Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>C(O)(=O)C>[C:18]1([C:16]2[N:6]3[CH:5]=[N:4][C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]3[N:1]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1nc[nH]c1N
Reactant: CN(C)C=CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 1.55 g. of ethyl 5-aminoimidazole-4-carboxylate and 1.75 g. of 3-dimethylaminoacrylophenone in 25 ml. glacial acetic acid is refluxed for 6 hours and when cooled no precipitate formed. The reaction is evaporated to dryness and dissolved in methylene chloride. After being washed with a saturated sodium bicarbonate solution and dried with anhydrous sodium sulfate, the solution was passed through a short column of hydrous magnesium silicate. Hexane addition to this solution gave the desired product, m.p. 200°-204° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Reaction time: 2 h

Procedure:
A mixture of trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol (50 mg, 0.2 mmol) and 10% palladium on carbon (7 mg) in methanol (2 mL) was hydrogenated under balloon pressure of H2 at room temperature for 2 h. The reaction mixture was filtered. The filtrate was concentrated to give the desired product, which was used directly in the next step. LCMS calculated for C13H18N3OS (M+H)+: m/z=264.1. Found: 264.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetate (351.7 mg, 0.732 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (173.0 mg, 0.732 mmol), Et3 N (122.4 μl, 0.878 mmol) in DMF (5.2 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:5, v/v) as eluent to afford methyl 2-[[1-[3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (338.4 mg, 87%) as an oil. To a stirred solution of this compound in THF (5.6 mL) and H2O (1.4 mL) was added LiOH (45.7 mg, 1.91 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHCl3, and treated with sat. NH4Cl, washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-Et2O—CHCl3-MeOH to afford 193.8 mg (59%) 40 as a white crystalline powder. mp 125–128; IR (KBr) 1716, 1600, 1533, 1255 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.67–2.03 (m, 4H), 2.50 (s, 3H), 3.33–3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27–4.31 (m, 2H), 4.42–4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87–6.95 (m, 3H), 7.11–7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 519 (M++1); Anal. Calcd for C28H30N4O6.1/2H2O: C, 63.75; H, 5.92; N, 10.62. Found: C, 63.61; H, 5.94; N, 10.27.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][NH:35][C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:35][CH2:34][CH:33]([OH:40])[CH2:32][CH2:31][NH:30][C:8](=[O:29])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=2[F:25])[C:11]=1[C:26]([NH2:27])=[O:28])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)NCC(O)CCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CNC(C)(C)C)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-amino-1-tert-butylamino-butan-2-ol by the procedure analogous to Example 6. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.8, 9.6 Hz), 7.04 (dd, 1H, J=6.4, 10 Hz), 5.45 (s, 2H), 3.66 (m, 1H), 3.34 (t, 2H, J=7.6 Hz), 2.58 (m, 2H), 2.25 (s, 3H), 1.69-1.60 (m, 2H), 1.12 (s, 9H) ppm; MS (APCl, m/z): 486 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[CH:15][CH:14]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Cc1cc(O)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cc(O)ccc1-c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
4-Bromo-3-methylphenol (1.87 g, 10 mmol), 4-isopropyl phenyl boronic acid (2.0 g, 12 mmol), potassium carbonate (4.1 g, 30 mmol) and palladium acetate (0.112 g, 0.5 mmol) are placed in water (100 mL). And the resulting mixture is stirred at room temperature over night under open air. The mixture is filtered through Celite and extracted with ethyl acetate (3×200 ml). The combined organic layers are washed with water, 1N HCl, water, brine, dried (MgSO4), concentrated and chromatographed to yield the title compound as a white solid (1.9 g).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:45])[C:13]([O:43][CH3:44])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:87][S:88]([CH:91]6[CH2:93][CH2:92]6)(=[O:90])=[O:89])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:87][S:88]([CH:91]6[CH2:93][CH2:92]6)(=[O:90])=[O:89])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:45])[C:13]([O:43][CH3:44])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (58) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=736 (M+H)+. 1H NMR (CDCl3): 0.90-1.01 (m, 1H), 1.05-1.15 (m, 1H), 1.15-1.45 (m, 5H), 1.45 (d, J=6.9 Hz, 6H), 1.4-1.55 (m, 3H), 1.6-1.8 (m, 2H), 2.85-2.95 (m, 1H), 2.15-2.25 (m, 2H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 1H), 2.6-2.7 (m, 1H), 2.65 (s, 3H), 2.9-3 (m, 1H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.85 (d, J=10.8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J=11.3 Hz, J=3.6 Hz, 1H), 4.6 (t, J=8.0 Hz, 1H), 5.0 (t, J=10.6 Hz, 1H), 5.5 (t, J=3.2 Hz, 1H), 5.60-5.70 (m, 1H), 6.75 (s, 1H), 7.02 (s, 1H), 7.2 (d, J=9.2 Hz, 1H), 7.5 (s, 1H), 7.9 (d, J=9.2 Hz, 1H), 11 (br s, 1H).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].Cl>C(Cl)(Cl)Cl>[CH:1]1([NH:8][C:16](=[O:19])[CH2:17][CH3:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: NC1C=CCCCC1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1C=CCCCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a mixture of 2-cycloheptenylamine (1.11 g, 10 mmoles), triethylamine (1.01 g, 10 mmoles) and chloroform (10 ml), propionyl chloride (0.93 g, 10 mmoles) was added dropwise at 0° to 5° C. After stirring at 20° C. for 3 hours, the reaction mixture was poured into a 1N hydrochloric acid, and the separated organic layer was washed with a saturated aqueous sodium chloride solution and concentrated to obtain 1.50 g of N-(2-cycloheptenyl)propionamide [Compound (51)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>CC(C)=O>[Cl:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C=NCCCl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CC(C)=O
Product: O=C(NCCCl)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of 2 g of 5-aminoindole in 125 mL of anhydrous acetone is added dropwise 1.25 g of 2-chloroethyl isocyanate. This solution was stirred for 16 h at room temperature, cooled at °20° C., and filtered. The solvent is evaporated and the residue was crystallized from methanol and washed with ether to give a brownish solid, yield 30%, mp 159°-161° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([O:7][CH3:8])[C:3](Cl)=[N:4][OH:5].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]([CH3:9])([O:7][CH3:8])[C:3]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[N:4][OH:5]
Reactant: COC(C)(C)C(Cl)=NO
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(C)(C)C(=NO)n1ccnc1
Yield: 85.2 %

Procedure:
A solution of 9.9 g (0.066 mol) of 2,2-dimethyl-2-methoxy-1-chloro-1-oximino-ethane is very slowly added dropwise to a mixture of 9.0 g (0.132 mol) of imidazole and 6.7 g (0.066 mol) of triethylamine in 50 ml of absolute tetrahydrofuran at 0° C., with stirring. The mixture is allowed to come to room temperature and is subsequently stirred for 10 hours. The reaction batch is filtered, the filtrate is concentrated and the concentrate is diluted with water. The product which has precipitated is filtered off with suction, washed with petroleum ether and dried. 10.3 g of 2,2-dimethyl-2-methoxy-1-(imidazol-1-yl)-1-oximino-ethane of melting point 155°-160° C. are obtained, that is to say 85% of theory. Intermediate: ##STR65##
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19]OS(C)(=O)=O)[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:26])([CH3:25])[N:4]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[CH3:34][S:35]([O-:37])=[O:36].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][S:35]([CH3:34])(=[O:37])=[O:36])[CH:15]=3)=[CH:12][CH:13]=2)[O:6][C:5]([CH3:25])([CH3:26])[N:4]1[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Reactant: CS(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CS(C)(=O)=O)no3)cc2)OC1(C)C
Yield: 77.5 %

Procedure:
(4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-(3-((methylsulfonyloxy)methyl)isoxazol-5-yl)phenyl)oxazolidine-3-carboxylate (200 mg, 0.413 mmol), sodium methanesulfinate (100 mg, 0.83 mmol), and 18-crown-6 (23 mg, 0.08 mmol) in acetonitrile (8 mL) are stirred at room temperature for 16 hours then the mixture is concentrated and purified by column chromatography on silica gel eluting with a gradient of ethyl acetate/heptane to afford the title compound (150 mg). m/z (Cl) 469 [M+H].
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].[C:26](#[N:29])[CH:27]=[CH2:28].C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CC(O)(C)C.O>[C:26]([CH2:27][CH2:28][O:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25])#[N:29]
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Reactant: C=CC#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCC#N
Temperature: 35 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of (+/−)-Tert-butyl (1R,5S,6S)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.), acrylonitrile (30.0 equiv.) and CESIUM CARBONATE (1.2 equiv.) in t-BuOH (0.57 M) was stirred at 35° C. for 3 hrs. The reaction was cooled to room temperature, followed by the addition of NaHCO3 (aq.) and water. The mixture was extracted with EtOAc and the combined organics were dried over MgSO4, filtered, and concentrated. The sample was purified by ISCO SiO2 chromatography to yield (+/−)-tert-butyl (1R,5S,6S)-6-(2-cyanoethoxy)-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate in 94% yield. LC/MS (m/z)=403.3 (MH+), Rt=0.92 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.46 Hz, 3H), 1.46 (s, 9H), 1.99-2.18 (m, 2H), 2.20-2.36 (m, 1H), 2.65 (t, J=6.06 Hz, 2H), 3.68 (br. s., 1H), 3.88 (t, J=5.99 Hz, 2H), 4.51 (br. s., 1H), 4.99 (d, J=9.15 Hz, 1H), 5.39 (br. s., 1H), 7.25 (d, J=4.99 Hz, 1H), 8.73 (d, J=4.94 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:14]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[O:13][C:8]([OH:12])([C:9](=[O:11])[OH:10])[CH2:7][C@@H:6]1[OH:21])(=[O:3])[CH3:2].[C:22](Cl)(=O)[CH3:23]>C(O)C>[C:1]([NH:4][C@H:5]1[C@H:14]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[O:13][C:8]([OH:12])([C:9](=[O:10])[O:11][CH2:22][CH3:23])[CH2:7][C@@H:6]1[OH:21])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)C1(O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a suspension of N-acetyl-neuraminic acid (1 g, 3.23 mmole) in anhydrous ethanol (75 ml) was added 1.5 ml acetyl chloride. The mixture was sealed and stirred at room temperature for 16 hrs. to form a clear solution. The resulting solution was vacuum evaporated to dryness. The white solid was washed with ethyl acetate and vacuum dried to afford the title compound as a white solid (1 g, 91.7%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[C:28]([Si:32]([O:35][CH2:36][CH2:37]I)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29].Cl>C1COCC1.O>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:37][CH2:36][O:35][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiHMDS in THF (72.9 mL of a 1 M solution, 72.9 mmol, 2.2 eq) at −78° C. under Ar was added a solution of (1R,4S)-methyl 4-((t-butoxycarbonyl)amino)cyclopent-2-enecarboxylate (prepared according to the procedure of US 20050101628 A1 (see page 31, column 1, Procedure B, step B)), 8.00 g, 33.2 mmol, 1 eq) in THF (40 mL) dropwise over 1 hr. After stirring for 30 min, a solution of t-butyl(2-iodoethoxy)dimethylsilane (13.29 g, 46.4 mmol, 1.4 eq) in THF (20 mL) was added. The solution was kept at −78° C. for 15 min, then gradually warmed to 0° C. over 2 hrs, and kept at 0° C. for 1 hr. 1 N HCl and water were added, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated. Purification by chromatography (400 g column) eluting with 5 to 20% EtOAc/heptane afforded the title compound of Step A. 1H NMR (CHLOROFORM-d) δ: 5.76-5.85 (m, 2H), 4.90 (d, J=9.0 Hz, 1H), 4.72-4.82 (m, 1H), 3.69 (s, 3H), 3.57-3.64 (m, 2H), 2.24 (dd, J=13.9, 8.0 Hz, 1H), 2.14 (dd, J=14.1, 3.5 Hz, 2H), 1.71-1.82 (m, 1H), 1.40-1.50 (m, 9H), 0.84-0.90 (m, 9H), 0.03 (s, 6H). ESI-MS (m/z): Calculated for C20H37NO5Si: 422.2 (M+23). found: 422.2.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13].[OH:14]S(O)(=O)=O.O.N([O-])=O.[Na+].NC(N)=O>O>[OH:14][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13]
Reactant: CCOC(=O)c1ccc(N)c(C)c1
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(O)c(C)c1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Ethyl 4-amino-3-methylbenzoate (3.85 g; 21.5 mmol) was dissolved in hot, 35% H2SO4 /water and the mixture then cooled to below 5° C. An ice-cold solution of 1.91 g (22.5 mmol) of sodium nitrite in 20 ml of water was then slowly added to the mixture such that the temperature of the mixture never exceeded 5° C. The mixture was stirred at 5° C. for 10 minutes and then treated with 1 g of urea and stirred for a further 10 minutes. A solution of 50 g (207 mmol) of cupric nitrate trihydrate in 750 ml of water was added to the reaction mixture followed by 2.87 g of cuprous oxide. The mixture was stirred for a further 15 minutes and then extracted with 3×300 ml ether. The ether extracts were combined and then washed with water and saturated NaCl solution and then dried (MgSO4). The solution was filtered, the solvent removed in-vacuo and the residue purified by flash chromatography (silica; 13% ethyl acetate in hexanes to 20% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31]C(NC(=O)CC2C=CC=CC=2)=S)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:25][CH3:26])=[C:12]([C:15](NCCCOC(C)C)=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.N[C@@H](CC)C[OH:47].NC1C=CC(OC2C3C(=CC(OC)=C(C(N[C@@H](CC)CO)=O)C=3)N=CC=2)=C(F)C=1>>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:25][CH3:26])=[C:12]([C:15]([OH:47])=[O:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NCCCOC(C)C
Reactant: CC[C@H](N)CO
Agent: CC[C@@H](CO)NC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)O
Yield: 81 %

Procedure:
Similar to the synthesis of compound 1, from compound 39c (300 mg), DMTMM•n-hydrate (329 mg), and (S)-2-aminobutan-1-ol (113 μL), compound 41a was yielded (297 mg, yield: 81%).
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:19][CH2:20][OH:21])[CH2:17][OH:18])=[CH:12][CH:11]=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]2[CH2:19][CH2:20][O:21][C:17]2=[O:18])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(CO)CCO)cc1
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc([C@H]2CCOC2=O)cc1

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2-(4-methoxyphenyl)-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (2R)-2-(4-methoxyphenyl)butyrolactone as a yellowish solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([Cl:32])[CH:11]=1>>[Cl:32][C:12]1[CH:11]=[C:10]([N:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]2(=[O:8])=[O:7])[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3Cl)CC2)c(C)c1
Yield: 21.2 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (101 mg) described in Preparation Example 4 and (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (204 mg) described in Preparation Example 119 and by the reaction and treatment in the same manner as in Example 4, the title compound (49 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:23].OC1CCC(C2C=CC(OCCCN3CCC[C@H](C)C3)=CC=2)CC1>>[ClH:23].[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc(OCCCN3CCCC3)cc2)CC1
Agent: C[C@H]1CCCN(CCCOc2ccc(C3CCC(O)CC3)cc2)C1
Agent: Cl
Product: O[C@H]1CC[C@H](c2ccc(OCCCN3CCCC3)cc2)CC1

Procedure:
A Reduction of 1-{3-[4-(4-oxocyclohexyl)phenoxy]propyl}pyrrolidine (456 mg) as described for (3S)-1-{3-[4-(4-hydroxycyclohexyl)phenoxy]propyl}-3-methylpiperidine, hydrochloride affords 120 mg of 1-{3-[trans-4-(4-hydroxycyclo-hexyl)phenoxy]propyl}pyrrolidine, hydrochloride as a white solid melting at 225° C.