Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:36])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:36])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCCO)c3ccc(Cl)cc3)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCCO)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (0.11 mmol) of the compound from Example 15 were introduced into 7 ml of dichloromethane at 0° C., 27.4 mg (0.11 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 33 mg (79% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:32])=[CH:4][C:5]([NH:9][C:10](=[O:31])[CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=2[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH2:12][CH3:13])=[C:6]([OH:8])[CH:7]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(#N)C>[CH2:37]([O:36][C:34]([NH:1][C:2]1[C:3]([Cl:32])=[CH:4][C:5]([NH:9][C:10](=[O:31])[CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=2[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH2:12][CH3:13])=[C:6]([OH:8])[CH:7]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)cc1O
Solvent: CC#N
Product: CCOC(=O)Nc1cc(O)c(NC(=O)C(CC)Oc2ccc(C(C)(C)CC)cc2C(C)(C)CC)cc1Cl

Procedure:
42 g of the 5-amino-4-chloro-2-[2-(2,4-di-tert-amylphenoxy)butanamido]phenol obtained in Step (i) above was dispersed in acetonitrile to which 10.4 g of ethyl chloroformate was added dropwise under refluxing. After refluxing for 3 hours, the reaction mixture was cooled to deposite crystals. The crystals were collected by filtration and dried to obtain 41.8 g of the above described compound.
Reaction SMILES: [OH2:1].O.O.[N+:4]([O-:7])([O-:6])=[O:5].[Pd+2:8].[N+]([O-])([O-])=[O:10].[O-2].[O-2].[O-2].[Al+3:16].[Al+3]>O>[Pd:8].[N+:4]([O-:7])([O-:6])=[O:5].[O-2:10].[O-2:1].[O-2:5].[Al+3:16].[Al+3:16]
Reactant: O
Reactant: [Pd+2]
Agent: O=[N+]([O-])[O-]
Agent: [Al+3]
Agent: [O-2]
Product: [Pd]

Procedure:
Palladium (II) nitrate trihydrate (0.270 g) was dissolved in water (21.0 ml) and added to gamma-alumina (5.0 g, from calcination of Catapal SB boehmite alumina in air at 580° C.) with stirring. Water was slowly removed in vacuo keeping the catalyst temperature about 55° C. and the catalyst was then dried further at 100° C. for 12 hours.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[N:17]O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[C].[Pd]>[N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH:14]3[NH2:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ON=C1CCCc2ccc(N3CCOCC3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1CCCc2ccc(N3CCOCC3)cc21
Yield: 30.4 %

Procedure:
A solution of crude 7-morpholin-4-yl-3,4-dihydro-2H-naphthalen-1-one oxime (384 mg) and 10% palladium-carbon (water content: 48%, 350 mg) in ethanol (10 mL) was stirred in a hydrogen atmosphere (0.4 Mpa) at room temperature for 8 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 110 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:31]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:32])[CH2:29][CH3:30]>>[CH2:28]([N:31]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH3:32])[CH2:29][CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCCN(C)Cc1ccc(N)cc1
Product: CCCN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-propyl-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol 9:1) C28H29N3O3
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][CH:27]=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]2[NH:8][C:7]3[CH:6]=[CH:5][C:4]([C:9]4[CH:15]=[CH:14][C:12]5[N:13]=[C:27](/[CH:26]=[CH:25]/[C:22]6[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=6)[NH:16][C:11]=5[CH:10]=4)=[CH:3][C:2]=3[N:1]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C=CC=O)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: COc1ccc(/C=C/c2nc3cc(-c4ccc5nc(/C=C/c6ccc(OC)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 262 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 3-(4-methoxyphenyl)acrylaldehyde. [M+H]+ calcd for C32H26N4O2: 499.21; found: 499.00.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[OH:8])=[O:4].[OH-].[K+].O>C(O)C>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH:7]2[O:8][CH2:2][C:3](=[O:4])[NH:5][CH2:6]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(C(O)CNC(=O)CCl)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2CNC(=O)CO2)cc1OC
Yield: 51.4 %

Procedure:
A mixture of 2-(2-chloroacetamido)-1-(3,4-dimethoxyphenyl)ethanol (3.30 g, 12.06 mM) and potassium hydroxide (2.98 g, 45.21 mM) in ethanol (300 ml) heated to reflux for one night. Water was added into the reaction solution, the solution was extracted with methylene chloride, the extract was dried over anhydrous sodium sulfate, then the solvent was evaporated in vacuo to obtain a crude product as a brown solid. The crude product was purified by flash chromatography (SiO2; eluted by gradient of range from ethyl acetate to 4% methanol/ethyl acetate), to obtain the above-described compound 1.47 g (yield 51.4%) as a light yellow solid.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:72]2[N:73]=[C:74]([NH:77]C(OC(C)(C)C)=O)[S:75][CH:76]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42]([CH3:71])[C:43](=[N:63]C(OC(C)(C)C)=O)[N:44](C(OC(C)(C)C)=O)[CH2:45][CH2:46][CH2:47][NH:48]C(=O)OC(C)(C)C)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:48][CH2:47][CH2:46][CH2:45][NH:44][C:43](=[NH:63])[N:42]([CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:72]3[N:73]=[C:74]([NH2:77])[S:75][CH:76]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)[CH3:71]
Reactant: CN(Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)C(=NC(=O)OC(C)(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1)C(=N)NCCCN
Yield: 7.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(4-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)imino)-2,11,11-trimethyl-9-oxo-10-oxa-2,4,8-triazadodecyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (27 mg, 0.022 mmol), TFA (103 μl, 1.34 mmol) and DCM (223 μl). The crude material was purified by reverse phase preparative HPLC (XSELECT C18, 5μ, 30×100 mm, ACN/H2O w/0.1% formic acid buffer), affording the title compound (1.1 mg, 7%) as a white solid. LCMS: Rt=0.32 min, m/z=643.3 (M+1) Method 2m_acidic. 1H NMR (500 MHz, D2O) δ ppm 7.65 (s, 1H) 7.00 (s, 1H) 5.48 (d, J=5.7 Hz, 1H) 4.89-4.83 (m, 1H) 4.60-4.45 (m, 2H) 3.25 (td, J=6.9, 3.6 Hz, 2H) 2.95 (t, J=7.7 Hz, 2H) 2.91 (s, 3H) 1.98-1.74 (m, 2H) 1.23-1.10 (m, 2H) 1.05-1.00 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[B:16]([O-])([O-:18])[O-:17].Cl>C1COCC1.CCOCC>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([B:16]([OH:18])[OH:17])[CH:7]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: [O-]B([O-])[O-]
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(Cl)cc1B(O)O
Reaction time: 8 h

Procedure:
A solution of 2-bromo-4-chloroanisole (5.0 g, 22.6 mmol) in dry THF (60 ml) under nitrogen was cooled to −70° C. and n-butyl lithium (12.4 ml of a 2.0 M solution in hexanes, 24.8 mmol) was added. After 10 min. at −70° C. trlbutyl borate (8.5 ml, 31.4 mmol) was added and the temperature was allowed to rise to room temperature overnight. Aqueous hydrochloric acid (40 ml, 2 M) was added and the product was extracted with 2×60 ml ether. The ethereal phase was extracted with aqueous sodium hydroxide (2×40 ml, 1 M). Acidification with concentrated HCl during ice-cooling gave a precipitate that was dissolved in ether. Drying over magnesium sulfate and evaporation of the solvent gave the title compound. Yield 1.93 g, 46%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].[OH-].[Na+].Br[CH2:19][CH3:20]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][N:12]([CH2:19][CH3:20])[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Clc1ccc(C23CNCC2C3)cc1Cl
Reactant: CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 4 h
Yield: 66.4 %

Procedure:
A stirred solution of 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (19.3 g, 72.9 mmol) in CH2Cl2 (100 mL) was rendered basic with 2N NaOH (100 mL). The resulting mixture was extracted with CH2Cl2 (2×100 mL) and the combined extracts dried, filtered and concentrated under reduced pressure. The residue was dissolved in acetonitrile (200 mL) and bromoethane (15.9 g, 146 mmol) added at room temperature. The mixture was stirred for 4 h during which time a white precipitate formed. After this time the reaction was concentrated under reduced pressure then treated with 2N NaOH (200 mL). Subsequent extraction with CH2Cl2 (3×100 mL) drying the combined extracts (MgSO4), filtration and concentration under reduced pressure afforded a crude residue. This residue was purified by passing through a silica gel plug, eluting with ether, to yield the title compound (12.4 g, 66%) as a clear, viscous oil. This material was then used directly for either chiral separation or hydrochloride salt formation as provided in Example II, Section D hereinbelow.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C:13]([CH3:17])([CH3:16])[CH2:14][O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:16][C:13]1([CH3:17])[C:12]2[CH:18]=[CH:19][C:9]([OH:8])=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: CC1(C)COc2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)COc2cc(O)ccc21
Yield: 73.8 %

Procedure:
To a solution of 6-(benzyloxy)-3,3-dimethyl-2,3-dihydrobenzofuran (3.48 g, 13.7 mmol) in methanol (200 mL) was added Pd/C (1.45 g) and the mixture was hydrogenated under 40 psi of hydrogen overnight. The reaction mixture was filtered through celite, washed with methanol. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/7) to give the title compound (1.66 g, 74%): MS (ES+) m/z 165.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.Cl[Sn]Cl.[C:21]([O-])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(OC[C@@H]2CCCN2)c1
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: CCO
Product: CN1CCC[C@H]1COc1cc(N)ccc1Cl
Reaction time: 0.67 h

Procedure:
(S)-2-(2-Chloro-5-nitro-phenoxymethyl)-pyrrolidine (3.42 g, 12.63 mmol) and SnCl2 (7.19 g, 37.9 mmol) in 45 mL EtOH were heated at 75° C. for 11 h. The reaction was treated with about 15 mL 1 N K2CO3 (aq) and stirred 40 min. The suspension was filtered through Celite and concentrated down to aqueous, which was then diluted with EtOAc and 1 N NaOH (aq). The layers were separated, and the organic layer was washed twice with 1 N NaOH and once with mix of brine and 1 N NaOH. The aqueous layers were extracted twice with fresh EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated down to dryness to yield the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[CH2:28]([NH:32][C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: CCCCN
Solvent: ClCCl
Product: CCCCNC(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
To a solution of 6-fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (1.0 mmole) in CH2Cl2 (3 ml) was added n-butylamine (5 mmole) and stirring was continued at 60° C. until completion of the reaction. The mixture was evaporated and the residue partitioned between aqueous HCl and AcOEt. The organic layer was dried, evaporated and the residue triturated with diethylether to give 3-butylcarbamoylmethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid as a white solid. MS: 431.4 ([M−H]−).
Reaction SMILES: [N:1]([CH2:4][C:5]([N:7]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]([N:7]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)N(c1ccccc1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: NCC(=O)N(c1ccccc1)C1CCCCC1
Reaction time: 5 h
Yield: 69 %

Procedure:
To a solution of 2-chloro-N-cyclohexyl-N-phenylacetamide (503 mg, 2.0 mmol) in acetone (30 mL) was added sodium iodide (800 mg, 5.6 mmol). The reaction mixture was heated at reflux for 4 hours before it was cooled to room temperature. The solid material was filtered off, and the solvent removed from the filtrate under reduced pressure, to afford 2-iodo-N-cyclohexyl-N-phenylacetamide, which was subjected to subsequent reactions without further purification. B. To a solution of 2-iodo-N-cyclohexyl-N-phenylacetamide (obtained from A. above) in anhydrous DMF (30 mL) was added sodium azide (325 mg, 5.0 mmol), and the contents were heated at 80° C. for 10 hours. The reaction mixture was filtered, the solids washed with acetone (2×5 mL), and the solvent removed from the filtrate under reduced pressure, to afford 2-azido-N-cyclohexyl-N-phenylacetamide. C. To a solution of 2-azido-N-cyclohexyl-N-phenylacetamide (obtained from B. above) dissolved in methanol (50 mL) was added 10% Pd/C (90 mg, 0.09 mmol), and the reaction suspension was hydrogenated at room temperature under hydrogen (50 psi) for 5 hours. After filtration and concentration, the crude product was purified on silica gel using a methanol/dichloromethane gradient (0% to 10% methanol) to furnish 2-amino-N-cyclohexyl-N-phenylacetamide (320 mg, 69% yield). D. To a solution of exo-2-chloro-syn-7-hydroxymethyl-5-oxo-bicyclo[2.2.1]heptane (35 mg, 0.20 mmol) in 1-butanol (6 mL) was added 2-amino-N-cyclohexyl-N-phenylacetamide (46 mg, 0.20 mmol) and triethylamine (50 μL, 0.36 mmol). The reaction mixture was stirred at 100° C. for 2 days, then cooled to room temperature, concentrated under reduced pressure, and the residue purified on silica gel (10% methanol/dichloromethane) to afford N-cyclohexyl-2-{[7-(hydroxymethyl)-5-oxobicyclo[2.2.1]hept-2-yl]amino}-N-phenylacetamide CVT-6440 (8 mg, 10% yield). (M+1)=371.15. B. Preparation of a Compound of Formula I in which X is —N— and Z is —C(O)—
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](CCl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]C(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C>O1CCCC1>[CH2:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]1[CH:15]=[CH:12][CH:11]=[CH:10][CH:17]=1
Reactant: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
The general coupling method used for compound 63a was applied using 4-benzyloxybenzyl chloride and BTPP in tetrahydrofuran to give the product benzyl ether. The benzyl ether (600 mg, 1.05 mmol) and 10% palladium hydroxide on carbon (160 mg) in 2:1 methanol/tetrahydrofuran (50 mL / 25 mL) was agitated under hydrogen at 55 psi for 48 hours. The reaction mixture was filtered through a pad of Celite and then subjected to column chromatography (2:1 EtOAc/CH2Cl2) to give compound 64 as a white solid (262 mg, 52% yield).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].Br[C:31]1[S:35][C:34]([C:36]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:33][CH:32]=1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:31]2[S:35][C:34]([C:36]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])=[CH:33][CH:32]=2)=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C(c1ccc(Br)s1)N1CCCCC1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(=O)N3CCCCC3)s2)cc1
Yield: 48 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (550 mg, 1.4 mmol) and (5-Bromo-thiophen-2-yl)-piperidin-1-yl-methanone (CAS 626242-11-3) (315 mg, 1.2 mmol) to give 260 mg (48% yield). MS (ES+) 466.2 (M+H)+
Reaction SMILES: S([O-])([O-])(=O)=[O:2].[Na+:6].[Na+].[O-:8][Si:9]([O-:11])=[O:10].[Na+].[Na+]>>[Si:9]([O-:2])([O-:11])([O-:8])[O-:10].[Na+:6].[Na+:6].[Na+:6].[Na+:6]
Reactant: O=[Si]([O-])[O-]
Reactant: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
637 g of anhydrous sodium sulfate and 501 g of anhydrous soda are dissolved in 50 kg of water glass having the composition as in Example 1, and the solution is spray-dried in a laboratory spray dryer (spray tower) from Anhydro to give an amorphous sodium silicate having an active substance content of about 83%. 15 kg of the amorphous sodium silicate are heat-treated at 720° C. for 90 min in a muffle furnace (Nabertherm, model W1000/H). The chilled product (about 10 kg) is pulverized using a jaw crusher and a disk mill.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].P([O-])([O-])([O-])=[O:13].[K+].[K+].[K+]>C(O)C>[OH:13][C@@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=P([O-])([O-])[O-]
Reactant: COC(=O)Cc1ccccc1
Agent: [K+]
Solvent: CCO
Product: COC(=O)[C@@H](O)c1ccccc1
Reaction time: 0.03 h

Procedure:
Experimental description: 90 mg methyl 2-phenyl acetate were dissolved in 500 μL ethanol and added to 240 mL potassium phosphate buffer pH 8.0. P450BM3 was added to the mixture at a final concentration of 2 μM. The mixture was split in 4 mL aliquots into 15 mL scintillation vials equipped with a stir bar. 500 μL of a 5 mM NADPH solution were added to each vial and stirred for 2 minutes. 500 μL of a cofactor regeneration solution containing 300 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 4 hours, the reaction mixtures were joined together and extracted with chloroform (3×100 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5% ethyl acetate:95% hexane) afforded the activated product ((S)-methyl 2-hydroxy-2-phenylacetate, 40.5 mg). 40 mg (0.24 mmol) of activated product were dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and added with 41 μL DAST (0.29 mmol). The reaction was stirred in dry ice for 12 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5% ethyl acetate: 95% hexane) afforded the fluorinated product ((R)-methyl 2-fluoro-2-phenylacetate) (30 mg, 75% yield, pale yellow oil) in 74% ee, as determined by chiral GC analysis. 1H-NMR (300 MHz, CDCl3): δ 3.75 (s, 3H, —OCH3), δ 5.77 (d, J=48 Hz, 1H, —CHF), δ 7.37-7.46 (m, 5H); 13C-NMR (75 MHz, CDCl3): δ2.8, 89.5 (d, J=184.5 Hz), 126.8, 126.9, 129.0, δ 129.9, δ 134.4 (d, J=34.5 Hz), δ 169.0. 19F-NMR (282 MHz, CDCl3): δ −180.29 (d, J=48.7 Hz). HRMS (EI+): exact mass calculated for C9H9FO2 requires m/z 168.0587, found 168.0594.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH2:25][CH2:26][O:27]C2CCCCO2)=[CH:18][CH:17]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[N:21][N:22]3[CH2:25][CH2:26][OH:27])=[CH:18][CH:17]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2cnn(CCOC3CCCCO3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@@H](Oc2ccc3cnn(CCO)c3c2)c2ccccc21
Reaction time: 0.33 h

Procedure:
Intermediate A (212 mg, 1.3 mmol) was added portionwise to a suspension of sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol) in DMF (3 mL) at RT and stirred for 20 min. A solution of Intermediate 11a (264.3 mg, 1.0 mmol) in DMF (1 mL) was then added dropwise and the resulting mixture stirred at 60° C. for 2.5 h. After cooling, the mixture was diluted with EtOAc (50 mL) and poured onto ice water. The organic layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and concentrated in vacuo. The residue was loaded on to a SCX-2 cartridge, eluting with MeOH then 2M NH3 in MeOH. Further purification by FCC, using 0-10% [2M NH3 in MeOH] in DCM to give the title compound as a brown oil. LCMS (Method 1): Rt 1.80 min, m/z 323 [MH+].