Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6](=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:6](=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)CCCCCCC(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCCCCCC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
Aluminium chloride (2.58 g) was added to a mixture of methyl 8-chloro-8-oxooctanoate (2.00 g) and anisole (5 ml) at 0° C. After stirring at room temperature for 14 hours, the reaction mixture was poured onto ice (50 g), stirred at room temperature for 1 hour and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl 8-(4-methoxyphenyl)-8-oxooctanoate (2.37 g, yield 88%) as crystals. The crystals were recrystallized from ethyl acetate-hexane to obtain colorless crystals. m.p. 57-58° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A solution of 6-chloro-2-pyridinamine (13.776 g, 107 mmol) in toluene (100 ml) and triethylamine (16.28 ml, 118 mmol) at 50° C. under argon was treated with 2,2-dimethylpropanoyl chloride (13.81 ml, 112 mmol). The reaction was then stirred at 50° C. for 4 h and then at rt for 18 h. 2M HCl (200 ml) was then added and the mixture was extracted with diethyl ether (3×500 ml). The organic extracts were dried (MgSO4), filtered and evaporated to give the product as a brown solid (21.005 g, 92%).
Reaction SMILES: [OH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:8]=2)[CH:3]1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@@H:16]1[CH3:28].[H-].[Na+].[CH3:31]I>C1COCC1>[CH3:31][O:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[CH:3]1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@@H:16]1[CH3:28]
Reactant: CI
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1Cc2cc(C(F)(F)F)ccc2C1N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3S)-4-[2-hydroxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazine-1-carboxylate (isomer 1 from step C in Example 9) (50 mg, 0.1 mmol) in THF (2 mL) at 0° C. was added NaH (8 mg, 60% in oil, 0.2 mmol). After being stirred for 10 min, MeI (28 mg, 0.2 mmol) was added. The mixture was stirred at ambient temperature for 1 h and quenched with aqueous NH4Cl. The resulting solution was extracted with EtOAc twice. The extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the crude product. LC/MS calculated for C21H29F3N2O3: (M+H)+ 415. found 415.2.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH2:36](Br)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCBr
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: CCCCOc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with butyl bromide
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN1CCCC1=O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: Brc1ccc2nccc(N3CCCCC3)c2c1
Temperature: 150 °C
Yield: 100.4 %

Procedure:
To a solution of 4-choro-6-bromoquinoline (726 mg, 3 mmol) in 3 mL of 1-methyl-2-pyrrolidinone was added piperidine (510 mg, 6 mmol). The reaction was heated to 150° C. for 5 h. The solvents were removed in vacuo at 100° C. and the residue dissolved in methylene chloride and washed with water. The methylene chloride was dried with sodium sulfate and concentrated. The residue was triturated with hexane and the solid filtered off to give 6-bromo-4-(1-piperidinyl) quinoline (877 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:7][N:8]2[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:39]([O-])=O.[Cl-].[NH4+]>CN(C)C=O.[Fe]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[N:7][N:8]2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[NH2:39]
Reactant: O=[N+]([O-])c1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 290 mg of 6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-nitro-1-trityl-1H-indazole in a mixture of 5 mL N,N-dimethylformamide/9 mL methanol/1 mL water were added 30 mg of ammonium chloride and 150 mg of iron powder, and stirred at 80° C. for 8 hours. After filtering off the insoluble substances through Celite, the solvent was evaporated, and the resultant residue was dissolved in 15 mL of ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated, to afford 252 mg of the title compound as pale brown non-crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C.CCOCC>[CH3:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[CH:20]=[N:1]2
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: Cc1cccc2ncn(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.60 g, 2.2 mmol), trimethyl orthoformate (3 mL, 26.8 mmol), and p-toluene sulfonic acid (0.060 g) in acetonitrile (20 mL) was heated to reflux for 30 hours. The mixture was cooled to room temperature. To the mixture, water (75 mL) and ether (20 mL) were added, and the resulting mixture was stirred for 2 hours. The suspension was filtered and washed with water and ether (50 mL each) to give 3-(5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (0.28 g, 47% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.08 min (99%); mp: 262-264° C.; 1H NMR (DMSO-d6) δ 2.09-2.16 (m, 1H, CHH), 2.62-2.84 (m, 6H, CH2, CH3, CHH), 5.42 (brs, 1H, NCH), 7.32 (d, J=7 Hz, 1H, Ar), 7.52 (d, J=8 Hz, 1H, Ar), 7.69 (t, J=8 Hz, 1H, Ar), 8.30 (s, 1H, CH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.35, 22.62, 30.88, 58.00, 119.81, 125.36, 129.57, 133.72, 140.15, 147.08, 149.07, 160.21, 169.91, 172.33, 172.44; LCMS: MH=272; Anal. Calcd. for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.67; H, 4.40; N, 15.41.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[OH:32][C:33]1([C:11]2[S:12][C:8]([C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]4[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=4)[N:5]=3)=[CH:9][N:10]=2)[C:41]2[C:36](=[CH:37][C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:40]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1ccc2c(c1)CCC2=O
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
A solution of 4-methyl-6-(thiazol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (1.5 g, 4.46 mmol) in THF (35.7 mL) was cooled to −78° C. LDA (2M, 6.69 mL, 13.38 mmol) solution was slowly added, and the resulting mixture was stirred as at −78° C. for 30 minutes. In a separate dry flask, methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate (1.06 g, 5.57 mmol) was dissolved in THF (5 mL), then this solution was added to the reaction mixture, which was then allowed to warm to rt over a period of 3 hrs, then stirred at rt for an additional 13 h. The reaction was quenched by addition of 2 mL MeOH and then loaded directly onto a silica gel chromatography column and purified with a gradient solvent system of 0-100% EtOAc/hexanes. The product-containing fractions were evaporated to give methyl 1-hydroxy-1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylate 16C (912 mg, 39%) as a light yellow solid. MS ESI calcd for C26H21F3N4O3S [M+H]+ 527, found 527.
Reaction SMILES: [C:1]([Si:5]([CH3:41])([CH3:40])[O:6][CH:7]([CH:19]([NH:27][C:28]([C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][CH:9]([CH2:13][CH2:14][C:15]([F:18])([CH3:17])[CH3:16])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:42]([CH2:44][NH2:45])[OH:43].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:20]([CH:19]([NH:27][C:28]([C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:41])[CH3:40])[CH2:8][CH:9]([C:10](=[O:11])[NH:45][CH2:44][CH2:42][OH:43])[CH2:13][CH2:14][C:15]([F:18])([CH3:17])[CH3:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NCCO
Reaction time: 17 h
Yield: 62 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-2-(3-fluoro-3-methyl-butyl)-6-phenyl-5-[(quinoxaline-2-carbonyl)-amino]-hexanoic acid (515 mg, 0.885 mmol) in methylene chloride (9 mL) was added ethanolamine (0.080 mL, 1.33 mmol), 1-hydroxybenzotriazole (215 mg, 1.59 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.50 mmol) and triethylamine (0.247 mL, 1.77 mmol). The resulting solution was stirred for 17 hours then diluted with ethyl acetate and washed with water then saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave the title compound (343 mg, 62%).
Reaction SMILES: C(OC(N1C[C@@H](C)N2[C@H](CC3C2=NC(C(F)F)=C(CO)C=3)C1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:46][C@@H:45]([CH3:47])[N:44]2[C@H:36]([CH2:37][C:38]3[C:43]2=[N:42][C:41]([C@H:48]([O:50][CH3:51])[CH3:49])=[C:40]([CH:52]=[O:53])[CH:39]=3)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[BH4-].[Na+]>>[C:27]([O:31][C:32]([N:34]1[CH2:46][C@@H:45]([CH3:47])[N:44]2[C@H:36]([CH2:37][C:38]3[C:43]2=[N:42][C:41]([C@H:48]([O:50][CH3:51])[CH3:49])=[C:40]([CH2:52][OH:53])[CH:39]=3)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CO[C@H](C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(C(F)F)nc3N21
Agent: [BH4-]
Agent: [Na+]
Product: CO[C@H](C)c1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15, intermediate b) from (4R,9aR)-7-formyl-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium borohydride.
Reaction SMILES: [F-].[Cs+].[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20]1[CH:24]=[C:23]([Si](C)(C)C)[O:22][N:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC#N.CCO>[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20]1[CH:24]=[CH:23][O:22][N:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCO
Product: O=C1N2C[C@@H](CC[C@H]2c2ccon2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
CsF (230 mg, 1.512 mmol was added to a solution of (2S,5R)-6-(benzyloxy)-2-(5-(trimethylsilyl)isoxazol-3-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (187 mg, 0.504 mmol) in CH3CN/EtOH (15 mL, 3:1). After stirring at rt for 2 hrs, the reaction mixture was concentrated and the residue was dissolved in DCM (25 mL), washed with water (3×), and saturated sodium chloride, then, dried, and concentrated. The residue was purified by silica gel column chromatography (6:1 petroleum ether/EA) to afford (2S,5R)-6-(benzyloxy)-2-(isoxazol-3-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (116 mg, 77%) as a white solid. ESI-MS (EI+, m/z): 300 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21]C(OCC3C=CC=CC=3)=O)[C@H:17]([O:32][CH3:33])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[C@H:17]([O:32][CH3:33])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1NC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1NC(C)=O

Procedure:
Methyl cis(±)-2-(acetylamino)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (185c) was dissolved in ethanol (25 mL). A 10% palladium-carbon catalyst (180 mg) was added, and the mixture was stirred in a hydrogen atmosphere overnight. The reaction solution was filtered through celite and then concentrated under reduced pressure to obtain 210 mg of the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][C:11]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[N:10][CH:9]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br>O1CCCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:16]([CH3:17])[C:14](=[O:15])[C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][N:10]=[C:11]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[CH:12]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(N2CCN(C)CC2)ncc1-c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(-c3ccccc3Cl)cn2)CC1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 0.074 g (0.21 mmol) 5-(2-chloro-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide in 5 ml tetrahydrofuran at −10° C. were added dropwise 0.29 ml (0.29 mmol) of 1 M potassium hexamethyldisilazide solution in tetrahydrofuran. Stirring was continued for ½ h at −10° C. At this temperature 0.42 ml 3.5-bis(trifluormethyl)-benzylbromide were added. The reaction was quenched with water after 10 min and the mixture was extracted with three 15 ml portions of ethyl acetate. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.113 g (92%) of the title compound as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([C:7]1[CH:8]=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:10]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)([CH3:6])[CH3:5].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:31])=[O:2])[CH:8]=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=2)[CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)(C)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 39.3 %

Procedure:
A solution of 2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid methyl ester (0.12 g, 0.28 mmol) in THF (4 ml) was treated at room temperature with a solution of KOH (0.17 g, 3.00 mmol) in methanol and water (3 ml, 6:1). After two days the mixture was acidified with citric acid and extracted with EtOAc. The combined organic extracts were washed with NaHCO3 solution (sat aq), brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid (0.045 g, 0.11 mmol) as a white solid in 39% yield. 1H NMR (d4-MeOD) 7.79-7.71 (m, 4H), 7.50-7.46 (m, 2H), 7.42-7.36 (m, 2H), 7.35-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.17-7.14 (m, 1H), 7.08-7.05 (m, 1H), 5.17 (s, 2H), 1.59 (s, 6H); LCMS method (A), RT=4.5 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[C:49]#[C:50][CH2:51][OH:52])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]#[C:50][CH2:51][OH:52])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1ccn(CC#CCO)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC#CCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.2 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 241 mg, 0.73 mmol) was suspended in methylene chloride (3.6 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (364 μL, 0.73 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (170 μL, 1.46 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 4-(3-Amino-pyrazol-1-yl)-but-2-yn-1-ol (110 mg, 0.73 mmol) was dissolved in methylene chloride (3.6 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to an orange foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 5% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-hydroxy-but-2-ynyl)-1H-pyrazol-3-yl]-propionamide (92 mg, 27%) as a white foam: ESI-LRMS m/e calcd for C22H26ClN3O4S [M+] 463.1, found 464.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.24 (m, 2H, CH2), 1.44-1.95 (m, 8H, 4×CH2), 2.10-2.37 (m, 1H, CH), 3.27 (s, 3H, SO2CH3), 3.56 (t, J=7.4 Hz, 1H, CH), 4.31 (t, J=1.7 Hz, 2H, OCH2), 4.82 (t, J=1.7 Hz, 2H, NCH2), 6.72 (d, Jo=2.3, 1H, Ar), 7.43 (d, Jo=2.3, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.4 Hz. 1H, Ar), 7.59 (d, Jm=1.4 Hz, 1H, Ar), 8.08 (brs, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[Cl-].[NH4+].O1CC[CH2:23][CH2:22]1>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])[C:22]#[CH:23]
Reactant: COCOCC(C)=CCCC(C)=CCCC(C)=O
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(C)(O)CCC=C(C)CCC=C(C)COCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of 6,10-dimethyl-11-(methoxymethyl)oxy-5,9-undecadien-2-one (67 mg, 0.26 mmol) in tetrahydrofuran (2 ml) was stirred on an ice bath under argon atmosphere. To the solution was added lithium acetylide ethylenediamine complex (30 mg, 0.33 mmol), and the mixture was warmed to room temperature and stirred for 3 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(methoxymethyl)oxy-6,10-dodecadien-1-in- 3-ol (61 mg, 83%).
Reaction SMILES: [F:1][CH:2]([F:15])[C@@H:3]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@H:6]2[NH:7]C(=O)[O:9][C@H:5]2[CH2:4]1.[Li+].[OH-]>CO.O>[NH2:7][C@H:6]1[C@@H:5]([OH:9])[CH2:4][C@H:3]([CH:2]([F:1])[F:15])[C@@H:12]([OH:13])[C@@H:11]1[OH:14]
Reactant: O=C1N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]2O1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]1O
Yield: 73.3 %

Procedure:
To a solution of (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-4,5-dihydroxyhexahydrobenzo[d]oxazol-2(3H)-one (255 mg, 1.48 mmol) in MeOH (2 mL) and water (3 mL) was added LiOH (600 mg, 25.0 mmol). The mixture was heated at reflux for 2 h. Solvents were evaporated and the residue was purified by silica gel column chromatography, eluted with 20% 2 M NH3 MeOH solution in DCM to give the product (1R,2R,3S,4S,6S)-3-amino-6-(difluoromethyl)cyclohexane-1,2,4-triol (214 mg, 99%) as a white solid. MS m/z 198.1 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 6.14 (t, J=57.2 Hz, 1H), 4.15 (br s, 1H), 3.63 (t, J=9.7 Hz, 1H), 3.30 (t, J=11.0 Hz, 1H), 2.91 (dd, J=10.4 Hz, 2.8 Hz, 1H), 2.20-2.36 (m, 1H), 1.97 (dt, J=14.4 Hz, 3.6 Hz, 1H), 1.53-1.60 (m, 1H).