Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[Mg].C(Br)C.[CH2:9]([OH:12])[C:10]#[CH:11].Cl[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:9]([OH:12])[C:10]#[C:11][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C#CCO
Reactant: CCCCC/C=C\C/C=C\CCl
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCCCC/C=C\C/C=C\CC#CCO
Temperature: 23 °C
Yield: 98.5 %

Procedure:
A solution off ethylmagnesium bromide in THF (10 ml) was prepared from magnesium (1.4 g, 57.7 mmol) and ethyl bromide (7.7 g, 71 mmol). Propargyl alcohol (1.53 g, 27.4 mmol) in dry THF (6 ml) was then added dropwise to the above ethylmagnesium bromide solution at 5° C. with vigorous stirring. The resulting viscous mixture was stirred at 23° C. under argon for twenty minutes. Cuprous chloride (0.14 g) was added and the reaction mixture was further stirred for twenty minutes. A solution of (Z,Z)-1-chloro-2,5-undecadiene (3.4 g, 18.2 mmol) in THF (2.0 ml) was then added dropwise to the above mentioned mixture over a period of twenty five minutes, at 20° C. The reaction mixture was stirred at 50° C. under argon for 18 h. The THF was removed at ~35° C. on a rotary evaporator and the resulting residue was treated with cold 1.5N H2SO4 (150 ml). It was extracted with ether, washed with water, and dried over Na2SO4. Evaporation of ether at reduced pressure gave 3.7 g of light yellow oil which was chromatographed on 70 g of silica gel. Elution with ether-petroleum ether (1:3) gave 2.3 g (61%) of (Z,Z)-5,8-tetradecadien-2-yl-1-ol which was evaporatively distilled at 137°-140° C./0.3 mm Hg as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:12]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]([CH2:18][N:3]2[C:2](=[O:1])[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4]2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
A mixture of methyl 6-hydroxynicotinate (3 g), 4-biphenylylmethyl bromide (5.8 g), potassium carbonate (8.2 g), and DMF (30 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially and concentrated. The resulting crystals were washed with diisopropylether and recrystallized from ethyl acetate/hexane to obtain the titled compound (5.1 g).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[N:19][C:12]=3[N:13]([CH2:17][CH3:18])[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:8][CH:9]=1.C(O)C>CC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[N:19][C:12]=3[N:13]([CH2:17][CH3:18])[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(CO)nc21
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Sodium borohydride (35 mg, 0.9 mmol) was added to a mixture of 1.16 g (3.7 mmol) of 4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one-7-carbaldehyde and 20 ml of ethanol under ice-cooling, followed by stirring for 30 minutes under ice-cooling. The reaction solution was mixed with acetone and concentrated under a reduced pressure, and the resulting residue was mixed with water and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) and further recrystallized from acetonitrile-ethanol to give 271 mg of 4-(3-chlorophenyl)-1-ethyl-7-hydroxymethylpyrido[2,3-d]pyrimidin-2(1H)-one. The yield was 23%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([O:14]C)=[O:13])=[CH:5][N:6]=[CH:7]2.[OH-].[K+]>CO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][N:6]=[CH:7]2
Reactant: COC(=O)c1cncc2cccc(Br)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cncc2cccc(Br)c12
Temperature: 70 °C

Procedure:
To a stirred solution of methyl 5-bromoisoquinolin-4-carboxylate (Intermediate-16) (10.1 g, 38.0 mmol) in MeOH (50 mL) was added, KOH (21.3 g, 380 mmol) dissolved in water (50 mL) and the reaction mixture was heated to 70° C. for 3 h. Then it was concentrated, diluted with water and washed with Et2O (100 mL×3). The aqueous layer was acidified with 2N HCl (pH=3) and the white solid obtained was filtered to yield the desired acid derivative 6.0 g (62.7%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[O:18][C:17](=[O:19])[CH2:16][CH2:15]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[O:18][C:17](=[O:19])[CH2:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C1CCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
p-Toluenesulfonyl chloride (23.65 g, 124.03 mmol) was added portion wise to a solution of (±)-dihydro-5-hydroxymethyl-2(3H)-furanone (example 56) (11.07 g, 95.43 mmol) and pyridine (15.4 mL, 190.86 mmol) in methylene chloride (300 mL) at 0° C. The solution was allowed to warm to rt and stirred overnight. The solution was then washed with water (2×100 mL), 0.5 n HCl until the washings were acidic and finally with saturated NaHCO3. After drying and concentrating, the residue was triturated with toluene to give the title compound as a white solid (19.63 g, 76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[C:18]#[N:19])([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[C:18]#[N:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc([N+](=O)[O-])ccc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(N)ccc1C#N
Yield: 92.4 %

Procedure:
To a mixture of (2-cyano-5-nitrobenzyl)carbamic acid t-butyl ester (2.39 g) and ethanol (180 mL) there were added water (12 mL), saturated aqueous ammonium chloride (5 mL) and iron powder (2.02 g), under a nitrogen atmosphere. The mixture was heated to reflux for 2 hours and then filtered through Celite to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure to obtain a residue. The Celite and filtered substance were washed with ethyl acetate (400 mL) and water (200 mL) in that order, and this washed solution was combined with the previous residue. After sufficiently shaking the mixture, the organic layer was separated off and the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (1.97 g) as an off-white solid.
Reaction SMILES: [ClH:1].[CH2:2]1[O:27][C:26]2[CH:25]=[CH:24][C:6]([O:7][CH2:8][C@H:9]3[C@H:14]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=4)[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:5][C:4]=2[O:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(O)C>[ClH:1].[CH2:2]1[O:27][C:26]2[CH:25]=[CH:24][C:6]([O:7][CH2:8][C@H:9]3[C@H:14]([C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)[CH2:13][CH2:12][N:11]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:10]3)=[CH:5][C:4]=2[O:3]1
Reactant: O=[N+]([O-])c1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Reactant: CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCN1CC[C@@H](c2ccc([N+](=O)[O-])cc2)[C@H](COc2ccc3c(c2)OCO3)C1

Procedure:
Compound (6) (1 g) was dissolved in abs. ethanol (50 ml). K2CO3 (0.7 g) and 1-bromopentane (0.63 ml) were added. Reflux for 6 h, filtering and evaporation to dryness gave a crystalline mass which was extracted with NaOH(4N)ether. The etheral layer was dried, evaporated and purified on a silica gel column using CH2Cl2 /CH3OH 9/1 as eluent. Precipitated as the hydrochloride from acetone/ether. Yield 0.5 g. M.p. 57° C.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].[OH:11][C:12]1(CC#N)C[CH2:16][CH2:15][CH2:14][CH2:13]1>>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[O:1][C:2]1([CH2:3][C:4]#[N:5])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCCC(O)CC#N
Reactant: N#CCC1(O)CCCCC1
Product: N#CCC1(OC2CCCCO2)CCCCC1

Procedure:
This compound is prepared essentially by the same method as described in Example 1, Step A-2, except that the 3-hydroxycaprylonitrile is replaced by 2-(1-hydroxycyclohexyl)acetonitrile. This method provides the title compound as a pale yellow liquid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:17][CH2:16]1.O>CN(C=O)C>[N:1]1([CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[Cl:8])([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[OH:17])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(C2(c3ccccc3Cl)CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(Cn1cncn1)(c1ccc(F)cc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 70 %

Procedure:
1,2,4-Triazole (0.04 mol) was added portionwise to sodium hydride (0.04 mol) in DMF (40 ml) and the solution stirred at room temperature until effervescence ceased. 1-o-Chlorophenyl-1-p-fluorophenyl ethylene oxide (0.02 mol) in DMF (10 ml) was added dropwise and the solution stirred at 80° for 4 hours. The solution was poured into water and triturated with petroleum ether to give a white crystalline solid which was filtered off and dried. Recrystallisation from petroleum ether (60°-80°)/methylene chloride gave the title compound (70%) as a white crystalline solid, m.p. 115°-116°.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)[OH:4].[C:21]1([CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:7]1[CH:8]=[CH:9][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)=[CH:6]1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.75 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (390 ml, 2.63 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight-at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated-brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (650 mg, 89%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.[NH2:26][C@H:27]([C:31]([N:33]1[CH2:53][CH2:52][CH2:51][C@H:34]1[C:35]([NH:37][C@H:38]([C:42]([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:26][C@H:27]([C:31]([N:33]3[CH2:53][CH2:52][CH2:51][C@H:34]3[C:35]([NH:37][CH:38]([CH:39]([CH3:40])[CH3:41])[C:42](=[O:43])[C:44]([F:45])([F:46])[C:47]([F:48])([F:49])[F:50])=[O:36])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Temperature: -22 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a solution of the benzoic acid derivative prepared above (0.240 g, 0.885 mmol) and NMM (0.446 g, 4.43 mmol, 0.489 ml) in CH2Cl2 (8.9 ml) at -22° C. under N2 was added IBCF (0.121 g, 0.885 mmol, 0.115 ml), and the reaction stirred at -22° C. for 20 min. The HCL.Val-Pro-Val-C2F5 (0.400 g, 0.885 mmol) was added in several portions, and the reaction was stirred at -22° C. for 0.5 h, followed by 4 h at room temperature. The reaction was diluted with CH2Cl2 (30 ml) and then washed successively with 10% HCl (2×15 ml), sat. NaHCO3 (2×15 ml), brine (1×15 ml), and dried over MgSO4. Solvent removal under vacuum gave an off-white foam which was purified by flash chromatography (silica gel; 25/75, hexane/EtOAc) to give 0.295 g (50%) of the title compound as a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a stirred solution of {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (3.02 g, 5.61 mmol) in CH2Cl2 (30 ml) was added TFA (4.3 ml). The reaction mixture was stirred at RT for 20 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. The product was purified by column chromatography (SiO2, H/EtOAc/MeOH, 50:50:0 to 0:90:10) to afford 1.79 g (73%) of the title product as a light brown oil. ES-MS m/e: 338.3 (M+H+).
Reaction SMILES: COC1C=CC(C[O:8][C@H:9]([C@H:63]([O:78]CC2C=CC(OC)=CC=2)[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[C@@H:10]([N:52]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[N:54]=[N:53]2)[CH2:11][O:12][C@@H:13]2[C@H:18]([O:19]CC3C=CC=CC=3)[C@@H:17]([O:27]CC3C=CC=CC=3)[C@@H:16]([O:35]CC3C=CC=CC=3)[CH:15]([CH2:43][O:44]CC3C=CC=CC=3)[O:14]2)=CC=1.[H][H]>C(O)C.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH2:57]([C:55]1[N:54]=[N:53][N:52]([C@H:10]([C@H:9]([OH:8])[C@H:63]([OH:78])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH2:11][O:12][C@@H:13]2[C@H:18]([OH:19])[C@@H:17]([OH:27])[C@@H:16]([OH:35])[CH:15]([CH2:43][OH:44])[O:14]2)[CH:56]=1)[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCC[C@@H](OCc1ccc(OC)cc1)[C@@H](OCc1ccc(OC)cc1)[C@H](CO[C@H]1OC(COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)n1cc(CCCCCC)nn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@H](CO[C@H]1OC(CO)[C@H](O)[C@H](O)[C@H]1O)n1cc(CCCCCC)nn1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
The compound (1.0 eq.) obtained in Step 1 was dissolved in a mixed solvent of ethylalcohol/methylene chloride (3:1, 0.01˜0.1 M) to which Pd(OH)2 (500 massa) was then added. The resulting reaction mixture was stirred for 5˜8 hrs at room temperature under 1 atm of hydrogen gas. After the filtration of the metal catalyst through a Celite pad, the reaction mixture was washed with a solution of ethylalcohol/methylene:chloride (3:1). After two rounds of centrifugation at 1000 rpm for 10 min, the supernatant was concentrated and dried in a vacuum. The concentrate was precipitated in a mixed solvent of hexane/ethyl acetate (1:1) to afford the object compound as a white wax solid (24 mg, 80%).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C@@H:17]3[C@H:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:21]([C:23](OCC)=[O:24])=[N:22][N:16]3[C:15]=2[CH:34]=1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C@@H:17]3[C@H:20]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:21]([C:23]([N:4]([O:3][CH3:2])[CH3:5])=[O:24])=[N:22][N:16]3[C:15]=2[CH:34]=1
Reactant: CNOC
Reactant: CCOC(=O)C1=NN2c3cc(F)ccc3OC[C@@H]2[C@@H]1c1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C1=NN2c3cc(F)ccc3OC[C@@H]2[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The HCl salt of N-methoxy-N-methylamine (4.47 g, 15.3 mmol) in anhydrous CH2Cl2 was cooled to −10° C. and treated with Me3Al (22.9 mL, 2.0M in hexanes, 45.8 mmol) and stirred 30 min. Trans-ethyl 8-fluoro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxylate (5-4, 5.2 g, 15.3 mmol) was added as a solution in CH2Cl2 and the reaction was warmed to 25° C. for 1 h. Upon completion, the reaction was carefully quenched by the addition of 0.5 N tartaric acid, and stirred an additional 30 min. The solution was extracted with CH2Cl2, dried with MgSO4, filtered and concentrated under reduced pressure to give trans-8-Fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-5). This material was used crude in the subsequent transformation. MS (M+H+, C19H18FN3O3) 356.3 found 356.4 required. 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5H), 7.19 (dd, J=8.9, 2.9 Hz, 1H), 6.86 (dd, J=9.2, 5.2 Hz, 1H), 6.64 (app dt, J=8.2, 3.1 Hz, 1H), 4.51 (d, J=5.1 Hz, 1H), 4.28 (dd, J=10.7, 2.6 Hz, 1H), 4.08 (ddd, J=10.7, 5.2, 3.6 Hz, 1H), 3.79 (s, 3H), 3.57 (t, J=10.7 Hz, 1H), 3.29 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][N:25]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1nccc2ccccc12
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3nccc4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with isoquinoline-1-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=487.1.
Reaction SMILES: [OH:1][CH:2]([CH2:22][O:23][C:24]1[C:29](Cl)=[N:28][CH:27]=[CH:26][N:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[CH2:6][CH2:5]1.[CH3:31][O-:32].[Na+]>CO>[OH:1][CH:2]([CH2:22][O:23][C:24]1[C:29]([O:32][CH3:31])=[N:28][CH:27]=[CH:26][N:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[CH2:6][CH2:5]1
Reactant: O=C1N(c2ccccc2)CCN1C1CCN(CC(O)COc2nccnc2Cl)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1OCC(O)CN1CCC(N2CCN(c3ccccc3)C2=O)CC1

Procedure:
With stirring, 10.1 g of 1-{1-[2-hydroxy-3-(3-chloropyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-one (see Example 6) and 1.41 g of sodium methylate in 110 ml of methanol are refluxed for 10 hours. The reaction mixture is concentrated in a water jet vacuum. The residue is dissolved in ethyl acetate and extracted with 2 N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with conc. ammonia and extracted with methylene chloride. The combined methylene chloride extracts are washed with water, dried over sodium sulphate and concentrated in a water jet vacuum. The residue crystallises from methylene chloride-ether to yield 1-{1-[2-hydroxy-3-(3-methoxy-pyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-one with a melting point of 128°-129° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18]C2NC3C=CC=CC=3N=2)[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[S:42])=[C:36]([N+:43]([O-:45])=[O:44])[CH:35]=1.[OH-].[Na+]>C(Cl)Cl>[CH2:28]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:41]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=2[N+:43]([O-:45])=[O:44])=[S:42])[CH2:13][CH2:14]1)[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CN(CCCN1CCN(CCCNc2nc3ccccc3[nH]2)CC1)CC(C)C
Reactant: COc1ccc(N=C=S)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(NC(=S)NCCCN2CCN(CCCN(CC(C)C)CC(C)C)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of N4-(3-{4-[3-(diisobutylamino)propyl]piperizano}propyl)-amine (intermediate of example 16) (103 mg, 0.33 mmol) and 4-methoxy-2-nitrophenyl isothiocyanate (139 mg, 0.66 mmol) in CH2Cl2 (10 mL) has been stirred for 4 h at room temperature. NaOH 1M is added until alkaline pH. Organic layer was washed with NaOH 0.5M and dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH: 90/10).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>>[F:10][C:9]([F:12])([F:11])[C:8]([Cl:17])=[N:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(NCc1ccc(Cl)cc1)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: FC(F)(F)C(Cl)=NCc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A mixture N-(p-chlorobenzyl)-2,2,2-trifluoroacetamide (100.0 g, 0.421 mol) and phosphorus pentachloride (87.7 g, 0.421 mol) is heated to 100° C., stirred for two hours and vacuum distilled to obtain the title product as a clear colorless liquid (66.3 g, bp 110°-112° C./7.5 mm Hg).