Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[K+]>CO.O>[CH3:25][S:22]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][NH:5][C@@H:6]2[CH2:8][C@H:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)N1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-N-((trans)-2-phenylcyclopropyl)acetamide (150 mg, 0.37 mmol) in a mixture of MeOH (6 mL) and H2O (4 mL) was added KOH (62 mg, 1.11 mmol) at 0° C. stirred for 2 h rt. Reaction mixture was concentrated and the residue was dissolved in water (10 mL) and acidified with 50% HCl and washed with ethyl acetate (2×10 mL). The aqueous layer was basified with saturated sodium carbonate solution and extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4 and concentrated under the reduced pressure to obtain the desired product (trans)-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine (57 mg, 51.8%) as colourless gummy oil. HPLC-97.64%, m/z 309.35 (M+H)+. H1NMR (CDCl3) δ ppm 7.23-7.25 (m, 2H), 7.16-7.13 (m, 1H), 7.02 (d, J=7.2 Hz, 2H), 3.81 (d, J=11.2 Hz, 2H), 2.76 (s, 3H), 2.60-2.66 (m, 4H), 2.30-2.34 (m, 1H), 1.82-1.88 (m, 3H), 1.52-1.56 (m, 2H), 1.29-1.36 (m, 2H), 0.95-1.06 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:17]2[N:16]=[C:15]3[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)=[N:14]3)=[CH:19][CH:18]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Oc3ccc(F)cc3)nc2n1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccc(F)cc4)nc3n2)cc1
Temperature: 4 °C
Yield: 73.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (14.3 g), N,N'-carbonyldiimidazole (15.2 g) and 2-amino-7-(4-fluorophenoxy)-1,8-naphthyridine (15.2 g). The product produced by precipitation in water (22.6 g; m.p. approximately 70° C.) is dissolved in boiling ethanol (130 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×15 cc) and dried at 25° C. under reduced pressure (0.067 kPa). N-[7-(4-fluorophenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (17 g) is produced, m.p. 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]([C:11]1[C:24]2[O:23][CH2:22][C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].[OH:28]O>C(Cl)Cl.C[Re](=O)(=O)=O.O=[Mn]=O>[Cl:27][C:6]1[CH:5]=[N+:4]([O-:28])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[C:24]2[O:23][CH2:22][C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(COC1)CO2
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2c(Cl)c[n+]([O-])cc2Cl)c2c1OCC1(COC1)CO2
Reaction time: 18 h

Procedure:
To a solution of 2-(3,5-Dichloropyridin-4-yl)-1-{9-methoxy-spiro[2H-1,5-benzodioxepin-3(4H),3′-oxetane]-6-yl}ethanone [121] (20.5 mg, 50 μmol) in CH2Cl2 (1 mL) was added 30% H2O2 (15 μL) and methyltrioxorhenium(VII) (5 mg). The mixture was stirred for 18 h, added MnO2 (5 mg) and was stirred for another hour. CH2Cl2 (10 mL) was added and the organic phase was washed with water. The combined organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard HPLC purification afforded 14 mg of the product.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10](/[CH:20]=[CH:21]/[C:22]([N:24]3[CH2:29][CH2:28][C:27]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([OH:30])[CH2:26][CH2:25]3)=[O:23])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:9]=1.O>N1C=CC=CC=1.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH2:20][CH2:21][C:22]([N:24]3[CH2:25][CH2:26][C:27]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([OH:30])[CH2:28][CH2:29]3)=[O:23])=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:12]=2)[CH:9]=1
Reactant: O=C(/C=C/c1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12)N1CCC(O)(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: O=C(CCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12)N1CCC(O)(Cc2ccccc2)CC1

Procedure:
Sodium borohydride (30 mg, 0.8 mmol) was added to a solution of (E)-1-{3-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-yl]-1-oxo-2-propenyl}-4-(phenylmethyl)-4-piperidinol (Description 20, 40 mg, 0.08 mmol) in pyridine/methanol (3:1, 4 mL) and the mixture was stirred under reflux for 2 h. Further portions of sodium borohydride (30 mg, 0.8 mmol) were added and the reaction was monitored by mass spectrometry until no starting material remained. The mixture was cooled, poured into water (75 mL) and extracted with ethyl acetate (3×25 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (35:65). The residue was recrystallised from ethanol/water and the solid was collected and dried in vacuo to give the title compound as a colorless solid. 1H NMR (360 MHz, CDCl3) δ 8.18 (1H, d, J 1.5 Hz), 7.74 (2H, d, J 8.5 Hz), 7.56 (1H, d, J 9.6 Hz), 7.44 (2H, d, J 8.5 Hz), 7.30 (3H, m), 7.15 (3H, m), 4.40 (1H, m), 3.47 (2H, m), 3.43 (1H, m), 3.24 (1H, m), 2.92 (1H, m), 2.68 (2H, s), 2.64 (2H, t, J 7.5 Hz), 1.46 (2H, m), and 1.24 (2H, m). m/z (ES+) 508, 510 (M+1).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].N([O-])=O.[Na+].[BrH:15]>O>[Br:15][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Br
Reactant: Cc1ccc(N)cc1C#N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1C#N
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Keep the solution of 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) and HBr (74%, 14.4 mL) stirring for 20 min, then the mixture was cooled to 0˜5° C., and the solution of NaNO2 (1.2 g, 17.4 mmol) in water (13.5 mL) was added. The reaction mixture was stirred for 10 min at 0˜5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and it was stirred for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed with saturated NaHCO3 solution, brine, and dried over Na2SO4. The crude product was purified by flask chromatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (Yield: 77%). 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 7.19 (d, J=8.0 Hz, 1 H), 2.51 (s, 3 H).
Reaction SMILES: [Na].[CH2:2]([OH:14])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].[Cl-].[NH4+]>O1CCCC1>[C:20]([O:19][C:15]([CH2:16][CH2:17][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:14][CH2:17][CH2:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: OCCOCCOCCOCCO
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCOCCC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
0.4 g of sodium is added to a solution of 91 g of tetraethylene glycol in 250 ml of tetrahydrofuran, and the mixture is stirred at room temperature. Once the sodium has dissolved, 145 ml of tert-butyl acrylate are added. The mixture is stirred for 12 h. The reaction solution is neutralized with ammonium chloride, concentrated, taken up in aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is concentrated. The residue is 39.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH2:31][CH2:30]1>>[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH2:31][CH2:30]1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: c1ccc2c(c1)NCCO2
Product: O=S(=O)(Nc1nccnc1-c1ccc(CN2CCOc3ccccc32)cc1)c1ccccc1C(F)(F)F
Yield: 65 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3,4-dihydro-2H-1,4-benzoxazine, the title compound was isolated as a yellow solid in 65% yield (97% purity by HPLC).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH:12][C@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[C:3]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:2]=1
Reactant: O[C@H]1CCOC1
Reactant: COc1ccc(C=O)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(O[C@@H]2CCOC2)c1
Temperature: 5 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (7.6 g; 50 mmol) was dissolved in THF (200 mL) followed by addition of (S)-3-hydroxytetrahydrofuran (6.0 mL; 75 mmol) and triphenylphosphine (19.7 g; 75 mmol). The resulting solution was cooled to 5° C. and diisopropyl azodicarboxylate (14.8 mL; 75 mmol) was added dropwise over 10 minutes. The clear orange solution was stirred at ambient temperature for 16 hours. Thin layer chromatography analysis using a 1:1 mixture of hexane/ethyl acetate determined the reaction to be complete. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (60 mL) and extracted twice with 20% aqueous sodium bisulfite (150 mL/extraction). The extracts were pooled and washed with ethyl acetate (75 mL). The aqueous layer was basified with solid sodium hydroxide (26 g) and then extracted with 3×150 mL of ethyl acetate (150 mL/extraction). The organic extracts were pooled, washed with 40 mL of brine, dried (Na2SO4), and concentrated to afford 7.4 g (66%) of a pale yellow oil. 1H NMR (CDCl3; 300 MHz) δ 2.2-2.4 (m, 2H); 3.8-4.1 (m, 7H); 5.0 (m, 1H); 7.0 (d, 1H); 7.4 (s, 1H); 7.5 (d, 1H); 9.9 (s, 1H). ES-MS [M+H]+=223.2
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[C:22]([CH3:29])[N:21]=1>>[CH2:16]([NH:15][C:13]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:25]1[C:20]([F:19])=[N:21][C:22]([CH3:29])=[CH:23][CH:24]=1)=[O:14])[CH2:17][CH3:18]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: Cc1ccc(B(O)O)c(F)n1
Product: CCCNC(=O)c1nnc2c(-c3ccc(C)nc3F)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (300.0 mg, 0.97 mmol) and 2-fluoro-6-methylpyridine-3-boronic acid (426.7 mg, 2.75 mmol) according to Method A to afford a white solid (124.2 mg, 38%). 1H NMR (300.132 MHz, CDCl3) δ 8.53 (bs, 1H), 7.94 (t, J=1.4 Hz, 1H), 7.92 (dt, J=8.6, 1.4 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.83 (dt, J=7.1, 1.2 Hz, 1H), 7.74 (dd, J=8.8, 7.3 Hz, 1H), 7.19 (dd, J=7.4, 1.3 Hz, 1H), 3.46 (q, J=6.7 Hz, 2H), 2.59 (s, 3H), 1.66 (sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=340 (M+H). HPLC 2.28 min.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[H-].[Na+].Br[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]#[N:9])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: N#Cc1ccccc1N
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 29.6 %

Procedure:
Combine anthranilonitrile (2.36 g, 20 mmol), sodium hydride (1.2 g (60% in oil), 30 mmol) and THF (50 mL), stir at ambient temperature for 30 minutes. Add 1-bromo4-chloro-2-nitro-benzene (7.1 g, 30 mmol) and stir at ambient temperature for 3 days. Pour the reaction mixture in ice-cold concentrated hydrochloric acid (200 mL) and filter the resulting solid. Purify by flash chromatography (dichloromethane) and recrystallize from hot ethyl acetate to give (1.62 g, 30%) of the title compound as orange needles: 1H NMR (CDCl3) δ 7.17 (d, 1H), 7.26 (t, 1H), 7.40–7.51 (m, 2H), 7.61 (t, 1H), 7.72 (d, 1H), 8.22 (d, 1H), 9.54 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([C:32]3[CH:33]=[CH:34][S:30][CH:31]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccc(I)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccc(-c3ccsc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a 25 mL press resistant vial which contained a suspension of (R)-2-[4-(4-Iodo-benzoyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.5 mmol), thiophene-3-boronic acid (130 mg, 1 mmol), palladium(II) acetate (20 mg, 0.1 mmol) and triphenyl phosphine (60 mg, 0.25 mmol) in DME (10 mL) was added potassium carbonate (500 mg, 3 mmol), ethanol (1 mL) and water (1 mL) at rt. The tube was sealed and the mixture was allowed to stir at rt for 30 min and then was heated to 98° C. and stirred at 98° C. for 16 h. After cooling to rt, the mixture was poured onto 200 mL ice-water solution and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL) and brine (20 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford title product, (130 mg, 60%); 1H NMR (400 MHz, CDCl3); δ 1.48 (s, 9H), 1.81-2.10 (m, 4H), 3.30-3.48 (m, 2H), 3.87-4.10 (m, 1H), 4.10-4.30 (m, 2H), 6.98-7. (m, 2H), 7.42-7.48 (m, 2H), 7.58-7.60 (m, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.80-7.84 (m, 4H):
Reaction SMILES: C([O:8][CH2:9][C:10]([CH3:31])([CH3:30])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:14][CH2:13]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:30][C:10]([CH3:31])([CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[CH2:16][CH2:17]1)[CH2:9][OH:8]
Reactant: CC(C)(COCc1ccccc1)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(CO)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 3-benzyloxy-2,2-dimethyl-1-(4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl)propane (2.5 g, 6 mol), 10% palladium on carbon (2.8 g), ammonium formate (3.8 g, 59.6 mmol) and methanol (130 mL) was heated 1 hour at reflux. The reaction mixture was allowed to cool to approximately 25° C., then filtered over celite (washing through with methanol and saturated sodium carbonate (20 mL)) and concentrated. The residue was dissolved in water and the solution was extracted with methylene chloride (3×20 mL). The combined extracts were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (8:2) to give 2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-1-propanol (1.6 g, 5.1 mol).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[C@H:8]([C:17](=[O:25])[N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[O:7][C:6]([C:26]([O:28]C)=[O:27])=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(N(CC)CC)C>O1CCCC1>[NH2:1][C@@H:4]1[C@@H:9]([NH:10][C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[C@H:8]([C:17](=[O:25])[N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[O:7][C:6]([C:26]([OH:28])=[O:27])=[CH:5]1
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1NC(=O)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](N)[C@H]1NC(=O)C(F)(F)F
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4S,5R,6R)-4-azido-6-(dipropylcarbamoyl)-5-(2,2,2-trifluoroacetylamino)-5,6-dihydro-4H-pyran-2-carboxylic acid, methyl ester (1 g) in dry tetrahydrofuran (10 ml) was added triphenylphosphine (0.75 g) and the reaction was stirred under nitrogen at 23° C. for 1.5 hours. To this was added water (2 ml) and triethylamine (2 ml) and the mixture was stirred for 16 hours at 23° C. The solvent was removed in vacuo and the residue was chromatographed over silica (Merck 9385, 50 g) using medium pressure (ca 4 psi) and dichloromethane/methanol (15:1 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white solid. (0.87 g). 1H NMR (250 MHz, D6 -DMSO) 9.25 (1H, d, J=9 Hz), 5.90 (1H, d, J=3 Hz), 4.79 (1H, d, J=9 Hz), 4.00 (1H, m), 3.71 (3H, s), 3.58 (1H, m), 3.40 (2H, m), 3.16 (1H, m), 2.95 (1H, m), 1.84 (2H, s), 1.57 (2H, m), 1.40 (2H, m), 0.81 (6H, m), Mass analysis: C16H24F3N3O5. 0.5 H2O. Required: C, 47.52; H, 6.23; N, 10.39. Found: C, 47.68; H, 6.05; N, 10.10.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:17]=[CH:18][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCN2CCOCC2)cc1
Yield: 100 %

Procedure:
A solution of 10 (6.00 g, 23.8 mmol) in 95% EtOH (40 mL) was hydrogenated over Pd/C (10%, 350 mg) at 58 psi H2 for 1 h at room temperature. The formed solid was removed by filtration through Celite, which was washed thoroughly with EtOH (100 mL) and MeOH (50 mL); the filtrate was concentrated in vacuo to give 11 (5.29 g, quant.) as a reddish brown oil, which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:12]([C:14]1([NH:17][C:18]([C@H:20]2[CH2:24][C@H:23]([S:25]([C:28]3[CH:33]=[CH:32][C:31](Br)=[CH:30][C:29]=3[C:35]([F:38])([F:37])[F:36])(=[O:27])=[O:26])[CH2:22][C@@H:21]2[O:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:19])[CH2:16][CH2:15]1)#[N:13].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:12]([C:14]1([NH:17][C:18]([C@H:20]2[CH2:24][C@H:23]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([N:7]4[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:10])[F:11])[CH2:9][CH2:8]4)=[CH:30][C:29]=3[C:35]([F:37])([F:36])[F:38])(=[O:27])=[O:26])[CH2:22][C@@H:21]2[O:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:19])[CH2:15][CH2:16]1)#[N:13]
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1
Reactant: FC(F)(F)CN1CCNCC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(N4CCN(CC(F)(F)F)CC4)cc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1

Procedure:
The title compound was prepared in analogy to example 176 using 1-(2,2,2-trifluoro-ethyl)-piperazine instead of morpholine and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-cyclopentyloxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 195) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 635.2 (M−H)−.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:16][C:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl cyclopropylsulfonylcarbamate (4.3 g, 20 mmol) was dissolved in dry THF (100 ml) and cooled to −78° C. To this solution was added n-BuLi (17.6 ml, 44 mmol, 2.5 M in hexane) slowly. The reaction mixture was allowed to warm to room temperature over a period of 1.5 h. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 ml, 2.5M in hexane) was added, stirred for 1 h and a neat solution of methyl iodide (5.68 g, 40 mmol) was added. The reaction mixture was allowed to warm to room temperature for overnight, quenched with aqueous saturated NH4Cl (100 ml) at room temperature. It was extracted with EtOAc (100 ml). The combined organic layer was washed with brine dried on Na2SO4, filtered and evaporated under reduced pressure to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid. (3.1 g, 81%). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.97 (s, 1H), 1.44 (s, 12H), 1.35-1.33 (m, 2H), 0.93-0.91 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]2[CH2:14][CH2:15][C:16]([F:18])([F:17])[C@@H:9]12)C1C=CC=CC=1.[ClH:19]>CO>[ClH:19].[F:18][C:16]1([F:17])[C@@H:9]2[C@H:10]([O:11][CH2:12][CH2:13][NH:8]2)[CH2:14][CH2:15]1
Reactant: FC1(F)CC[C@H]2OCCN(Cc3ccccc3)[C@@H]21
Agent: Cl
Solvent: CO
Product: FC1(F)CC[C@H]2OCCN[C@@H]21
Reaction time: 1 h

Procedure:
Trans-4-benzyl-5,5-difluorooctahydrocyclopenta[b][1,4]oxazine (350 mg, 1.38 mmol) was dissolved in MeOH (10 mL). 3M HCl in MeOH (1.5 mL) was added and the solution was stirred for 1 hour. The solvent was evaporated and further azeotroped using toluene. The residue was then dissolved in MeOH (10 mL), and 20% Pd(OH)2/C (20% by wt, 50 mg) added. Hydrogen was purged through the reaction for 10 minutes and stirring was continued at room temperature under 1 atm of hydrogen for 16 hours. The reaction was filtered through celite, and the filtrate was concentrated to afford trans-5,5-difluorooctahydrocyclopenta[b][1,4]oxazine hydrochloride. 1H NMR (400 MHz, CD3OD) δ4.16 (dd, J=13.6, 4.0 Hz, 1H), 3.78-3.92 (m, 2H), 3.65 (m, 1H), 3.43 (dd, J=13.2, 2.4 Hz, 1H), 3.28-3.31 (m, 2H), 2.15-2.55 (m, 2H), 1.89 (m, 1H). MS ESI calc'd. for C7H11F2NO [M+H]+ 164. found 164.