Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCOCC.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: BrCCCCCCCCCOCc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCCCCCCCCOCc1ccccc1)C(=O)OCC
Yield: 95.7 %

Procedure:
Methyl-malonic acid diethyl ester (0.850 ml, 4.99 mmol) was added to a suspension of sodium hydride (55% oily suspension, 139.5 mg, 3.197 mmol) in THF (0.8 ml) over seven minutes under ice-cooling, and the mixture was stirred until foaming was terminated at room temperature (for about 25 minutes). A solution of (9-bromo-nonyloxymethyl)-benzene (593 mg, 1.89 mmol) in THF (0.12 ml) was added to the reaction solution at room temperature over 15 minutes, and the mixture was then stirred at 90° C. for five hours. The reaction mixture was diluted with ether and water was then added, followed by extraction with ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1→20/1) to give 2-(9-benzyloxy-nonyl)-2-methyl-malonic acid diethyl ester (735 mg, 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O)[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1OC
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (10.0 g, 50.0 mmol, 1.0 equiv; commercially available), 3-ethoxy-4-methoxy-benzaldehyde (10.8 g, 60.0 mmol, 1.2 equiv; commercially available) and acetic acid (11.4 mL, 200.0 mmol, 4.0 equiv) in ethanol (40 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyano borohydride (6.27 g, 100.0 mmol, 2.0 equiv), dissolved in ethanol (20 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 5 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate to yield 9.71 g (53%) of the title compound as a white solid. MS (ISP): 365.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:14]C(=O)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[ClH:18]>>[ClH:18].[NH2:14][C@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH2:2][OH:1]
Reactant: CC(=O)N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A suspension of 0.98 g of N-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]acetamide in 10 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 100° C. for 10 hours (dissolution). The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 20 cm3 of diethyl ether and re-evaporated under the same conditions to give beige-colored crystals, which are washed with 3 times 20 cm3 of diethyl ether and then filtered off on a sinter funnel and finally dried in a fume cupboard. 0.92 g of (2R)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride is obtained in the form of beige-colored crystals melting at 192° C. [1H NMR spectrum (250 MHz, (CD3)2SO-d6, δ in ppm): 3.06 (limiting AB: 2H); from 3.25 to 3.65 (mt: 3H); 5.45 (t, J=4.5 Hz: 1H); 7.65 (t, J=7 Hz: 1H); 7.79 (broad d, J=7 Hz: 1H); from 8.05 to 8.40 (mt: 5H)].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].CS(C)=O.[CH2:19]([NH:21][CH2:22]C)C.[F-].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O>[CH3:19][N:21]([CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: CCNCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)c1cccc([N+](=O)[O-])c1S(N)(=O)=O
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-6-nitro-benzenesulfonamide (500 mg, 2.10 mmol), DMSO (3 ml), diethyl amine (10 ml of 2 M solution in THF), Bu4NHSO4 (34 mg, 0.1 mmol) and KF (58 mg, 1.0 mmol) is heated in an autoclave at 70° C. for 16 h. The mixture is diluted with water and extracted with CH2Cl2. The solvent is removed and the residue subjected to chromatography (SiO2, TBME/cyclohexane 1:9→TBME) to give 2-dimethylamino-6-nitro-benzenesulfonamide as a colorless solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[C:9]([C:11](=[CH:17][NH:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:12](OCC)=[O:13])#[N:10]>O1CCCC1>[CH3:25][C:24]1[C:19]2=[N:18][CH:17]=[C:11]([C:9]3[NH:10][N:7]=[N:6][N:5]=3)[C:12](=[O:13])[N:20]2[CH:21]=[CH:22][CH:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(C#N)=CNc1ncccc1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Yield: 50.7 %

Procedure:
Aluminum chloride (3.51 g., 0.0263 mole) was added to cold (-30°) tetrahydrofuran (180 ml.). Sodium azide (5.12 g., 0.0788 mole) was added and the mixture heated under reflux for 30 minutes. The mixture was cooled to 5°. Ethyl 2-cyano-3-(3-methyl-2-pyridylamino)acrylate (5.0 g., 0.0216 mole) was added and the mixture heated under reflux for 18 hours. The tetrahydrofuran was removed under reduced pressure. The residue was treated with ice water (100 ml.) and acidified to pH 3 with 6N hydrochloric acid. The mixture was filtered and the collected solid recrystallized from N,N-dimethylformamide to give the title compound (2.5 g., 50.7%), m.p. 310°-311° (decomp).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[CH:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1>>[CH:22]1([C:25]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)=[O:9])[CH2:3][CH2:2]2)=[O:26])[CH2:24][CH2:23]1
Reactant: O=C(O)C1CC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)C2CC2)CC1

Procedure:
Intermediate 42 (76 mg, 0.25 mmol) was reacted with cyclopropane carboxylic acid by Method E. Flash chromatography eluted with EtOAc and recrystallization from EtOAc:hexane afforded compound 52 (47 mg, 51%) as a white solid: Mp 195-196° C. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.22 (d, J=8.7 Hz, 2H), 6.25 (d, J=7.7 Hz, 1H), 4.15 (t, J=14.8 Hz, 2H), 3.77-3.68 (m, 1H), 3.25 (t, J=11.5 Hz, 1H, obscured), 2.81 (t, J=11.1 Hz, 1H), 1.98 (m, 1H), 1.93-1.75 (m, 2H), 1.41-1.17 (m, 2H), 0.75-0.65 (m, 4H). Purity 100%. HRMS calculated for C17H20F3N3O3+H+ 372.1535. found (ESI(+), [M+H]) 372.1546.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:31]#[N:32])[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:9]1=2.Cl.C(N(CC)CC)C.[N-:50]=[N+:51]=[N-:52].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=1)[CH2:6][N:7]([C:31]1[N:50]=[N:51][NH:52][N:32]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[C:10]2[CH:22]=[C:23]([C:27]([F:28])([F:29])[F:30])[C:24]([CH3:26])=[CH:25][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Yield: 98.8 %

Procedure:
Heat a mixture of (S)-tert-butyl 5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.0 g, 3.36 mmol), triethylamine hydrochloride (694 mg, 5.04 mmol) and sodium azide (328 mg, 5.04 mmol) in anhydrous toluene (20 mL) at reflux under nitrogen for 12 h. Dilute the cooled mixture with ethyl acetate (100 mL) and wash with 2 N HCl (2×50 mL), water (50 mL) and brine (50 mL) and dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure to provide the title compound as an off-white foam (2.12 g, >99%), which is used in the next step without purification. ESI MS m/z 637 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:32](=[O:33])[C:31]3[C:26](=[C:27]([O:35][CH3:36])[C:28]([O-])=[CH:29][CH:30]=3)[O:25][C:24]=2[CH:37]([CH3:39])[CH3:38])=[CH:19][CH:18]=1.[Na+].ClC1C=CC(C2C(=O)C3C(=C(OC)C(O)=CC=3)OC=2C(C)C)=CC=1.[H-].[Na+].N1C=CC=CC=1>C(Cl)Cl.O1CCCC1.CN(C)C1C=CN=CC=1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:32](=[O:33])[C:31]3[C:26](=[C:27]([O:35][CH3:36])[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:29][CH:30]=3)[O:25][C:24]=2[CH:37]([CH3:39])[CH3:38])=[CH:21][CH:22]=1
Reactant: COc1c([O-])ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: COc1c(O)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Agent: [H-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(OS(=O)(=O)C(F)(F)F)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Reaction time: 8 h

Procedure:
A solution of trifluoromethanesulfonic acid anhydride (3.5 g, 2.1 ml, 12.4 mmol, 2 eq.) in anhydrous methylene chloride (10 ml) is added dropwise to a stirred solution of sodium 3-(4-chlorophenyl)-2-isopropyl-8-methoxy-4-oxo-4H-chromen-7-olate (2.28 g, 6.22 mmol; prepared by treating 3-(4-chlorophenyl)-7-hydroxy-2-isopropyl-8-methoxy-chromen-4-one with a molar equivalent of sodium hydride in dry tetrahydrofuran), pyridine (2 g, 2.1 ml, 25.5 mmol, 4.1 eq.) and 4-dimethylaminopyridine (0.076 g, 0.62 mmol, 0.1 eq.) in anhydrous methylene chloride (60 ml) at 0° C. After stirring overnight, the solution is washed with 1M HCl solution. The organic phase is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation in vacuo to afford the title compound as a brown foam. The product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC.CN(C)C=O.[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N+:8]([C:3]1[C:2]([CH:11]=[CH2:12])=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncccc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cccnc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The mixture of 327 mg of 3-bromo-2-nitropyridine, 256.5 mg of dichlorobis(triphenylphosphine)palladium (II), 518 μL of tributyl(vinyl)tin, and 6 mL of N,N-dimethylformamide, was stirred at 80° C. for 3 hours. The reaction mixture was cooled back to room temperature, then 500 mg of potassium fluoride and 1.5 mL of water were added thereto, and stirred at room temperature for 30 minutes. The insolubles were filtered through celite, a saturated aqueous solution of sodium hydrogen carbonate was added, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the thus obtained residue was purified by silica gel column chromatography, to obtain 236 mg of 2-nitro-3-vinylpyridine [120-1] as a pale red solid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>O.[Cl-].C([N+](CC)(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]=[C:11]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[O:8][CH2:9][CH2:10]1
Reactant: C=CCCOc1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: O
Product: C=C1CCOc2cccnc21
Temperature: 110 °C
Yield: 52.8 %

Procedure:
A reaction tube was charged with 2-Bromo-3-but-3-enyloxy-pyridine (106 mg, 0.45 mmol), triphenylphosphine (35 mg, 0.133 mmol), palladium acetate (10 mg, 0.044 mmol), potassium acetate (223 mg, 2.27 mmol), tetraethylammonium chloride hydrate (151 mg, 0.91 mmol) and degassed DMF (2 mL). A rubber septum was used to seal the tube and the contents were then flushed several times with argon, then closed tightly with a cap. The mixture was heated at 110° C. under argon for 18 hours, cooled to room temperature then diluted with 200 mL ethyl acetate. The organic layer was washed with sat. NaHCO3, then brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 5% ethyl acetate in hexanes, afforded the title compound (35 mg, 52%) as white solid. 1H NMR (CDCl3) □2.79-2.84 (m, 2H), 4.25 (t, 2H, J=5.7 Hz), 5.06-5.08 (m, 1H), 6.19 (d, 1H, J=1.6 Hz), 7.08-7.17 (m, 2H), 8.20 (dd, 1H, J=1.6, 4.7 Hz); ES-MS m/z 148.0 (M+H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:27]([Sn:31](Cl)([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>O1CCCC1>[CH3:12][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([Sn:31]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:3][N:4]=[C:5]2[N:10]=1)([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:21]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)O[Si](CC)(CC)CC)ccn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (440 mg, 1.20 mmol) in tetrahydrofuran (4 ml) was added isopropylmagnesium chloride (0.63 ml of a 2M solution in tetrahydrofuran, 1.26 mmol). After stirring at −78° C. for 5 min tributyltin chloride (0.36 ml, 1.32 mmol) was added, the reaction stirred for 10 min at −78° C., then allowed to warm to ambient temperature, to give a solution of 7-(1-methyl-1-triethylsilanyloxyethyl)-3-tributylstannanylimidazo[1,2-α]pyrimidine: m/z (ES+) 581 (M++H).
Reaction SMILES: [N+:1]([CH:4]([CH:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][CH3:6])([O-])=O.O1CCNC1>[Ni].CO>[NH2:1][CH:4]([CH:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][CH3:6]
Reactant: CCCCC(O)C(CC)[N+](=O)[O-]
Agent: [Ni]
Agent: C1COCN1
Solvent: CO
Product: CCCCC(O)C(N)CC
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
Catalytic hydrogenation of the 3-nitro-4-octanol to the 3-amino-4-octanol alkanolamine A sample of 3-amino-4-octanol (3A4O) was synthesized by the reduction of the 3-nitro-4-octanol by a Parr Autoclave unit. The stainless steel, 2 liter autoclave was loaded with Grace 3201 Raney Nickel (RaNi, 90 g wet, 45 g dry, 10 wt %) and methanol (MeOH, 300 g). The autoclave was sealed, assembled, purged with nitrogen then hydrogen, pressurized with hydrogen (600 psig), stirred at 600 RPM, and warmed to 40° C. The nitro-alcohol (491 g) was diluted with absolute ethanol (EtOH, 150 g) and pumped into the autoclave (4 ml/min) After 3.5 h the addition was complete and after 4 h the reaction was judged complete as no hydrogen uptake was observed. The autoclave was cooled, stirring stopped, vented, and purged with nitrogen. The autoclave was disassembled and the contents were vacuum filtered to remove the RaNi catalyst. This resulted in the isolation of a light yellow liquid (92 area %) that was concentrated in vacuo (55° C./full vacuum) before product was taken overhead (57-62° C./full vacuum). This resulted in the isolation of a clear, colorless, semi-solid (344 g, 95.3 area %, 75% overall yield) that contained some oxazolidine (2.2 area %) and some secondary amines (0.5 area %).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[CH:6]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=1[OH:24]>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=1[O:24][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[F:12]
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using 3,4-difluorophenyl methyl sulfone and the product of example 1 step (iii).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[S:8][CH:9]=[C:10]([CH3:12])[N:11]=1>>[Br:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH3:12])[N:11]=1)=[O:4]
Reactant: Cc1csc(N)n1
Reactant: O=C(Br)CBr
Product: Cc1csc(NC(=O)CBr)n1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A16 (Step 5) starting from bromoacetyl bromide and 2-amino-4-methylthiazole.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.O.[NH2:17][NH2:18]>CCO>[NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([NH:17][NH2:18])=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: COC(=O)c1ccc(-c2nnn[nH]2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a suspension of methyl 4-(1H-tetrazol-5-yl)benzoate (1.00 g, 4.16 mmol) in EtOH (15 mL) was added hydrazine hydrate (3.0 mL). After stirring for 15 hrs at reflux, the reaction mixture was allowed to warm up to rt. A white solid precipitated out. Filtration, washing with EtOH (2×3 mL), EtOH/water (2×3 mL) and water (2×3 mL) and drying under vacuo at 70° C. for 5 hrs gave 677 mg of the title compound as a white solid in a 80% yield.
Reaction SMILES: C(OC([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=O)C1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:40][CH2:41][CH2:42][OH:43]>ClCCl.O>[NH2:11][C:12]([CH3:16])([CH3:17])[C:13]([NH:40][CH2:41][CH2:42][OH:43])=[O:15]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(N)C(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid (0.5 g) in dichloromethane (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g), 1-hydroxybenzotriazole (0.43 g) and 2-aminoethanol (1.16 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (0.10 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 2-(2-amino-2-methylpropionylamino)ethanol (0.11 g). To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (70 mg) in N,N-dimethylformamide (0.5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg), 1-hydroxybenzotriazole (23 mg) and 2-(2-amino-2-methylpropionylamino)ethanol (0.11 g), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, 5 mol/L aqueous sodium hydroxide solution (0.25 mL) was added to the filtrate, and the resulting mixture was stirred at room temperature for 1 hour. To the mixture was added acetic acid (0.09 mL), and the mixture was diluted with water (1 mL). The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol=90/10-10/90) to give 3-(β-D-glucopyranosyloxy)-4-(4-{(1E)-3-[1-(2-hydroxyethylcarbamoyl)-1-methylethylcarbamoyl]prop-1-enyl}phenyl)methyl)-5-isopropyl-1H-pyrazole (14 mg). This material was dissolved in methanol (0.5 mL). To the solution was added 10% palladium-carbon powder (7 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (11 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(F)c(F)cc1OCc1ccccc1

Procedure:
To a vigorously stirred mixture of 4,5-difluoro-2-nitrophenol (1 g, 5.71 mmol) and anhydrous potassium carbonate (1.9 g, 14.28 mmol) in acetone (20 mL). is added benzyl bromide (750 μl, 6.28 mmol) and the dark heterogeneous mixture is heated to reflux for 10 h; or until all starting material had been consumed according to LC/MS analysis. The dark mixture is then filtered, dried over magnesium sulfate, and filtered again to afford, after solvent removal, a light brown crystalline solid that was used in the next step without further purification.