Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:33])[CH2:22][C:23]34[CH2:32][CH:27]5[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]5)[CH2:24]3)[CH2:30]4)=[C:16]([CH3:34])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>CO.O1CCOCC1>[ClH:35].[ClH:35].[CH3:34][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[NH:20][C:21](=[O:33])[CH2:22][C:23]12[CH2:30][CH:29]3[CH2:31][CH:25]([CH2:26][CH:27]([CH2:28]3)[CH2:32]1)[CH2:24]2
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(N2CCNCC2)ccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-[4-(2-(tricyclo[3.3.1.13,7]dec-1-yl)acetylamino)-3-methylphenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.05 g, Example 36c) was dissolved in methanol (2 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to 2/3 original volume under reduced pressure. Diethyl ether was gradually added to the solution and the resulting precipitate collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a solid (0.043 g)
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([C:19]1[CH:31]=[C:30]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:32](Cl)=[O:33])=[CH:27][C:28]=3[CH2:29]2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>O1CCOCC1>[C:1]([NH:9][NH:10][C:32]([C:26]1[CH:25]=[CH:24][C:23]2[C:22]3[C:30](=[CH:31][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=3)[CH2:29][C:28]=2[CH:27]=1)=[O:33])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)Cl)ccc1-2
Reactant: CCCCCCC(=O)NN
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)NNC(=O)CCCCCC)ccc1-2
Temperature: 0 °C
Yield: 69.8 %

Procedure:
Then, in a 50 ml-three-necked flask, 0.32 g (2.22 mM) of heptanohydrazide and 15 ml of dioxane were placed. To the mixture, a solution of the above-prepared 7-octyl-2-fluorenecarbonyl chloride in 5 ml of dioxane was added, followed by addition of 0.84 ml of pyridine at about 85° C. under stirring and further stirring for 30 minutes at 85°-88° C. After the reaction, the reaction mixture was cooled and poured into 200 ml of ice water to precipitate a crystal. The crystal was recrystallized from a mixture solvent of toluene-acetone to obtain 0.68 g of N-heptanoyl-N'-(7-octyl-2-fluorenecarbonyl) hydrazine (Yield: 69.8%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:6])[CH:4]=[CH2:5].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[S:13]([O:1][CH2:2][CH:3]([OH:6])[CH:4]=[CH2:5])([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: C=CC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=CC(O)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 18 h

Procedure:
1,2-Dihydroxy-3-butene (20.00 g; 0.227 mol; 1.05 equiv) was dissolved in pyridine (200 mL). The reaction mixture was cooled in an ice bath and p-toluenesulfonyl chloride (p-TsCl) (41.11 g; 0.216 mol) was added in four portions over 30 min. After thorough mixing, the reaction mixture was placed at 4° C. for 18 h, at which time thin layer chromotography (hereinafter TLC) analysis indicated no p-TsCl. The mixture was concentrated to about half the original volume at reduced pressure from a 40° C. water bath and then diluted with ether (200 mL). The mixture was washed with water (100 mL), ice-cold 3N HCl until the washes remained acidic (2×100 mL), and saturated sodium bicarbonate (100 mL). After drying the organic solution (MgSO4), the solvent was removed to afford 41.73 g of a 91:9 mixture (1H nmr analysis) of the desired compound and the corresponding di-tosylate. The crude product solidified over several days at -20° C. It was recrystallized from methylene chloride (50 mL) by the addition of hexanes (100 mL) and chilling to -20° C. to afford two crops (total 33.33 g; 61%) of the desired compound which was pure by TLC analysis, mp 38°-44° C. 1H nmr (300 MHz, CDCl3): 7.800 (2H, d, J=8.25 Hz); 7.356 (2H, d, J=8.19 Hz); 5.751 (1H, ddd, J=5.38, 10.46, 16.55 Hz); 5.378 (1H, br d, J=17.05 Hz); 5.247 (1H, br d, J=10.48 Hz); 4.396 (1H, m); 4.066 (1H, dd, J=3.39, 10.20 Hz); 3.906 (1H, dd, J=7.41, 10.22 Hz); 2.451 (3H, s); 2.276 (1H, d, J=4.50 Hz). IR (KBr, cm-1): 3520 (s,b); 1650 (w); 1600 (s); 1350 (s); 1170 (s). Combustion Analysis: Theor--C, 54.53; H,5.82;N, 0. Found--C, 54.84; H, 5.86;N, <0.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Procedure CC: To a stirring solution of 4-bromo-2-fluorobenzoic acid (11.0 mmol) and oxalyl chloride (2.0 mmol) in dichloromethane (0.10M), add 2 drops of dimethylformamide as a catalyst. Stir at room temperature for 3 hours. After this time, concentrate the reaction in vacuo. Assume total conversion to the acid chloride.
Reaction SMILES: C(O)(=O)C.C(OC(=O)C)(=O)C.[CH:12]1([C:21]([OH:23])=[O:22])[CH:14]([C:15]([OH:17])=[O:16])[CH:13]1[C:18]([OH:20])=O>>[O:22]=[C:21]1[O:23][C:18](=[O:20])[CH:13]2[CH:12]1[CH:14]2[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C1C(C(=O)O)C1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C1C2C(=O)OC(=O)C12
Yield: 82.9 %

Procedure:
Acetic acid (58.8 ml, 933 mmol) and acetic anhydride (20.4 ml, 185 mmol) were added to cyclopropane-1,2,3-tricarboxylic acid (24.4 g, 140 mmol), followed by reacting the mixture while heating under reflux for 2 hours, concentrating the reaction solution into a half volume, filtering off deposited crystals, washing them with heptane and drying under reduced pressure, to obtain 2,4-dioxo-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (18.1 g, 116 mmol, 83%).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:24][C:23](=[O:25])[NH:22][N:21]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].Br[CH:27]([CH3:29])[CH3:28].[H-].[Na+]>CN(C=O)C>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:24][C:23](=[O:25])[N:22]([CH:27]([CH3:29])[CH3:28])[N:21]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4n[nH]c(=O)o4)c3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4nn(C(C)C)c(=O)o4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a stirred solution of 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (0.2 g, 0.5 mmol) and 2-bromo propane (0.08 g, 0.6 mmol) in DMF (1 mL) at 0° C. was added 60% sodium hydride (in mineral oil) (0.040 g, 0.1 mmol) and the reaction was stirred for 2 h at RT. The reaction was quenched with water (25 mL) and extracted with EtOAc (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20% EtOAc in hexanes) to give 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-3-isopropyl-1,3,4-oxadiazol-2(3H)-one (50 mg, 22%) as a white solid. MS (ESI, pos. ion) m/z: 380.0 (M+1); 1H NMR (400 MHz, CDCl3): δ ppm 8.86 (br s, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.09 (s, 1H), 8.01 (dd, J=8.4, 1.6 Hz, 1H), 7.78 (d, J=2.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 5.51-5.57 (m, 1H), 4.42-4.49 (m, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.48 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[N+:8]([C:11]1[C:12]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]2)=[C:13]2[CH2:20]CC[C:14]2=[N+:15]([O-])[CH:16]=1)([O-:10])=[O:9]>>[C:5]([O:4][CH:2]1[C:14]2=[N:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]([N:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:34])[CH2:22]3)=[C:13]2[CH2:20][CH2:1]1)(=[O:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 21.7 %

Procedure:
A mixture of Ac2O (0.90 g, 8.8 mmol) and tert-butyl [(3S)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (270 mg, 0.714 mmol) was sealed and heated at 90° C. for 1 h, then allowed to cool to room temperature. The excess Ac2O was removed under reduced pressure. The residue was dissolved in DCM, and then poured into ice cold aq. Na2CO3. The mixture was extracted with DCM twice. The combined extracts were dried, filtered and concentrated under reduced pressure to give a crude product, which was purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to provide the sub-title compound as a yellow powder (65 mg, 22%). LCMS calc. for C20H29N4O6 (M+H)+: m/z=421.2. Found: 421.3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[C:15](#[N:18])[CH:16]=[CH2:17]>C(O)(=O)C>[C:15]([CH2:16][CH2:17][S:11]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])#[N:18]
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Reactant: C=CC#N
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(=O)(=O)CCC#N)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of 19.9 g (0.1 mol) of p-acetamidobenzenesulfinic acid (Organic Synthesis, Coll. Vol. I, page 7), 100 ml of water, 40 ml of acetic acid and 6.6 ml (0.1 mole) of acrylonitrile was heated on a steam bath for 2 hours. The resulting slurry was cooled to room temperature, filtered, washed with water and air dried to give 17.1 g (68 percent) of white solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])[CH3:5].[Li+].[OH-]>>[CH3:31][N:13]1[C:12]2[CH:32]=[CH:33][C:9]([C:7]([NH:6][C@@H:4]([CH3:5])[C:3]([OH:34])=[O:2])=[O:8])=[CH:10][C:11]=2[N:15]=[C:14]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: COC(=O)[C@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C)C(=O)O
Yield: 86.3 %

Procedure:
(S)-2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carbonyl]-amino}-propionic acid (83 mg) was prepared by following General Procedure E starting from (S)-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester (99 mg), and LiOH (0.5 ml, 2.0 N solution in water). LC/MS: m/z 481.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](Br)[CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1.Cl.CCN(C(C)C)C(C)C>C(O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[N:7]=[C:6]([N:18]2[CH2:17][CH2:16][N:15]([CH:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)[CH2:20][CH2:19]2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Brc1ccnc(Br)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Brc1nccc(N2CCN(C3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of 2,4-dibromopyrimidine (50 mg, 0.210 mmol) and 1-(tetrahydro-2H-pyran-4-yl)piperazine, 2 Hydrochloride (51.1 mg, 0.210 mmol) in Ethanol (1 mL) was treated with DIPEA (0.147 mL, 0.841 mmol) and DMAP (cat.) and stirred at ambient temperature for 1 h. The reaction mixture was concentrated in vacuo and triturated with water, filtered and the solid washed with water then dried in vacuo to provide 2-bromo-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyrimidine (43 mg, 0.130 mmol, 61.9% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (s, 2H) 1.73 (br. s., 2H) 2.48 (br. s., 1H) 2.61 (br. s., 4H) 3.38 (t, J=11.24 Hz, 2H) 3.65 (br. s., 4H) 4.02 (br. s., 2H) 6.40 (d, J=6.25 Hz, 1H) 7.95 (d, J=5.86 Hz, 1H). LC/MS (m/z) ES+=327 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C(C(C)=O)C.[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:21][CH2:20][C:19]([F:26])([F:18])[C:22]([F:25])([F:24])[F:23])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.05 ml), anhydrous potassium carbonate (3.29 g) and hexamethyl phosphoric acid triamide (2.07 g) was heated at 70°-80° C. for 4.5 days under stirring, then insolubles were filtered off. The filtrate was concentrated, to which was added water. The mixture was subjected to extraction with ethyl acetate. The extract solution was dried on magnesium sulfate, followed by removing the solvent by evaporation. The residue was chromatographed on a column of silica gel (50 g), eluted with chloroform-methanol (10:1), and recrystallized from ethyl acetate-hexane to yield 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles, m.p. 148°-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)N1CCN(C)CC1

Procedure:
4-Bromo-2-methylbenzoic acid (10 g, 46.5 mmol), and HBTU (23 g, 60.5 mmol) were dissolved in DMF (150 mL), then N-methyl piperazine (6.0 g, 60.5 mmol) and DIPEA (21 mL, 121 mmol) were added. The reaction was stirred overnight before the removal of the DMF in vacuo, the gum was quenched with 2.0N NaOH (100 mL), extracted with diethyl ether (3×200 mL), dried (MgSO4) and solvent removed in vacuo to yield a viscous gum. Purification on silica using 0-10% MeOH in DCM as eluent, gave the title compound as viscous oil. The oil was dissolved in the minimum amount of diethyl ether, iso-hexane was added to give a colourless solid which was filtered and dried (11.8 g, 86%); 1H NMR (CDCl3) 7.40 (s, 1H), 7.36 (d, 1H), 7.04 (d, 1H), 3.86-3.79 (m, 2H), 3.27-3.21 (m, 2H), 2.51-2.45 (m, 2H), 2.32-2.29 (m, 8H); MH+ 298.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=O.Cl.O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: COCC(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COCCN1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-methoxyacetyl)-7-nitro-1,2,3,4-tetrahydroquinoline (D6) (212 mg, 0.85 mmol) in dry THF (9 ml) at 0° C. under an argon atmosphere, was added borane/THF complex (4.5 ml, 4.5 mmol). The reaction was stirred at 0° C. for 0.5 h then ambient temperature for 3 h. 2M Hydrochloric acid (3 ml) was added cautiously followed by water (10 ml). The mixture was extracted with EtOAc (2×10 ml) which was dried over MgSO4 and concentrated in vacuo to give the desired product as an orange solid in quantitative yield. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.39 (m, 2H), 7.00 (m, 1H), 3.61 (dd, 2H), 3.52 (dd. 2H), 3.41 (m, 2H), 3.37 (s, 3H), 2.80 (t, 2H), 1.95 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22]([OH:24])=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22]([N:39]1[CH2:38][CH2:37][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])[CH2:41][CH2:40]1)=[O:24]
Reactant: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](N(C)Cc3ccc(F)cc3F)CN2Cc2cccc(Cl)c2)CC1
Yield: 7 %

Procedure:
As described for Example 64e, (2S,4S)-1-(3-chloro-benzyl)-4-[(2,4-difluoro-benzyl)-methyl-amino]-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 1-(2-methoxy-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (40 mg) in 7% yield as colorless oil. MS m/e=570.1 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:16]1
Reactant: [H][H]
Reactant: CN1CCC[C@@H](CN2CCN(Cc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CO
Product: CN1CCC[C@@H](CN2CCNCC2)C1
Yield: 95.2 %

Procedure:
A solution of 3.46 g of the compound obtained in step 3.3, in 100 ml of methanol, is hydrogenated in the presence of 1.9 g of wet 10% Pd/C under 800 kPa of hydrogen pressure at 40° C. for 3 hours. The medium is filtered and then evaporated, to give 2.26 g of a colourless oil.
Reaction SMILES: I.CS[C:4]1[CH2:5][CH2:6][C:7]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]3[CH2:20][CH:9]2[CH2:10][CH2:11]3)[N:8]=1.[NH3:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:21][C:4]1[CH2:5][CH2:6][C:7]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]3[CH2:20][CH:9]2[CH2:10][CH2:11]3)[N:8]=1
Reactant: CSC1=NC2(CC1)C1CCC(C1)C2c1ccccc1
Reactant: N
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CO
Product: NC1=NC2(CC1)C1CCC(C1)C2c1ccccc1

Procedure:
50 mmoles of 5'-methylthio-3-phenyl-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline] hydriodide are treated with 250 ml of aqueous ammonia at 70° C. andunder a nitrogen pressure of 80 bars for 24 hours. After stripping off the solvent, an oil which slowly solidifies is obtained. After conversion intothe addition salt of fumaric acid, colorless crystals of melting point 242° C. (from methanol/water 1:1) are obtained.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C@@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:2]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[Br:22][CH2:14][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[O:7][C@@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@H](C)Oc1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H](C)Oc1cccc(CBr)c1
Temperature: 80 °C

Procedure:
To a 250 mL round-bottom flask was (S)-methyl 2-(m-tolyloxy)propanoate (2.0 g, 10.3 mmol, 1 equiv), NBS (1.83 g, 10.3 mmol, 1 equiv), AIBN (169 mg, 1.03 mmol, 0.1 equiv) and CCl4 (100 mL). The reaction mixture was refluxed for 16 h at 80° C. The completion of the reaction was monitored by analytical HPLC. The reaction mixture was allowed to cool to room temperature. The crude mixture was dissolved in AcOEt (100 mL) and washed with a 0.5N HCl aqueous solution (×2), a saturated NaHCO3 solution (×2) and brine, dried over Na2SO4. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0->60%) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.O[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:17][N:16]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OCc1cc(OCc2nc(-c3ccccc3)oc2C)no1
Reaction time: 15 h

Procedure:
To a mixture of 3-(5 methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (0.859 g), methyl 2-(2-hydroxyphenyl)acetate (0.499 g), triphenylphosphine (0.944 g) and tetrahydrofuran (15 mL) was dropwise added a solution (40%, 1.74 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give methyl 2-[2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetate as an oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v). This oil was dissolved in methanol-tetrahydrofuran (1:1, 20 mL) and a 1N aqueous sodium hydroxide solution (10 mL) was added. The mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water, 1N hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 2-[2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazoly]methoxylphenyl]acetic acid. Recrystallization from ethanol-hexane gave colorless needle crystals (0.651 g, 52%). melting point: 152-153° C.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)=O.[C:16]([O:20][C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)([CH3:19])([CH3:18])[CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:16]([O:20][C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:1][C:3]1[C:8]([C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)=[O:37])([CH3:17])([CH3:19])[CH3:18]
Reactant: Cc1cnc(CNCCCCNC(=O)OC(C)(C)C)c(C)c1
Reactant: CC(=O)OC(C)(C)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)OC(C)(C)c1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1ncc(C)cc1C
Yield: 75 %

Procedure:
Using General Procedure B: Reaction of acetic acid 1-(2-formyl-pyridin-3-yl)-1-methyl-ethyl ester, {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2CH2Cl2 gave acetic acid 1-(2-{[(4-tert-butoxycarbonylamino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester (0.83 g, 75%). Deprotection with TFA using General Procedure F gave acetic acid 1-(2-{[(4-amino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester. 1H NMR (CDCl3) δ 1.30 (m, 2H), 1.53 (m, 2H), 1.76 (s, 6H), 1.94 (s, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 2.60 (m, 4H), 3.84 (s, 2H), 3.97 (s, 2H), 7.15 (m, 1H), 7.21 (s, 1H), 7.64 (d, 1H, J=7.0 Hz), 8.18 (s, 1H), 8.50 (d, 1H, J=3.0 Hz).