Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].OC1C=CC=CC=1C=O>CN(C=O)C>[CH2:25]([NH:27][C:28]([O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: O=Cc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 20 mmol) in DMF (100 mL) was added triethylamine (3.5 mL, 25 mmol) and the solution was stirred for 15 min at room temperature. Ethyl isocyanate (1.95 mL, 25 mmol) was added and the reaction mixture was stirred for 2 h at room temperature until no more hydroxybenzaldehyde was detected by TLC (Rf=0.78 for product and 0.89 for starting material using 1:1 hexanes/EtOAc). The reaction solution was concentrated by azeotropic removal of DMF with water. The resulting suspension was filtered, washed with water and dried in a vacuum oven to afford 96% of the title compound as a light buff solid.
Reaction SMILES: [H-].[Na+].O1CCCC1.[OH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH2:17]([Sn:21]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]I)[CH2:18][CH2:19][CH3:20]>O.C(OCC)(=O)C>[CH2:17]([Sn:21]([CH2:22][O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCCN1CCOCC1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a mixture of sodium hydride (72%, 230 mg, 7.0 mmol) and tetrahydrofuran (20 ml) was added N-(2-hydroxyethyl)morpholine (843 μl, 6.96 mmol) at room temperature. Then, the reaction mixture was stirred at 45° C. (external temperature) for 20 minutes. To the reaction mixture was added tributyl-iodomethyl-tin (2.0 g, 4.64 mmol) at 0° C. (external temperature). Then, the mixture was stirred at 45° C. for 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, heptane:ethyl acetate=9:1) to obtain the title compound (1.7 g, 4.0 mmol, 85%).
Reaction SMILES: CC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([OH:18])[CH2:13][C:14]#[C:15][CH2:16][CH3:17].N1C=CC=CC=1.CC1C=CC(S(OCCC#CCC)(=O)=O)=CC=1.[O:42]=[CH:43][C:44]1[CH:52]=[CH:51][C:49](O)=[C:46]([O:47][CH3:48])[CH:45]=1>C(Cl)Cl>[CH2:12]([O:18][C:49]1[CH:51]=[CH:52][C:44]([CH:43]=[O:42])=[CH:45][C:46]=1[O:47][CH3:48])[CH2:13][C:14]#[C:15][CH2:16][CH3:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCC#CCCO
Agent: CCC#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC#CCCOc1ccc(C=O)cc1OC
Yield: 38.7 %

Procedure:
4-Methylbenzenesulfonyl chloride (5.7 g, 30 mmol), 3-hexyn-1-ol (1.5 mL, 20 mmol) and pyridine (3.2 mL, 40 mmol) in CH2Cl2 (20 mL) were treated according to Procedure 4 giving hex-3-ynyl 4-methylbenzenesulfonate (3.8 g, 75%) as a colourless oil. Vanillin (0.76 g, 5.0 mmol) was alkylated with hex-3-ynyl 4-methylbenzenesulfonate (1.9 g, 7.5 mmol) according to Procedure 4 and the crude product was recrystallised from EtOAc/petrol to provide 4-(hex-3-ynyloxy)-3-methoxybenzaldehyde (0.45 g, 39%) as a colourless crystalline solid; mp 80-81° C.; δH (400 MHz, CDCl3) 1.12 (t, J=7.6 Hz, 3H, CH3), 2.17 (tq, J=7.6, 2.4 Hz, 2H, CH3CH2), 2.73 (tt, J=7.6, 2.4 Hz, 2H, OCH2CH2C), 3.92 (s, 3H, OCH3), 4.19 (t, J=7.6 Hz, 2H, OCH2), 7.00 (d, J5,6=8.0 Hz, 1H, H5), 7.41 (d, J2,6=1.6 Hz, 1H, H2), 7.44 (dd, J5,6=8.0, J2,6=1.6 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 12.4, 14.0, 19.5, 56.0, 67.6, 74.3, 84.0, 109.5, 111.8, 126.6, 130.3, 149.9, 153.5, 190.8; vmax 1023, 1134, 1263, 1586, 1680, 2877, 2972 cm−1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:6]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([N:7]2[CH:8]=[CH:9][C:5]([CH2:4][NH2:1])=[N:6]2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(CN=[N+]=[N-])n2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2ccc(CN)n2)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (75 mg, 0.27 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added water (0.5 mL) and triphenylphosphine resin (0.11 g, 3 mol/g, 200-400 mesh, 1.2 equiv). The suspension was stirred overnight. Filtration and concentration afforded C-[1-(4-methanesulfonyl-phenyl)-1H-pyrazol-3-yl]-methylamine as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=C([CH:20]=1)C#N)=[N:9][NH:8][C:7]2=[O:22].[OH-:23].[K+].[CH2:25]([OH:27])[CH3:26]>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:26]([CH:20]=1)[C:25]([OH:23])=[O:27])=[N:9][NH:8][C:7]2=[O:22]
Reactant: CCO
Reactant: N#Cc1cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F
Temperature: 100 °C
Yield: 89 %

Procedure:
5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorobenzonitrile (102) (6.1 g, 19.44 mmol) and potassium hydroxide (10.91 g, 194.44 mmol) were added to ethanol (30 mL) and water (70 mL) and heated at 100° C. for 5 hours. The ethanol was evaporated off and the aqueous was extracted with ethyl acetate (1×75 mL). The aqueous was then acidified to pH1 with conc HCl to afford a solid, this was filtered, washed with water and dried to afford the desired compound as a beige solid (5.73 g, 89%); 1H NMR (400.132 MHz, DMSO) δ 4.63 (2H, s), 7.21 (1H, dd), 7.44-7.40 (1H, m), 7.64 (1H, dd), 7.82 (1H, t), 7.98 (1H, dd), 8.34 (1H, dd), 12.87 (1H, s), 13.12 (1H, s); m/z (LC-MS, ESI+), RT=0.87 (M+H 333).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[H-].[Na+].Br[CH:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14].Cl>CN(C=O)C.O>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][CH:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:6]=1
Reactant: COC(=O)C(Br)CC(C)C
Reactant: Nc1ncc(Br)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CC(C)C)Nc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-amino-5-bromopyrimidine (3.12 g, 17.93 mmol) in dry DMF (60 mL) at 0° C. under dry nitrogen was added NaH (860 mg, 21.52 mmol) portionwise and the reaction was warmed to rt and stirred for 1 hour. The reaction was cooled again to 0° C. and methyl 2-bromo-4-methylpentanoate (4.7 g, 22.42 mmol, Bull. Chem. Soc. Jpn. 1989, 62, 2562) was added dropwise and the reaction was warmed to rt and stirred another 4 hours. Water was added, the aqueous phase neutralized with aq. 10 % HCl, and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8 then 3/7 then 4/6) to afford methyl 2-[(5-bromo-2-pyrimidinyl)amino]-4-methylpentanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[C:8](=[O:14])[C:7]=2[CH:15]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>CC#N.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.O>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[C:8](=[O:14])[C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)N(C)CCC2
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])CCCN(C)C2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
A mixture of 8-Methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (227 mgs, 1.1 mmol) in MeCN/TFAA (1:1, 2 mL) was cooled to 0° C. and treated with potassium nitrate (123 mg, 1.2 mmol), then warmed to room temperature and stirred for 2 h. Poured mixture in water, extracted (EtOAc), washed with brine and the organic layer dried (MgSO4), filtered and concentrated. ISCO purification (0 to 100% EtOAc/hexane, 40 g SiO2 column) provided 8-Methoxy-2-methyl-7-nitro-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (40 mgs). 1H-NMR (CDCl3) δδ 7.63 (s, 1H), 7.41 (s, 1H), 3.98 (s, 3H), 3.24 (t, J=6.3 Hz, 2H), 3.19 (s, 3H), 2.78 (t, J=7.1 Hz, 2H), 2.10-2.04 (m, 2H); LC/MS (ESI+): 250.98 (M+H). The regioisomer 8-Methoxy-2-methyl-9-nitro-2,3,4,5-tetrahydro-benzo[c]azepin-1-one was also isolated as a mixture with 8-Methoxy-2-methyl-7-nitro-2,3,4,5-tetrahydro-benzo[c]azepin-1-one. 1H-NMR (CDCl3) δ 7.22 (d, J=8.6 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 3.32 (t, J=6.1 Hz, 2H), 3.15 (s, 3H), 2.72 (t, J=6.8 Hz, 2H), 2.06-1.99 (m, 2H); LC/MS (ESI+): 250.98 (M+H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.C(OP([CH:18]([CH3:26])[C:19](=O)[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=O)OCC)C.O.[NH2:28][NH2:29]>>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]1[C:18]([CH3:26])=[C:3]2[C:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)=[N:29][N:28]=1
Reactant: CCOP(=O)(OCC)C(C)C(=O)CC(C)(C)C
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Solvent: O
Product: Cc1c(CC(C)(C)C)nnc2c1C1CCC2C1

Procedure:
light-yellow oil. MS (ESI): 297.1 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, (1,4,4-trimethyl-2-oxo-pentyl)-phosphonic acid diethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:31]=[C:32]1[NH:45][C:35]2=[N:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42](O)=[O:43])[CH:39]=[C:34]2[O:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][N:2]([CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:42](=[O:43])/[CH:41]=[CH:40]/[C:38]1[CH:39]=[C:34]2[O:33][C:32](=[O:31])[NH:45][C:35]2=[N:36][CH:37]=1
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)oc2c1
Reactant: CNCc1cc2ccccc2n1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2[nH]c(=O)oc2c1
Yield: 34 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(2-oxo-2,3-dihydro-oxazolo[4,5-b]pyridine-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.23 g, 34%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 12.64 (br s, 1H), 8.37-8.12 (m, 2H), 7.64 (d, J=15.3 Hz, 1H), 7.51-7.26 (m, 3H), 7.17-7.07 (m, 1H), 7.04-6.94 (m, 1H), 6.42-6.17 (m, 1H), 5.06-4.85 (m, 2H), 3.73-3.68 (m, 3H), 3.12-2.99 (m, 3H); MS (ESI) m/e 363 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:22][N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31]C(=O)C)[CH2:25][CH2:24]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.C1COCC1.CO.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:22][N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCN1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NN1CCN(CCO)CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Acetic acid 2-(4-{[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-amino}-piperazin-1-yl)-ethyl ester (100 mg, 200 μmol) was combined with THF (2 mL), methanol (1 mL) and water (1 mL) to give a light yellow solution. Lithium hydroxide (14.3 mg, 599 μmol) was added and the mixture was stirred for 1 h at room temperature. Subsequently the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 12 g, 0% to 100% ethyl acetate in n-heptane) to give the title compound (32 mg, 35%) as light yellow solid; MS (EI) 459.2 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=O)C.[C:18](Cl)(=[O:20])[CH3:19].Cl>ClC1C=CC(Cl)=CC=1Cl>[C:18]([C:17]1[CH:16]=[C:12]([CH:11]=[CH:10][C:9]=1[OH:8])[C:13]([OH:15])=[O:14])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CC(=O)c1cc(C(=O)O)ccc1O
Temperature: 135 °C
Reaction time: 1 h

Procedure:
36.6 g (0.274 mol) of AlCl3 are suspended in 50 ml of 1,2,4-trichloro-benzene and treated with 9 g (50 mmol) of 4-acetoxybenzoic acid. After dropwise addition of 7.84 g (0.1 mol) of acetyl chloride, the reaction mixture is heated to 130-140° C., the evolution of HCl gas occurring from approximately 60° C. The mixture is stirred for approximately 1 hour at 130° C. and then allowed to cool to 60-70° C., and the mixture is poured cautiously into stirred ice water. It is extracted several times with ethyl acetate, then the combined organic phases are extracted with saturated aqueous sodium bicarbonate solution and the combined aqueous phases are adjusted carefully to pH<1 using concentrated HCl, the 3-acetyl-4-hydroxybenzoic acid separating as sparingly soluble material.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH2:14]([O:17][C:18]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=1[NH2:20])[CH:15]=[CH2:16].Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:14]([O:17][C:18]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=1[NH:20][C:1](=[O:3])[CH3:2])[CH:15]=[CH2:16]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCOc1cc(OC)ccc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CCOc1cc(OC)ccc1NC(C)=O
Temperature: 25 °C

Procedure:
3 mg of 4-(dimethylamino)pyridine and 1 ml of acetic anhydride were successively added to 2 ml of pyridine containing 1.09 g of 2-allyloxy-4-methoxyaniline, and the reaction solution was then stirred at room temperature. After the disappearance of the raw material had been confirmed, 5 N HCl and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then solidified from t-butyl methyl ether-hexane, so as to obtain 1.04 g of the subject compound.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:11]1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of tert-butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]-carbamate (0.7 g) in dichloromethane (5 ml) was treated with trifluoroacetic acid (3 ml) for 1 hour. The reaction solution was concentrated and the residue was taken up in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 221.26 (C11H15N3O2); MS (ESI): 222 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][CH2:22][NH2:23])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:24]([N:31]1C=CN=C1)(N1C=CN=C1)=[O:25].CCN(C(C)C)C(C)C.N[OH:46].Cl>C1COCC1.C(Cl)Cl>[CH3:20][C:19]1[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]2[CH2:21][CH2:22][N:23]([OH:46])[C:24]([NH2:31])=[O:25])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCN
Reactant: NO
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCN(O)C(N)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 27.1 %

Procedure:
To a suspension of 2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-ethylamine (84 mg, 0.27 mmol) in THF (3 mL) was added 1,1′-carbonyldiimidazole (44 mg, 0.27 mmol) and the mixture was heated to 60° C. After 2 h, the mixture was concentrated in vacuo. The residue was re-dissolved in DMF (3 mL) and treated with DIPEA (0.13 mL, 1.35 mmol) and NH2OH.HCl (75 mg, 1.08 mmol) and the reaction mixture was stirred overnight. Then the mixture was diluted with CH2Cl2 (20 mL) and washed with brine (5×15 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 25:1:1) afforded the product as a white solid (27 mg, 27%). 1H NMR (CDCl3) δ 1.53-1.57 (m, 1H), 1.70 (d, 2H, J=15.0 Hz), 1.92-2.09 (m, 5H), 2.43-2.45 (m, 8H), 3.86 (d, 2H, J=9.0 Hz), 4.70 (br s, 1H), 6.43 (br s, 1H), 7.09 (dd, 2H, J=6.0, 3.0 Hz), 7.46 (d, 2H, J=9.0 Hz), 8.53 (d, 2H, J=3.0 Hz), 10.07 (br s, 1H). 13C NMR (CDl3) δ 19.33, 24.96, 33.13, 38.80, 55.54, 66.00, 122.70, 130.80, 139.36, 147.73, 161.02, 162.06. ES-MS m/z 370 [M+H]+. Anal. Calcd. for C20H27N5O2.0.2CH2Cl2: C, 62.78; H, 7.15; N, 18.12. Found: C, 62.86; H, 7.46; N, 17.97.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[N:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1)=[O:28]>CC#N>[Br-:25].[CH3:36][C:33]1[N:32]=[N:31][C:30]([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])=[CH:35][CH:34]=1
Reactant: Cc1ccc(NC(=O)CBr)nn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: Cc1ccc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)nn1
Product: [Br-]

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (0.20 mmol) and 2-bromo-N-(6-methyl-pyridazin-3-yl)-acetamide (Example 49a (0.20 mmol) were stirred together in anhydrous MeCN at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the yellow solid purified by flash silica gel column chromatography eluting with 0-15% MeOH/dichloromethane to give the title compound (65 mg) as a tan solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH3:13]COCC.[N+](=C)=[N-]>C1COCC1>[Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(CCBr)cc1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCBr)cc1
Yield: 99 %

Procedure:
A solution of 9.16 g (40 mmol) of 4-(2-bromoethyl)benzoic acid in 100 mL of THF was combined with an ether solution containing excess diazomethane. The excess diazomethane was consumed by addition of glacial acetic acid and the resultant solution was concentrated, in vacuo. The residue obtained was partitioned between saturated NaHCO3 (150 mL) and ethyl acetate (150 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (70 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo, yielding the product as a yellow oil (9.65 g, 99% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=[C:9](Br)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:50][C:51]1[C:52](B(O)O)=[CH:53][S:54][CH:55]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:43])[C:7]1[CH:8]=[C:9]([C:52]2[C:51]([CH3:50])=[CH:55][S:54][CH:53]=2)[CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)OC(C)(C)C)c2)c1CCC(=O)OCC
Reactant: Cc1cscc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Temperature: 85 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
3-Bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester (2.0 g) was dissolved in 1,2-dimethoxyethane (40 mL), followed by addition of Pd(PPh3)4 (80 mg), 2 M solution of sodium carbonate (6 mL) and 4-methyl-3-thiopheneboronic acid (641 mg). The resulting reaction mixture was stirred at 85° C. for 2 h. After cooling the reaction mixture was filtered through Celite™, diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to the title compound (1.8 g, 88% yield).