Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[C:9](Cl)(Cl)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[CH:19]1[C:29]2[C:28](=[O:30])[NH:27][C:26]3[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=3[NH:24][C:23]=2[CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]([N:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:29]=3[C:28](=[O:30])[NH:27][C:26]3[CH:31]=[CH:32][CH:33]=[CH:34][C:25]2=3)=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: O=C(Cl)Cl
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CN1CCC(OC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A quantity of 4.9 gm (0.0425 mol) of 1-methyl-4-piperidinol was added dropwise to a mixture of 22.5 ml of a 20% solution of phosgene in toluene, 100 ml of dioxane, and 4.75 gm (0.045 mol) of anhydrous sodium carbonate while external cooling with ice was carried out. The mixture was stirred for a further 60 minutes at ambient temperature, 9.0 gm (0.0428 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one were added to the reaction mixture, and this was then refluxed for four hours. The mixture was filtered, the filtrate was concentrated by evaporation in vacuo, and the crude product obtained was purified by column chromatography on 500 gm of silica gel [eluant: ethyl acetate/methanol (volume ratio of 10:1)]. After recrystallization from ethyl acetate, the resulting colorless crystals melted at 203°-204° C. and were identical--according to the mixed melting point, thin layer chromatogram, and IR spectrum--to a product prepared according to Example 4. Yield: 7.6 gm (51% of theory).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:11]/[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[N:11]1[CH:10]=[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: [N-]=[N+]=Nc1ccncc1/C=N/c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1-n1cc2cnccc2n1
Temperature: 105 °C
Yield: 68.4 %

Procedure:
A mixture of [1-(4-azidopyridin-3-yl)meth-(E)-ylidene]-(2,6-dichlorophenyl)amine (7.2 mmol) in toluene (20 mL) was heated to 105° C. for 18 hours. The reaction mixture was cooled and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-70% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (1.30 g, 68% yield). 1H NMR (300 MHz, CDCl3): δ 9.31 (d, J=1.4 Hz, 1H), 8.36 (d, J=6.4 Hz, 1H), 8.30 (d, J=1.0 Hz, 1H), 7.65 (dt, J=6.4, 1.2 Hz, 1H), 7.54-7.52 (m, 2H), 7.46 (dd, J=9.5, 6.4 Hz, 1H). LCMS (Method D): RT=3.46 min, m/z: 264 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][C@@:8]2([CH3:46])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([NH:24][C:25]5([C:28]6[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=6)[C:31]([OH:33])=O)[CH2:27][CH2:26]5)=[O:23])[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=3)[C:9]2=[O:45])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:73][C:74]([CH3:78])([CH3:77])[CH2:75][OH:76]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]2([CH3:46])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](=[O:23])[NH:24][C:25]5([C:28]6[CH:29]=[C:30]([C:31](=[O:33])[NH:73][C:74]([CH3:78])([CH3:77])[CH2:75][OH:76])[CH:34]=[CH:35][N:36]=6)[CH2:27][CH2:26]5)[CH2:20][CH2:21]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=3)[C:9]2=[O:45])=[CH:47][CH:48]=1)#[N:2]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(C(=O)O)ccn5)CC4)CC3)n21
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO)NC(=O)c1ccnc(C2(NC(=O)C3(NC(=O)c4cnc5n4[C@](C)(Cc4ccc(C#N)cc4)C(=O)N5c4cc(Cl)cc(Cl)c4)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
To a stirred solution of 2-{1-[(1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-amino]-cyclopropyl}-isonicotinic acid (30 mg, 0.044 mmol), in 3 mL DMF was added HATU (25 mg, 0.66 mmol) diisopropylethylamine (0.3 mL) and 2-amino-2-methyl-propan-1-ol (5.8 mg, 0.66 mmol). The solution was allowed to stir at room temperature overnight (18 h). The reaction was diluted with water (5 mL), then extracted with a 5% methanol/dichloromethane solution (3×10 mL). The organic layers were combined, dried (MgSO4) and concentrated. The resulting oil was purified by reversed phase HPLC to afford 28 mg of the title compound, m/z 755.7.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:12]([C:22]([F:25])([F:24])[F:23])[CH:11]=2)=[CH:4][C:3]=1[N+:27]([O-])=O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C>[NH2:27][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:12]([C:22]([F:25])([F:24])[F:23])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1N
Temperature: 25 °C
Yield: 40.3 %

Procedure:
N-(4-methyl-3-nitrophenyl)-4-morpholino-3-(trifluoromethyl)benzoamide (68 mg, 0.17 mmol) was dissolved in ethanol (1.7 mL), tin chloride (190 mg, 0.83 mmol) was added thereto, and the mixture was subjected to a reaction with reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and then washed with an aqueous sodium hydrogen carbonate solution. The organic layer was washed with distilled water (10 mL×3), dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated solution was crystallized using ethyl acetate (2 mL) and n-hexane (20 mL) to obtain the title compound as a bright yellow solid (26 mg).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:13]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCCCOc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution N-hydroxyphthalimide (2.45 g), 4-pentyloxybenzyl alcohol (Aldrich, 2.92 g) and triphenylphosphine (4.72 g) in THF was added drop-wise diethyl azodicarboxylate (1.2 eq.). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (petroleum ether/EtOAc, 1/2, v/v) and gave 2-(4-pentyloxy-benzyloxy)-isoindole-1,3-dione. This phthalimide intermediate (4.35 g) was dissolved in dichloromethane and methyl-hydrazine (1.1 eq.) was added. The reaction mixture stirred at room temperature for 60 minutes and the formed solid material was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (petroleum ether/EtOAc, 5/1, v/v), and gave the title compound (2.55 g). 13C-NMR (CDCl3) δ 159.1, 130.1, 129.2, 114.5, 77.7, 68.0, 29.0, 28.2, 22.5, 14.0.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6](=[O:18])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([CH3:11])[C:9]=1[CH3:10].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[OH:2][CH2:3][CH2:4][C:5]1[C:6](=[O:18])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([CH3:11])[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)n(C)n(-c2ccccc2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(CCO)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a cooled (0° C.) solution of (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-acetic acid methyl ester (122 mg, 0.479 mmol) in ethanol (5 mL) were added CaCl2.2H2O (68.9 mg, 0.469 mmol) and sodium borohydride (37.4 mg, 0.937 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 4-(2-hydroxy-ethyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (33.7 mg, 31% yield). LCMS 233.3 (M+1).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:52])[NH:29][C@@H:30](O[Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:31]([CH3:33])[CH3:32])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:71]1CCC[CH2:72]1>>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:52])[NH:29][C@H:30]([CH2:72][OH:71])[CH:31]([CH3:32])[CH3:33])[N:27]=2)[CH2:22]1
Reactant: CC(C)[C@@H](NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-1-(t-butyldiphenylsilyloxy)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.98 g, 2.60 mmol) (obtained as described in Reference Example 36(2)) in anhydrous tetrahydrofuran (100 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (6.23 ml, 6.23 mmol) in an ice bath. The mixture was stirred in the ice bath overnight. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (95:5) as the eluant to afford 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidine (755 mg, yield 100%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:17])[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH:14]=2)[CH:6]=[CH:7][CH:8]=1>C(O)C.N#N.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][CH2:11][C:10]2=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2=CC(C)(C)CCC2=O)c1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: COc1cccc(C2CC(C)(C)CCC2=O)c1
Yield: 100 %

Procedure:
Dissolve 2-(3-methoxy-phenyl)-4,4-dimethyl-cyclohex-2-enone (13 g, 56.4 mmol) in ethanol (500 ml), exchange with N2 3×, and add 10% palladium on activated carbon (0.3 g, 2.82 mmol). Stir under atmospheric pressure of H2 over night. Filter off catalyst and concentrate to give the title compound (13.1 g, 99%): 1H NMR (CDCl3) δ 7.24-7.19 (m, 1H), 6.85-6.64 (m, 3H), 3.78 (s, 3H), 1.97-1.89 (m, 1H), 1.82-1.75 (m, 3H), 1.64-1.55 (m, 1H), 1.25-1.14 (m, 2H), 1.0 (s, 3H), 0.96 (s,3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:4]([CH3:11])[N:3]=1.S(Cl)([Cl:15])(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[C:6]([Cl:15])=[C:5]([C:7]([F:8])([F:10])[F:9])[N:4]([CH3:11])[N:3]=1
Reactant: Cn1nc(N)cc1C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cn1nc(N)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
2.0 g (12.1 mmole) 3-Amino-1-methyl-5-trifluoromethylpyrazole in 20 ml acetonitrile was treated with 1.8 g (13.3 mmole) sulfuryl chloride and the mixture stirred for 2 hours at room temperature. It was poured into aqueous saturated sodium hydrogen carbonate, extracted with ethyl acetate, dried over sodium sulfate and concentrated. 2.24 g 3-Amino-4-chloro-1-methyl-5-trifluoromethylpyrazole was obtained, which was treated without further purification as described under 2 (Example 1) to give 4-chloro-3-hydrazino-1-methyl-5-trifluoromethylpyrazole.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([Br:10])[C:3]=1[N+:11]([O-:13])=[O:12].C=O.[C:16](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:10][C:4]1[C:3]([N+:11]([O-:13])=[O:12])=[C:2]2[NH:1][CH2:16][O:9][CH2:8][CH2:7][N:6]2[N:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1c([N+](=O)[O-])c(Br)nn1CCO
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1c(Br)nn2c1NCOCC2

Procedure:
Treatment of 2-(5-amino-3-bromo-4-nitro-1H-pyrazol-1-yl)ethanol 1 with paraformaldehyde and sodium triacetoxyborohydride in dichloroethane containing acetic acid affords 8-bromo-9-nitro-1,2,4,5-tetrahydropyrazolo[5,1-d][1,3,5]oxadiazepine 2. The reaction of the compound 2 with KOH in the presence of Pd2dba3 and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl in 1,4-dioxane, water provides 9-nitro-1,2,4,5-tetrahydropyrazolo[5,1-d][1,3,5]oxadiazepin-8-ol 3, which upon treatment with MeI and cetylammonium bromide in 1,4-dioxane/water/KOH affords compound 8-methoxy-9-nitro-1,2,4,5-tetrahydropyrazolo[5,1-d][1,3,5]oxadiazepine 4 (J. Am. Chem. Soc. 2006, 128, 10694). Hydrogenation of 4 with Pd/C at 60 psi of hydrogen yields 8-methoxy-1,2,4,5-tetrahydropyrazolo[5,1-d][1,3,5]oxadiazepin-9-amine 5.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:13])[O:8][N:7]=1)([CH3:5])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:5][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[O:13])[O:8][N:7]=1)([CH3:4])[CH:2]=[O:1]
Reactant: CC(C)(CO)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C=O)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To 180 mg (0.53 mmol) of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide in DCM (1.74 mL) are added 317 mg (0.75 mmol) of (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin-periodinane). The reaction mixture is stirred at RT for 1 h, diluted with sat. aq. NaHCO3 solution and stirred for additonal 30 min. The layers are separated; the organic layer is washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure, the residue is purified by silica gel chromatographie (eluent: EE) to afford 93.0 mg of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]amide. Yield: 52%; ESI-MS: 336 [M+H]+; HPLC (Rt): 1.12 min (method E)
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[N:16](COCC[Si](C)(C)C)[CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[N:19]=2)[OH:14])OCC[O:4]1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:14][CH:13]([C:15]1[NH:19][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:17][N:16]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3](=[O:4])[CH2:1][CH3:2]
Reactant: CCC1(CCCCCC(O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)CCCCCC(O)c1ncc(-c2ccc3ccccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The alcohol F2 was dissolved in TFA/DCM (1:1) and stirred for 4 hr at RT. The reaction was quenched with sat. aq. NaHCO3 solution and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and solvent was removed under reduced pressure. The crude product was purified by flash chromatography, using EtOAc/petroleum ether as eluents and the product was obtained as a white solid. 1H NMR (300 MHz, DMSO) δ: 8.30 (1H, s), 7.97-7.75 (6H, m), 7.58-7.41 (2H, m), 5.81 (1H, br s), 4.75 (1H, m), 2.37 (4H, m), 1.80 (2H, m), 1.51-1.19 (6H, m), 0.88 (3H, t, J=7.3 Hz). MS (ES) C22H26N2O2 requires: 350, found: 351 (M+H)+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][CH:13]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH:30]([CH2:34][OH:35])[C:31](O)=[O:32])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH:30]([CH2:34][O:35][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:31]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)=[O:32])(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: C1=COCCC1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: O=C(O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)Cc1cccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 1 was repeated, except that dihydropyran (0.4 ml) and methyl m-aminophenylacetate (604 mg) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (893 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(methoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (624 mg).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(=O)OCC>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([S:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:28][CH2:29][S:30][CH3:31])=[O:27])=[C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CSc2cccnc2)cc1-c1ccccc1
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)c1ccc(CSc2cccnc2)cc1-c1ccccc1)C(=O)O

Procedure:
The desired compound was prepared by saponification of [4-(3-pyridylthiomethyl)-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 236 using the procedure of Example 159. 1H nmr (300 MHz., DMSO-d6): δ 8.54, m, 1H; 8.39, dd, 1H; 7.83, m, 2H; 7.29-7.47, m, 8H; 4.39, s, 2H; 4.24, m, 1H; 2.25, m, 2H; 1.98, s, 3H; 1.85, m, 2H. MS (CI NH3): 453 (MH+); 304, 194. EA: calc'd for C24H24N2O3S2: C, 63.69; H, 5.34; N, 6.19; found C, 63.35; H, 5.20; N, 6.02.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.[C:23]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH3:23])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: C#CC(C)(C)N1CCC(OC)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2yl)-3-(1,1-dimethylprop-2-ynyl)-6-methoxy-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:30])[C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=O)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:30])[C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][CH2:19][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:31][CH:32]=1
Reactant: CN(C)C1CCN(C(=O)CCc2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1
Solvent: C1CCOC1
Product: CN(C)C1CCN(CCCc2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere around bottom flask is charged with 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethylamino)piperidin-1-yl]carbonyl]ethyl]-1H-indole (0.194 g, 0.428 mmol). The flask was then placed in an ice bath and boranetetrahydrofuran complex (1.71 ml of a 1.0 M solution in THF, 1.71 mmol) was added. The reaction mixture was then removed from the ice bath and stirred at room temperature for about 90 minutes. The progress of the reaction was monitored by thin layer chromatography. A 1:1 tetrahydrofuran:methanol solution (0.20 ml total) was added, followed by the addition of 2.0 ml of 5.0 N sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:18][OH:19]>>[OH:19][CH2:18][C@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CCC[C@@H](N)CO
Product: CCC[C@H](CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2R)-2-amino-1-pentanol (CAN 80696-30-6) as starting materials and isolated (72 mg, 77%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 313.1311 (MH+).
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC(OCC(C)C)=O.C([Mg]Br)=C.O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [O-][n+]1cccc2ccccc21
Agent: C=C[Mg]Br
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
0.8 g (5.51 mmol) of quinoline N-oxide is dissolved in 15 ml of anhydrous THF at 20° C., in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet. This solution is treated with 0.78 ml (6.07 mmol) of isobutyl chloroformate; the suspension obtained is cooled to −78° C. 11 ml (11 mmol) of a 1M solution of vinylmagnesium bromide in THF are then added dropwise. After stirring for 90 minutes at −78° C., the solution is slowly returned to ambient temperature (30 minutes), and then hydrolyzed with 15 ml of water.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3].[CH:23]1([CH:26]=O)[CH2:25][CH2:24]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[CH2:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[CH2:10][CH2:11][N:12]([CH2:26][CH:23]2[CH2:25][CH2:24]2)[CH2:13][CH2:14]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCNCC1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a stirred solution of [4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-carbamic acid isobutyl ester (0.058 g, 0.14 mmol) in ClCH2CH2Cl (0.75 mL) at room temperature under Ar was added cyclopropanecarboxaldehyde (0.012 mL, 0.156 mmol, 1.2 eq.) and HOAc (0.075 mL, 1% v/v). The mixture was stirred for 0.5 h then Na(OAc)3BH (0.041 g, 0.2 mmol, 1.5 eq.) was added. The mixture was stirred for 16 h, diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL) and saturated brine (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to give [1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-carbamic acid isobutyl ester (0.061 g, 95%). MS (ESI): 471.2/472.2 (M+1).