Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[C:19]([C:23]3[C:28]([Cl:29])=[CH:27][C:26]([O:30]CC4C=CC(OC)=CC=4)=[CH:25][C:24]=3[Cl:40])[NH:20]2)=[CH:16][CH:15]=1)=[O:13].Cl>C(Cl)Cl.CO.O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[C:19]([C:23]3[C:24]([Cl:40])=[CH:25][C:26]([OH:30])=[CH:27][C:28]=3[Cl:29])[NH:20]2)=[CH:16][CH:15]=1)=[O:13]
Reactant: COc1ccc(COc2cc(Cl)c(-c3cc4ccc(C(=O)Nc5ccc6ccccc6n5)cc4[nH]3)c(Cl)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2cc(-c3c(Cl)cc(O)cc3Cl)[nH]c2c1
Reaction time: 2.5 h

Procedure:
To a suspension of 2-[2,6-dichloro-4-(4-methoxybenzyloxy)-phenyl]-1H-indole-6-carboxylic acid quinolin-2-ylamide (200 mg, 0.352 mmol) in DCM (7.5 mL) and MeOH (2.5 mL) was added 4 M HCl in dioxane (7.5 mL) and the mixture was stirred for 2.5 hr. The reaction was concentrated under reduced pressured and the concentrate partitioned between EtOAc (150 mL) and sat NaHCO3 (30 mL). The organic phase was dried over Na2SO4 and the solvent evaporated. The residue was triturated with DCM to afford the title compound as an orange solid. MS (m/z) 448.1 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 11.72 (d, J=1.14 Hz, 1H), 11.04 (s, 1H), 10.68 (s, 1H), 8.36-8.43 (m, 2H), 8.18 (s, 1H), 7.96 (d, J=8.08 Hz, 1H), 7.89 (d, J=8.34 Hz, 1H), 7.79 (dd, J=8.34, 1.26 Hz, 1H), 7.74 (dd, J=15.35, 1.20 Hz, 1H), 7.66 (d, J=8.34 Hz, 1H), 7.52 (t, J=7.52 Hz, 1H), 7.02 (s, 2H), 6.53 (d, J=1.77 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11].C[O-].[Na+].O>CO>[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH:11]=[CH:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=Cc1ccsc1
Reactant: CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)C=Cc1ccsc1
Yield: 81.4 %

Procedure:
3-Thiophene carbaldehyde (500 μL, 5.71 mmol) and 3,3-dimethylbutan-2-one (710 μL, 5.71 mmol) were dissolved in methanol (5.0 mL). To this was added sodium methoxide (340 mg, 6.29 mmol), and then the mixture was stirred under reflux overnight. After addition of water, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated off in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 95/5) to give the title compound (904 mg, 4.65 mmol, yield 81%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:23]([C:29]([NH:28][CH2:26][CH3:27])=[O:30])[CH2:24][CH2:25]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN=C=O
Reactant: CN(C)c1ccc(-c2nc3c(N4CCNCC4)c(Br)cnc3[nH]2)cc1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Yield: 55 %

Procedure:
This was prepared from [4-(6-bromo-7-piperazin-1-yl-3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-dimethyl-amine (20 mg, 0.050 mmol), using CHCl3 (1.5 mL) and ethyl isocyanate (1.1 eq, 0.055 mmol, 43 μL). Filtration of the precipitate after 16 h gave the product (13 mg, 56%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.05 (t, J=7.1 Hz, 3H, CH2CH3), 3.00 (s, 6H, N(CH3)2), 3.09 (qd, J=7.1, 5.4 Hz, 2H, NHCH2), 3.50-3.52 (m, 4H, piperazine N(CH2)2), 3.55-3.57 (4H, m, piperazine N(CH2)2), 6.55 (t, J=5.4 Hz, 1H, NHCH2), 6.82 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 8.01 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.18 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][N:11]=1>O>[C:20]1([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:7][C:4]3[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=3)=[N:11][N:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: Nc1ccc(N)cc1
Solvent: O
Product: Nc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 110 °C

Procedure:
Benzene-1,4-diamine (0.337 g, 3.12 mmol) and 1-chloro-4-phenylphthalazine (0.500 g, 2.08 mmol) were treated with 7.5 mL 2-BuOH in a sealed tube and heated to 110° C. The reaction quickly became a solid, yellow mass. After several hours, the reaction was cooled and diluted with water. The slurry was then partitioned between DCM and 1N NaOH. The aqueous layer was extracted into DCM (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, ISCO, 40 g, 0-10% MeOH/MC to give N1-(4-phenylphthalazin-1-yl)benzene-1,4-diamine as an orange-brown solid. MS m/z=313 [M+H]+. Calc'd for C20H16N4: 312.4.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:13]2[C:18]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)(=[O:22])=[O:21])=[CH:17][C:16]([Cl:34])=[CH:15][N:14]=2)=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:13]2[C:18]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=3)(=[O:21])=[O:22])=[CH:17][C:16]([Cl:34])=[CH:15][N:14]=2)=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:36][CH3:35])=[O:6]
Reactant: O=C(O)c1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Yield: 22.1 %

Procedure:
To a vial containing 2-chloro-3-[5-chloro-3-(4-chloro-3-trifluoromethylbenzene-sulfonylamino)-pyridine-2-carbonyl]benzoic acid (24 mg, 0.04 mmol) were added HATU (75 mg, 0.2 mmol), DMF (1 mL), a 2.0 M solution of MeNH2 in THF (0.3 mL, 0.6 mmol), and (i-Pr)2NEt (35 L, 0.2 mmol). The solution was maintained at room temperature for 15 h. EtOAc (20 mL) was added, and the organic phase washed with saturated aqueous NaCl (2×10 mL) and dried over MgSO4. The volatiles were removed in vacuo, and the resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA). The pure fractions were lyophilized to afford the title compound (5 mg, 5% yield): HPLC retention time=2.69 minutes. MS (ES) [M+H]+ expected 566.0. found 565.9. 1H NMR (400 MHz, CDCl3) δ 10.98 (s, 1H), 8.17-8.21 (m, 3H), 8.00 (dd, J=2.4, 8.8 Hz, 1H), 7.65-7.69 (m, 2H), 7.41 (t, J=7.2 Hz, 1H), 7.30 (dd, J=1.6, 7.2 Hz, 1H), 6.01 (bs, 1H), 3.01 (d, J=5.2 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:11]([Cl:23])[CH:10]=2)=[CH:6][CH:5]=1.Cl.C(=O)([O-])O.[Na+]>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:11]([Cl:23])[CH:10]=2)=[CH:24][CH:25]=1
Reactant: O=C(Cn1cncn1)c1ccc(Oc2ccc(Br)cc2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: OC(Cn1cncn1)c1ccc(Oc2ccc(Br)cc2)cc1Cl
Reaction time: 4 h
Yield: 94.8 %

Procedure:
While stirring and passing a current of nitrogen through the reaction mixture, 0.56 g (14.7 mmol) of sodium borohydride is added in portions at room temperature and within a period of 15 minutes to a solution of 5.8 g (14.7 mmol) of 2-[4-(4-bromophenoxy)-2-chlorophenyl]-1-(1H-1,2,4-triazol-1-yl)-ethan-2-one in 40 ml of methanol. The temperature of the reaction mixture rises from 22° to 38°. When the addition is complete, stirring is continued for a further 4 hours at room temperature and then 2.2 g of concentrated hydrochloric acid are added, followed somewhat later by the addition of 22 ml of 10% sodium hydrogen carbonate solution. The title compound is precipitated in crystalline form. It is isolated by filtration, washed with water and dried, to give 5.5 g of 2-[4-(4-bromophenoxy)-2-chlorophenyl]-1-(1H-1,2,4-triazol-1-yl)-ethan-2-ol om the form of a beige crystalline powder. Melting point 115°-118° C.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[OH:9].C(N(CC)CC)C.[C:17]([C:23]([O:25][CH3:26])=[O:24])#[C:18][C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:17]1([C:23]([O:25][CH3:26])=[O:24])[O:9][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]2=[N:2]1
Reactant: N=C1CCCCN1O
Reactant: COC(=O)C#CC(=O)OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CC1(C(=O)OC)N=C2CCCCN2O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-iminopiperidin-1-ol hydrochloride in chloroform was added triethylamine. The mixture was stirred for 5 min. at room temperature, then cooled to 0° C. and 1.2 eq. of dimethyl acetylenedicarboxylate were added dropwise under stirring. The cooling bath was removed and the mixture was stirred at room temperature for one hour. The solvent was removed under reduced pressure and the solution was partitioned between ethyl acetate and half saturated aq. ammonium chloride. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered through silica gel. The solvent was removed under vacuum to afford methyl 2-(2-methoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2H-[1,2,4]oxadiazolo[2,3-a]pyridine-2-carboxylate as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](N)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].C(I)[I:21].N(OCCC(C)C)=O>C1COCC1.[Cu]I>[Cl:1][C:2]1[N:10]=[C:9]([I:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: ICI
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(N)nc21
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(I)nc21
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a mixture of 117a (2.99 g, 10.0 mmol), CH2I2 (4.0 ml, 51.0 mmol), and CuI (1.91 g, 10.0 mmol) in THF was added isoamyl nitrite (4.0 mL, 30.0 mmol). The mixture was heated at reflux for 1.0 h and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and 1N aqueous HCl solution. The organic phase was washed with saturated aqueous NH4Cl, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 117b (2.02 g, 49%) as a yellow solid. MS-ESI: [M+H]+ 411.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.S(Cl)(Cl)=O.[C-:16]#[N:17].[Na+]>C(Cl)Cl.C(=O)([O-])O.[Na+].CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:16]#[N:17])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(CO)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
The product from step (iii) (5.38 g) was dissolved in dry DCM (50 ml) and dry DMF (2.3 ml) added followed by thionyl chloride (2.17 ml). The reaction mixture was stirred at RT overnight, and then diluted with aqueous sodium hydrogen carbonate, extracted with DCM, dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was dissolved in DMF (20 ml), sodium cyanide (1.30 g) was added and stirred at RT overnight. The reaction mixture was diluted with water, extracted with ether, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent 1:2 ether/isohexane) to give the subtitle compound (4.50 g).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][C@@H:2]1[OH:3].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C>C(O)C>[S:29]([O:8][CH2:7][C@H:5]1[O:6][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@@H:2]([OH:3])[CH2:4]1)([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)C[C@@H]2O)c(=O)[nH]1
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](O)[C@H](n3ccc(=O)[nH]c3=O)O2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
With moisture excluded, a solution consisting of 228 mg. (1.0 millimoles) of 1-(3-deoxy-β-D-threopentofuranosyl)-uracil [Prepared according to the method described by Horwitz et al., J. Org. Chem. 31, pp. 205--211 (1966)] and 2.5 ml. pyridine was chilled to 0° C. and a solution consisting of 236 mg. (1.24 millimoles) p-toluenesulfonyl chloride and 2.5 ml. pyridine was added dropwise while the temperature of the reaction mixture was maintained at 0° C. The reaction vessel was securely sealed and set aside at 3° to 5° C. for about 16 hrs. Afterwards, a small portion of crushed ice was added to the reaction mixture and refrigeration was continued for about 1 to 2 hrs. This mixture was further diluted with 50 ml. of ice-cold water and the dilute aqueous solution was extracted three times with 30 ml. portions of chloroform. The chloroform extracts were combined and dried over anhydrous sodium sulfate. After removing the chloroform by evaporation under reduced pressure, the residue thus obtained was dissolved in hot absolute ethanol. Some decolorizing charcoal was added to the ethanol solution, the charcoal was removed by filtration, and the filter was washed with hot absolute ethnol. The ethanol was removed from the combined filtrate and washings under reduced pressure, and the residue thus obtained was azeotroped with absolute ethanol under reduced pressure. There was thus obtained 182.8 mg. of 1-(5-O-tosyl- 3-deoxy-β-D-threopentofuranosyl)uracil as an amorphous solid.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][C@@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>C1COCC1>[O:38]=[C:33]([N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][C@@H:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)C(=O)Cl
Reactant: c1ccc(CNC[C@@H]2COCCN2Cc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(=O)N(Cc1ccccc1)C[C@@H]1COCCN1Cc1ccccc1
Reaction time: 3 h
Yield: 107.5 %

Procedure:
To a solution of 1-phenyl-N-{[(3R)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine (3.3777 g, 11.40 mmol) in THF (114 mL) was added N,N-diisopropylethylamine (3 mL, 17.22 mmol). To the solution was added methyl chloro(oxo)acetate (1.15 mL, 12.50 mmol) dropwise via syringe, and the mixture was stirred for 3 h. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (200 mL) and washed with sat. aq. NaHCO3 followed by water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude methyl oxo((phenylmethyl){[(3R)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate (4.6881 g, >100% crude yield) as a yellow oil. LCMS: (M+H)+: 383.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[SH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Sc1ccccn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccn2)CC1
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol)and diisopropylethylamine(2.6 mL, 15 mmol) in dry dichloromethane (30 mL) was added anhydrous trifluoromethanesulfonic acid (1.0 mL, 6.0 mmol) at −78° C. The mixture was stirred for 1 minute under ice cooling, and cooled to −78° C. To the reaction mixture was added 2-mercaptopyridine (1.67 g, 15 mmol), and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, successively, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50 ethyl acetate-hexane 1:5) to give the titled compound as pale yellow oily substance (937 mg, 64%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH3:16])[CH:10]1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CN(C=O)C.N1C=NCC=1>CN(C)C1C=CN=CC=1.CCOCC>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH3:16])[CH:10]1[O:17][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC1CCCC(OCc2ccccc2)C1O
Agent: C1=NC=NC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1CCCC(OCc2ccccc2)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxy-3-methoxy-cyclohexan-2-ol, 51d, (2.31 g, 9.78 mmol), tert-butyl-chlorodimethyl-silane (2.21 g, 2.73 mL, 14.66 mmol) in 20 dry DMF at room temperature was added 4H-imidazole (1.997 g, 29.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.12 g, 0.98 mmol). The resulting mixture was stirred at room temperature overnight. It was then diluted with ether, washed with water, aqueous saturated citric acid solution and water again. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The colorless crude oil was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=1)[CH3:2].CO.C(N(C1C=CN=C(C)C=1[N+]([O-])=O)CC)C.[ClH:33]>[Pd].C(#N)C>[ClH:33].[ClH:33].[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([CH3:10])[N:9]=1)[CH3:15]
Reactant: CCN(CC)c1ccc([N+](=O)[O-])c(C)n1
Agent: [Pd]
Agent: CCN(CC)c1ccnc(C)c1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CCN(CC)c1ccc(N)c(C)n1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
Into a 500 mL PARR reactor bottle was placed 6.3 gram (30 mmol) of 6-diethylamino-3-nitro-2-picoline and 75 mL of reagent grade methanol. The mixture was stirred at room temperature for a few minutes to fully dissolve the diethylaminonitropicoline, then 1 gram of 5% Palladium on carbon was added. The resulting mixture was placed upon the PARR hydrogenation shaker and hydrogenated at 50 psi H2 atmosphere at room temperature. After 3 hours the reaction was removed from the hydrogenation shaker and evaluated by thin layer chromatography to show that all starting material had been consumed and one product had formed. The product containing methanol solution was filtered through a pad of Supercel Celite slurried in methanol on a medium porosity sintered glass funnel to remove the palladium on carbon catalyst. The Celite pad was washed with 25 mL of methanol. The resulting nearly colorless filtrate was treated with 7 mL of concentrated hydrochloric acid (0.84 moles hydrogen chloride) and the lightly colored solution was transferred to a 500 mL flask. The product mixture was concentrated under reduced pressure at 50° C. to afford a wet amorphous semi-solid product mixture. This was treated with 50 mL of acetonitrile and stirred rapidly for 45 minutes then filtered on a Buchner funnel. The resulting off-white solid was washed with 25 mL of acetonitrile, dried by sucking air through for 30 minutes, then dried under high vacuum over night. The off-white product of N2,N2-diethyl-6-methyl-2,5-pyridinediamine dihydrochloride was 7.2 grams (28.5 mmol, 95.1% yield). Mass Spectrum analysis indicated an Electron Impact EI+ m/e of 179.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:21])[C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=1.Br>O1CCOCC1>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:21])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)c1ccc(C=C2CCCCC2=O)cc1
Agent: Br
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(C=C2CCCCC2=O)cc1
Yield: 51.2 %

Procedure:
A solution of 1.3 g of ethyl 2-[4-(2-oxo-1-cyclohexylidenemethyl)phenyl]propionate in 15 ml of dioxane and 100 ml of a 10% aqueous solution of hydrogen bromide was heated under reflux for 1 hour. After cooling, the reaction mixture was extracted with ether. The extract was washed with water and dried over anhydrous sodium sulfate. The ether was distilled off to leave an oily substance, which was then vacuum distilled to give 0.6 g of the desired product having a boiling point of 210°-215° C./0.3 mmHg (bath temp.). This product solidified and crystallized after cooling. m.p. 108°-110° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[N:4][C:5]([Br:12])=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:3]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[N:4][C:5]([Br:12])=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)nc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)nc2)c1N=[N+]=[N-]
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Methyl 3-amino-6-bromo-6′-morpholino-2,3′-bipyridine-4-carboxylate (230 mg, 0.59 mmol) was dissolved in TFA (2.9 mL) and the solution was cooled in an ice bath. Solid sodium nitrite (89 mg, 1.29 mmol) was added slowly with stirring to give a red solution. After 30 min, powdered sodium azide (380 mg, 5.85 mmol) was added in portions with gas evolution. Et2O (29 mL) was added with stirring after 0.5 hr, water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with, water (3×), saturated Na2CO3 solution (until the aqueous phase was basic), and brine (1×). After drying the solvent with sodium sulfate, the solvent was removed. Flash chromatography (step gradient elution with DCM containing 0 to 20% EtOAc) afforded methyl 3-azido-6-bromo-6′-morpholino-2,3′-bipyridine-4-carboxylate (240 mg, 0.57 mmol, 98% yield) yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.73 (1H, d, J=2.44 Hz), 7.99 (1H, dd, J=9.00, 2.59 Hz), 7.71 (1H, s), 6.68 (1H, d, J=8.85 Hz), 4.00 (3H, s), 3.79-3.86 (4H, m), 3.59-3.66 (4H, m).