged with argon for several minutes. The mixture was brought to reflux and a solution of AIBN (40 mg, 0.22 mmol) and tris trimethylsilylsilane (220 mg, 0.89 mmol) in toluene was added dropwise over 4 hours via syringe pump. The initiator was added via syringe pump over 4 hours. The resulting mixture was reluxed for 16 hours then it was concentrated in vacuo and purified directly by MPLC (0-50% EtOAc:Hex). MS: cal'd 230 (MH+), exp 230 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:18]([CH3:34])[C:17]=1[CH3:35].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:18]([CH3:34])[C:17]=1[CH3:35]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)CCOc4ccccc4)c(C)c3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCCOc4ccccc4)c(C)c3C)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-3-phenoxypropaneamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mxitue was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]Cl)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][C:26]#[CH:27])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][C:26]#[CH:27])=[O:23])=[CH:28][CH:29]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C#CCOC(=O)c1ccc(O)cc1
Reactant: ClCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C#CCOC(=O)c1ccc(OCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 3.9 parts of 3-chloro-6-[4-(2-chloroethyl)-1-piperidinyl]pyridazine, 2.64 parts of (2-propynyl) 4-hydroxybenzoate, 2.76 parts of potassium carbonate and 75 parts of N,N-dimethylacetamide was stirred overnight at 110° C. After cooling, the reaction mixture was poured into 100 parts of water and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 5.2 parts (86.7%) of (2-propynyl) 4-[2-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 122.0° C. (comp. 120).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH:13]=O>CCO.Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:3]2[C:4](=[O:7])[C:5](=[CH:13][C:12]3[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:10]([O:9][CH3:8])[CH:11]=3)[CH2:6][O:1][CH2:2]2)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19]
Reactant: O=C1CCOCC1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Solvent: CCO
Product: COc1cc(C=C2COCC(=Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC

Procedure:
A solution of 6.0 g (0.06 mole) of tetrahydro-4H-pyran-4-one and 25 g (0.127 mole) of 3,4,5-trimethoxybenzaldehyde in 75 ml of EtOH and 10 ml of concentrated HCl is stirred and heated at reflux for 3 hours. The product gradually precipitates from the cooled solution. The yield of yellow crystals is 12.0 g (44%), m.p. 187°-189°.
Reaction SMILES: F[C:2]1[C:3]([C:11](=O)[CH3:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH3:14][NH:15][NH2:16]>>[CH:8]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:11]([CH3:12])=[N:16][N:15]([CH3:14])[C:2]=12)([CH3:10])[CH3:9]
Reactant: CC(=O)c1nccc(C(C)C)c1F
Reactant: CNN
Product: Cc1nn(C)c2c(C(C)C)ccnc12
Temperature: 140 °C
Reaction time: 2 h

Procedure:
1-(3-Fluoro-4-isopropyl-pyridin-2-yl)-ethanone (prepared in the previous step, 2.50 g, 15.15 mmol) and methyl hydrazine (1.04 g, 23.00 mmol) were combined in 8 mL of glycol. The reaction solution was stirred at 140° C. for 2 hours. After cooling, it was quenched with water, extracted with DCM, then washed with water, brine and concentrated. Column chromatography using 15 to 35% ethyl acetate in hexane as eluant afforded the title compound as a pale yellow solid. Spectroscopic data: 1H-NMR (300 MHz, CDCl3): δ ppm 1.39 (d, J=6.73 Hz, 6 H), 2.64 (s, 3 H), 3.65 (hept, J=6.73 Hz, 1 H), 4.23 (s, 3 H), 7.14 (d, J=4.69 Hz, 1 H), 8.44 (d, J=4.69 Hz 1 H).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:22]1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CC1CCCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2)C1

Procedure:
Proceeding as in example 2, with 0.035 mole (10.4 g) of 2,4'-dichloro-5-nitro-benzophenone, 0.07 mole (7 cm3) of 3-methylpiperidine and 0.035 mole (5 g) of calcium carbonate mixed in ethanol, 12 g (Yield : 96%) of the expected product are obtained. M.P. 112° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]3[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=3[S:22][N:21]=2)=[O:19])=[CH:13][C:12]=1[C:30]([F:33])([F:32])[F:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]3[CH:25]=[CH:26][C:27]([O:29][C:6]4[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:28][C:23]=3[S:22][N:21]=2)=[O:19])=[CH:13][C:12]=1[C:30]([F:32])([F:31])[F:33]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1nsc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)nsc3c2)n1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 72 mg (0.44 mMol) 2-amino-4,6-dichloropyrimidine, 143 mg (0.40 mMol) 6-hydroxy-benzo[d]isothiazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide and 280 mg (1.32 mMol) K3PO4 in 2 ml NMP is stirred for 6 h at 70° C. Then the mixture is diluted with EtOAc and water, the aq. layer separated off and extracted twice with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2→CH2Cl2/EtOH 9:1) gives the title compound: MS: [M−1]=482/484; TLC(CH2Cl2): Rf=0.12.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(C)(c2ccc(Br)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccc(Br)cc2)CCNCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (284) (5.36 g, 16 mmol) in EtOH (75 mL) was added KOH (17.9 g, 320 mmol). The resulting mixture was stirred at 80° C. for overnight before being cooled down to RT. The solvent was removed and the residue was partitioned in water (30 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (10 mL×5). The combined organic layers were washed with brine, dried, and concentrated in vacuo to give crude 4-(4-bromophenyl)-4-methylpiperidine (285) in quantitative yield, which was used directly in next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)=[O:2].[C:8]([O:11][CH2:12][CH2:13]Br)(=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([C:3]1[N:4]([CH2:9][C:8]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][N:7]=1)=[O:2]
Reactant: CC(=O)OCCBr
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccnc1C=O

Procedure:
A mixture of 2-formylimidazole (5.16 g), bromoethyl acetate (7.1 ml) and potassium carbonate (11.1 g) in. DMF (50 ml) was stirred for 20 hours at 60° C. The insolubles were removed by filtration, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1), to give ethyl (2-formyl-1H-imidazol-1-yl)acetate (1.10 g) as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+]>C1COCC1.CCO>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 4[(5,5-dimethyl-5,6-dihydronaphthalen-8(7H)-one-2-yl)azo]benzoate (Compound D10, 60 mg, 0.171 mmol) in 2 ml of THF and 7 ml of EtOH at 0° C. was added NaBH4 (6.5 mg, 0.171 mmol) and the mixture stirred for 3 h. The reaction was quenched by slow addition of cold water. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The crude product was purified by flash chromatography (silica, ethyl acetate/hexane, 1:3) to afford the title compound as a red oil.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:32][O:33][C:34](=[O:39])[C:35]([NH2:38])([CH3:37])[CH3:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH3:32][O:33][C:34](=[O:39])[C:35]([NH:38][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]3([OH:19])[CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:30])([CH3:37])[CH3:36]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)O)c(C)c1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)NC(C)(C)C(=O)OC)c(C)c1
Yield: 82.1 %

Procedure:
4-{1-Ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (389 mg, 0.962 mmol), α-aminoisobutyric acid methyl ester hydrochloride (221 mg, 1.44 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (276 mg, 1.44 mmol), 1-hydroxybenzotriazole hydrate (195 mg, 1.44 mmol) and triethylamine (536 μL, 3.85 mmol) are stirred overnight. The reaction is concentrated and partitioned between EtOAc (150 ml) and 1N HCl (50 ml). The aqueous layer is extracted with EtOAc (100 ml). The combined organic layers are washed with, water (50 ml), NaHCO3 (50 ml), brine (50 ml), dried (anhydrous MgSO4), concentrated and chromatographed (12 g SiO2, 15% EtOAc/Hexanes) to yield the title compound (398 mg, 82%).
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:24].[K+]>C(#N)C>[O:24]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2([CH2:5][CH2:6][N:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:2][CH2:3]2)[CH2:7][CH2:8]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCc3ccccc32)CC1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)c3ccccc32)CC1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of the Boc-piperidine (602 mg, 2 mmol) in acetonitrile (10 ml) was added potassium permanganate (KMnO4, 950 mg, 6 mmol). The reaction mixture was stirred at 70° C. for 15 hours, filtered through Celite, and the filter cake was washed with dichloromethane. The filtrate and washings were concentrated and the residue was dissolved in acetonitrile (10 ml) and reacted with KMnO4 (950 mg, 6 mmol) at 70° C. for another 24 hours. After filtration, washing and concentrating, the residue was purified by flash column chromatography (CH2Cl2/CH3CN: 1:0 to 9:1) to provide tert-butyl 4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (A4). LC-MS: m/e=260.0 (M+H−tBu). Rt=3.46 min. 1H-NMR (500 MHz, CDCl3): 8.07 (dd, J=1.5, 7.8, 1H), 7.60-7.57 (td, J=7.9, 1.2, 1H), 7.50 (d, J=7.9, 1H), 7.36 (t, J=7.6, 1.0, 1H), 4.10 (br.d, J=13.2, 2H), 3.08 (t, J=13.8, 2H), 2.71 (t, J=6.7, 2H), 2.27 (t, J=6.9, 2H), 2.05 (td, J=13.4, 4.7, 2H), 1.73 (br.d, J=13.2, 2H), 1.52 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:16])[C:9]3[S:15][CH:14]=[CH:13][C:10]=3[CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:26])([F:25])[C@:19]([OH:24])([CH3:23])[C:20](O)=[O:21]>>[F:17][C:18]([F:26])([F:25])[C@:19]([OH:24])([CH3:23])[C:20]([NH:1][C:2]1[C:7]2[C:8](=[O:16])[C:9]3[S:15][CH:14]=[CH:13][C:10]=3[CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: Nc1cccc2c1C(=O)c1sccc1CS2
Reactant: C[C@](O)(C(=O)O)C(F)(F)F
Product: C[C@](O)(C(=O)Nc1cccc2c1C(=O)c1sccc1CS2)C(F)(F)F
Yield: 99 %

Procedure:
Substantially the same procedure as in Reference Example 7 was repeated using 9-amino-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one obtained in Reference Example 5 (0.56 g, 2.26 mmol) and (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid obtained in Reference Example 12 (0.72 g, 4.52 mmol) to give (S)-9-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino)-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one (0.87 g, 99%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:30])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C1(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(OC)=O)C4=O)=CC=3)=CC=2)CCCCC1>>[CH:5]1([NH:8][C:9](=[O:34])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:32])[CH3:33])[C:28]([OH:30])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)NC4CCCCC4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)NC4CCCCC4)cc3)cc2C1=O
Yield: 93 %

Procedure:
The compound of example 34 was prepared analogous to compound of example 8 by hydrolysis of compound of example 33.