Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][CH:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1.[CH3:17][N:18](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:17]#[N:18])[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1
Reactant: CC(=O)N(C)C
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(Cl)n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(C#N)n1
Temperature: 120 °C
Yield: 59 %

Procedure:
Add 2-sec-butylamino-6-chloro-isonicotinic acid methyl ester (1.22 g, 5.0 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene (222 mg, 0.4 mmol), zinc cyanide (587 mg, 5.0 mmol), and zinc dust (78 mg, 1.2 mmol) in N,N-dimethylacetamide (10 mL) and heat in a sealed tube at 120° C. overnight. Cool to room temperature, filter through a filtering agent, concentrate and purify (silica gel chromatography, eluting with 10:90 to 15:85 ethyl acetate:hexanes) to give the title compound (703 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][CH2:11][C:12]#[CH:13]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]#[C:12][CH2:11][CH2:10][C:9]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COC(=O)CCC#Cc1ccc(Cl)cc1
Yield: 48.1 %

Procedure:
A mixture of 1-chloro-4-iodobenzene (56 g, 235 mmol), dichlorobis(triphenylphosphine)palladium (II) (6.9 g, 9.8 mmol) and copper (I) iodide (1.9 g, 9.8 mmol) in diethylamine (200 mL) was degassed with bubbling nitrogen. Methyl 4-pentynoate (Description 1, 22.0 g, 196 mmol) was added dropwise and the mixture was degassed with bubbling nitrogen. The mixture was heated under reflux for 24 h., cooled and poured into saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate and the combined organic fractions were washed with saturated aqueous ammonium chloride. The solvent was evaporated under reduced pressure and the residue was triturated with hexane. The mixture was filtered, dried (MgSO4) and concentrated under reduced pressure. The mixture was refrigerated and the solid was collected and dried in vacuo to give the title compound as pale brown solid (21.0 g, 48%). 1H NMR (360 MHz, CDCl3) δ 7.31 (2H, d, J 7.5 Hz), 7.25 (2H, d, J 7.5 Hz), 3.72 (3H, s), 2.73 (2H, t, J 7.3 Hz), and 2.62 (2H, t, J 7.3 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.Cl.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[C:10]1([NH:16][N:17]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: O=Cc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C(=NNc1ccccc1)c1ccncc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
4-Pyridinecarboxaldehyde (1.75 g, 16 mmol), phenylhydrazine hydrochloride (2.26 mL, 16 mmol) and triethylamine (1.65 g, 16 mmol) were dissolved in ethanol (50 mL) and heated for 1 h. The reaction mixture was cooled to room temperature. The resulting precipitates were collected and washed with petroleum ether to afford 3.04 g (94%) of 1 as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][OH:4].CC(C)([O-])C.[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1>COCCOC.O>[CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][O:4][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1
Reactant: CCC(C)CO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCC(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To 2-methyl-1-butanol (0.855 mL) in DME (4 mL) was added sodium tert-butoxide (760 mg). The mixture was stirred at room temperature until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) was added followed by DME (4 mL). The reaction was heated at 110° C. overnight. The mixture was cooled and concentrated in vacuo to give a yellow residue. The residue was taken up in water (30 mL) and extracted with EtOAc (2×30 mL). The organics were separated and washed with brine (30 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow/brown residue. This material was taken on to the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[C:44](Cl)(=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>O1CCOCC1.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:44]([O:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:14])[CH3:15])[NH:8][C:9]([O:11][CH3:12])=[O:10])(=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCC(=O)O[C@@H](CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 105, 200 mg (0.33 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(methoxy-carbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]-hydrazine (Example 73a) in 2.6 ml of dioxane and 0.4 ml of pyridine are reacted with 0.15 ml (0.495 mmol) of palmitic acid chloride and 2 mg (0.017 mmol) of DMAP. To complete the reaction a further 0.3 ml of palmitic acid chloride and a small amount of DMAP are added and the mixture is stirred. Extraction and column chromatography (SiO2, ethyl acetate/hexane 3:2) yields the pure title compound: TLC Rf (H')=0.47; tRet (V)=25.2 min; FAB-MS (M+H)+ =844.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][S:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccs1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CSc1cccs1)OC
Yield: 97 %

Procedure:
To a solution of 2-thiophenethiol (12.3 g, 106 mmol) in acetone (180 ml), bromoacetaldehyde dimethyl acetal (13.6 ml, 115 mmol) was added, followed by potassium carbonate (21.8 g, 158 mmol). The reaction was refluxed for 16 h, cooled, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over silica (eluent: petrol:DCM, 2:1) to afford the product as an orange oil (21.0 g, 97%). M/Z 204 (M+). Found C, 47.0; H, 5.7; S, 32.3; O, 15.8. Calc. for C8H12O2S2 C, 47.0; H 5.9; S, 31.4; O, 15.7. 1H NMR (300 MHz, CDCl3) δ 7.35 (dd, 1H, J=1.22 & 5.37 Hz), 7.17 (dd, 1H, J=1.22 & 3.58 Hz), 6.97 (dd, 1H, J=3.58 & 5.37 Hz), 4.51 (t,1 H, J=5.65 Hz), 3.35 (s, 6H), 2.98 (d, 2H, J=5.65 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]([Mg]Br)#[C:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[C:13]#[C:14][CH3:15]
Reactant: CC#C[Mg]Br
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC1(O)C(=O)Nc2ccc(Br)cc21
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 5-bromoisatin (2.5 g, 11 mmol) in dry THF (100 cm3) at −10° C. under a nitrogen atmosphere was added 1-propynylmagnesium bromide (0.5 M in THF, 47 cm3, 23.5 mmol). After 1 h, the mixture was poured into saturated ammonium chloride and extracted with EtOAc (×3), washed with brine, dried (MgSO4) and evaporated to afford 5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (2.83 g, 10.6 mmol, 97%) which was used without further purification: (CDCl3) δ 1.83 (s, 3H), 6.79 (d, 1H, J=8.0 Hz), 6.90 (s, 1H), 7.41-7.44 (m, 2H), 10.59 (s, 1H); MS ((−) ESI) m/z 264 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:4]2[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]2=[O:7])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1(C)NC(=O)NC1=O
Product: COc1ccc(CN2C(=O)NC(C)(C)C2=O)cc1

Procedure:
Using 5,5-dimethylimidazolidine-2,4-dione (3.00 g) and 4-methoxybenzyl chloride (3.81 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (4.32 g) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[O:16][CH3:17].O.[OH-].[Na+]>CO>[CH3:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:9][C:4]=1[C:3]([OH:18])=[O:2]
Reactant: COC(=O)c1cc(N2CCOCC2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(N2CCOCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (170 mg) was dissolved in MeOH (5 ml) and H2O (5 ml) and treated with 1 M aq. sodium hydroxide (2 ml). After stirring at r.t. for 16 h the mixture was concentrated and partitioned between EtOAc and H2O. the aqueous layer was acidified (pH 2.0) and then extracted further with EtOAc (×3). The combined organic fraction was washed with brine, dried (MgSO4) and reduced in vacuo to give 2-methoxy-5-morpholin-4-yl-benzoic acid (90 mg) as a yellow oil. (LC/MS (basic method): Rt 0.91 min., [M+H]+ 238).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH3:17])[CH2:13][S:12](=[O:15])(=[O:14])[CH2:11][C:10]([NH2:16])=[N:9]1.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:23]([O-:25])=[O:24])=[CH:4][C:3]=1[C@:8]1([CH3:17])[CH2:13][S:12](=[O:14])(=[O:15])[CH2:11][C:10]([NH2:16])=[N:9]1
Reactant: C[C@@]1(c2ccccc2F)CS(=O)(=O)CC(N)=N1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)CC(N)=N1
Yield: 100 %

Procedure:
To a solution of (R)-5-(2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (497 mg, 1.94 mmol, Eq: 1.00) in conc. sulfuric acid (14.8 g, 8.06 ml, 151 mmol, Eq: 78) was added at 0° C. 100% nitric acid (189 mg, 134 μl, 3.01 mmol, Eq: 1.55) and the mixture was stirred at 0° C. for 1 hour. Poured into sat NaHCO3-sol., extracted with ethyl acetate, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left the (R)-5-(2-fluoro-5-nitro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (584 mg, 1.94 mmol, 100% yield) as a light yellow oil. MS (ISP): m/z=302.1 [M+H]+.
Reaction SMILES: C1([C@H]([N:9]([C@@H:21]2[CH2:27][CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][C:23]=3[CH2:22]2)[CH2:10][C@@H:11]([OH:20])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C)C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:37]([O:36][C:34]([CH2:33][O:32][C:30]1[CH:29]=[CH:28][C:24]2[CH2:25][CH2:26][CH2:27][C@@H:21]([NH:9][CH2:10][C@@H:11]([OH:20])[CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][C:23]=2[CH:31]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@H](N(C[C@@H](O)COc1ccccc1)[C@H](C)c1ccccc1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](NC[C@@H](O)COc1ccccc1)CCC2
Yield: 85.8 %

Procedure:
A mixture of (2R)-1-[N-((R)-1-phenylethyl)-((6R)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (2.0 g) and 10% palladium on activated carbon (50% wet, 0.70 g) in ethanol (24 ml) and tetrahydrofuran (12 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3.5 hours, and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed (chloroform-methanol) over silica gel to afford (2R)-1-[((6R)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (1.37 g).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:21])[NH:8][C:9](=[O:20])[N:10]([CH:19]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1)#[C:2][CH2:3][CH2:4][CH3:5]>CO.[Pd]>[CH2:1]([C:6]1[C:7](=[O:21])[NH:8][C:9](=[O:20])[N:10]([CH:19]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CO
Product: CCCCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 14 h

Procedure:
To a solution of 1.03 g (3.50 mmol) of 5-(1-pentynyl)-2'-deoxyuridine in 25 mL of MeOH was added a catalytic amount of 10% Pd on charcoal. The mixture was hydrogenated under 300 psi of H2 for 14 h at room temperature. The mixture was filtered through Celite and concentrated, affording a quantitative yield of product.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH:4]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:5](N(OC)C)=[O:6].[H-].C([Al+]CC(C)C)C(C)C.Cl>C(Cl)Cl>[F:1][C:2]([F:16])([F:17])[CH2:3][CH:4]([CH2:11][C:12]([F:13])([F:14])[F:15])[CH:5]=[O:6]
Reactant: CON(C)C(=O)C(CC(F)(F)F)CC(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: O=CC(CC(F)(F)F)CC(F)(F)F
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 65 %

Procedure:
To a solution of 4,4,4-trifluoro-N-methoxy-N-methyl-2-(2,2,2-trifluoroethyl)-butyramide (2.67 g, 10 mmol) in CH2Cl2 (10 mL), diisobutylaluminum hydride (2.9 mL, 16 mmol) was added over 10 min at −70° C. The reaction mixture was stirred at −70° C. for 40 min, then transferred via a cannula to a flask containing 30 mL of 2N HCl at 0° C. 10 mL of conc. HCl was added and the mixture was stirred at 25° C. for 30 min. Phases were split and the aqueous phase was extracted with 5 mL of CH2Cl2. The combined organic phase was washed with brine and dried over MgSO4. NMR analysis of the solution using an internal standard indicated formation of the title product in 65% yield. The solution was used as such for further transformations.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([C:8]1[C:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:10][C:11]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH3:7].[OH-].[Na+]>CO>[C:27]1([C:9]2[C:8]([CH:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:33])=[O:2])=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:10]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCC(C(=O)OC)c1c(-c2ccccc2)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(-c2ccccc2)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Yield: 68.1 %

Procedure:
This compound was prepared according to general method D from methyl-2-(4-phenyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.018 g; 0.041 mmol), sodium hydroxide 5N (0.100 mL; 0.50 mmol) in methanol (1 mL) at 60° C. for 72 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.012 g (68%)of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1Cl.[F:17][C:18]([F:26])([F:25])[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:22]1[CH2:23][CH2:24][CH:19]([C:18]([F:26])([F:25])[F:17])[CH2:20][CH2:21]1
Reactant: CNc1cc(Cl)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 26a from methyl-2-chloro-4-methylamino-5-nitro-benzoate (1.37 g, 5.6 mmol), 4-trifluoromethylpiperidine×HCl (1.27 g, 6.7 mmol), DIPEA (3.8 mL, 22 mmol) and dioxane (50 mL).
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[F:20][C:21]([F:38])([F:37])[C:22](=[O:36])[CH2:23][C:24]1([CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[O:27][CH2:26][CH2:25]1>C1COCC1.C1COCC1.C(C1C=CC=CC=1)C.CCCCCCC>[F:38][C:21]([F:20])([F:37])[C:22]([CH2:5][C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=[CH:2][CH:3]=1)([OH:36])[CH2:23][C:24]1([CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[O:27][CH2:26][CH2:25]1
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(F)cc21
Reactant: Cc1ccnc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC1(CC(O)(Cc2ccnc3ccccc23)C(F)(F)F)CCOc2ccc(F)cc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
To a chilled (−78° C.) solution of 105.2 μL (0.79 mmol) of lepidine in 5 mL of THF at −78° C. was added 398 μL (0.79 mmol) of a 2 M solution of lithium diisopropyl amide in THF/ethyl benzene/heptane. The reaction was then warmed to −30° C. After 30 minutes, the mixture was cooled to −78° C. and then 200 mg (0.724 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one (Example 1) in 1 μL of THF was added. The reaction mixture was warmed to room temperature for 1 hour and monitored by TLC. The reaction mixture was then cooled to −78° C., quenched with saturated ammonium chloride solution, warmed to room temperature, and THF was removed by concentrating in vacuo. The residue was extracted with diethyl ether, dried over sodium sulfate, and concentrated. The residue was purified on PLC plate (hexanes-EtOAc (6:4)) to afford a mixture of two diastereomers. The diastereomers were partially purified by a second PLC plate (CH2Cl2-MeOH (95:5)). One of the diastereomers was triturated with diethyl ether and the solid was collected by filtration to afford 20 mg (6%) of the title compound as a single diastereomer (M+1=420). The other diastereomer was chromatographed a second time on a PLC plate (CH2Cl2-MeOH (95:5)). The solids were triturated with diethyl ether and collected by filtration to afford 10 mg (3%) of the second diastereomer (M+1=420).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3F)CC2)c(C)c1
Yield: 71.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (863 mg) described in Preparation Example 100 and oxazolidin-2-one (261 mg), the title compound (623 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:59]([C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OC)(C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([O:25][C:66]([C:65]2[CH:64]=[CH:63][C:62]([N+:59]([O-:61])=[O:60])=[CH:70][CH:69]=2)=[O:67])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (539.00 g, 751.00 mmol) in tetrahydrofuran (6.76 L) is added triphenylphosphine (393.96 g, 1.50 mol) and 4-nitrobenzoic acid (251.02 g, 1.50 mol). The mixture is cooled to 10° C. whereupon diisopropyl azodicarboxylate (40% v/v in toluene, 744.41 mL, 759.30 g, 1.50 mol) is added dropwise over 15 minutes and allowed to warm to 23° C. After 18 hours, the mixture is diluted with methyl tert-butyl ether (2 L), washed sequentially with aq. sat. NaHCO3 (2×2 L) and brine (1 L), and concentrated in vacuo. The residue is slurried in heptane (5 L) at 40° C. for 30 minutes then cooled to 23° C. The resulting solid is filtered and washed sequentially with heptane (2×500 mL), heptane/methyl tert-butyl ether (3×1 L). The combined filtrates are concentrated in vacuo and residue is purified by chromatography (2.5 kg of SiO2; eluent:hexane/ethyl acetate 95:5 to 75:25) followed by recrystallization in heptane (10 L/kg) to yield the title compound as a white solid (273 g, 49% yield).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]2)=[CH:10][C:9]=1[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[C@H:14]([C:18]([F:20])([F:21])[F:19])[O:15]2)=[CH:10][C:9]=1[Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1=Cc2cc(Cl)c(Cc3ccccc3)cc2OC1C(F)(F)F
Solvent: CO
Product: O=C(O)C1=Cc2cc(Cl)c(Cc3ccccc3)cc2O[C@H]1C(F)(F)F

Procedure:
A racemic mixture of the compound prepared in Example 9k, Step 3 was chirally resolved using the same protocol as for Example 9d, Step 1 as peak 2 with retention time 5.76 min: ESHRMS m/z 367.0343 (M−H, C20H11ClF3O3, Calc'd 367.0329). 1HNMR (DMSO-d6/400 MHz) 13.34 (brs, 1H), 7.81 (s, 1H), 7.61 (s, 1H), 7.25-7.29 (m, 2H), 7.17-7.19 (m, 3H), 6.99 (s, 1H), 5.89 (q, 1H, J=7.1 Hz), 4.00 (s, 2H). [□]25589=+2.0 in MeOH.