Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH2:3][O:4][CH2:5][CH3:6].CCN(CCO)C[CH2:11][N:12]1[C:16]2[C:17]([N:19]([CH3:24])C(N(C)C=2[N:14]=[C:13]1[CH2:25][C:26]1C=CC=CC=1)=O)=O.Cl>CCOCC>[N:12]1[CH:13]=[CH:25][CH:26]=[C:2]([CH2:3][O:4][C:5]2[N:14]=[C:13]([N:12]3[CH2:11][CH2:24][NH:19][CH2:17][CH2:16]3)[CH:25]=[CH:26][CH:6]=2)[CH:11]=1
Reactant: CCOCC
Reactant: CCN(CCO)CCn1c(Cc2ccccc2)nc2c1c(=O)n(C)c(=O)n2C
Agent: Cl
Product: c1cncc(COc2cccc(N3CCNCC3)n2)c1
Reaction time: 8 h

Procedure:
A solution of 2-bromo-6-(pyridin-3-ylmethoxy)-pyridin-hydrochloride prepared as above (25.07 g, 94.6 mmol) was suspended in 275 mL of dry dioxane and then 65.06 g (756.5 mmol, 8 equiv.) of piperazine and 14.19 g (94.6 mmol) of NaI were added. The reaction mixture was then heated slowly to reflux under an atmosphere of dry N2. After about 1 h, the solids in the reaction mixture went partially into solution. Reflux was continued for 48 h at which time the reaction mixture was cooled and taken up in cold water, giving a pale yellow solution. This was extracted four times with ethyl acetate and the combined extracts were backwashed once with water and washed with saturated NaCl solution. The organic solution was dried with MgSO4 and the solvent was evaporated to give 20.7 g of pale yellow oil. This oil was dissolved in 500 mL of dry ether and stirred rapidly while 75 mL of 1 M HCl/ether solution was added dropwise (the mixture was seed with a small amount of mono-HCL salt prepared earlier by the same procedure on smaller scale). The HCl salt crystallized and was granulated overnight at room temperature under N2 atmosphere. The crystalline salt was filtered off and washed with dry ether and dried in a stream of dry N2 and residual ether was removed by pumping in high vacuum for 5 h to give 21.67 g (75%) of off white solid, m.p.=141–143° C.
Reaction SMILES: CC1(C)COC2(CCC(CCN[C@H](C3C=CC=CC=3C)C)(O)CC2)OC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1(C)CO[C:43]2([CH2:63][CH2:62][C:46]3([O:51][C:50](=[O:52])[N:49]([C@H:53]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[CH3:61])[CH3:54])[CH2:48][CH2:47]3)[CH2:45][CH2:44]2)[O:42]C1>>[C:56]1([CH3:61])[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[C@@H:53]([N:49]1[CH2:48][CH2:47][C:46]2([CH2:62][CH2:63][C:43](=[O:42])[CH2:44][CH2:45]2)[O:51][C:50]1=[O:52])[CH3:54]
Reactant: Cc1ccccc1[C@H](C)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: Cc1ccccc1[C@H](C)NCCC1(O)CCC2(CC1)OCC(C)(C)CO2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: Cc1ccccc1[C@H](C)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 3,3-dimethyl-9-{2-[(S)-1-o-tolyl-ethylamino]-ethyl}-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 12,12-di methyl-3-[(S)-1-o-tolyl-ethyl]-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 17% of theory; LC (method 8): tR=1.23 min; Mass spectrum (ESI+): m/z=302 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:37][NH:38][O:39][CH3:40]>ClCCl>[CH3:40][O:39][N:38]([CH3:37])[C:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:14][CH:13]=2)[CH2:20][CH2:19]1)=[O:23]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC(C(=O)O)CC2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a suspension of 1-{4-[(tert-butoxycarbonyl)amino]phenyl}piperidine-4-carboxylic acid (1.3 g, 4.1 mmol) in dichloromethane (40 mL) is added carbonyldiimidazole (0.79 g, 4.9 mmol) and the mixture is stirred at room temperature for 30 minutes before N,O-dimethylhydroxylamine hydrochloride (1.0 g, 10 mmol) is added. After stirring for 30 minutes, the reaction mixture is concentrated under reduced pressure. The residue is partitioned between diethyl ether and water. The ethereal phase is washed 2× with water and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide tert-butyl [4-(4-{[methoxy(methyl)amino]carbonyl}piperidin-1-yl)phenyl]carbamate as a pale yellow solid (1.5 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-chloro-phenylboronic acid (51 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][NH:12][C:11]1=[O:16])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]([OH:15])[CH2:13][NH:12][C:11]1=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN1C(=O)NCC1O
Reaction time: 16 h
Yield: 82.2 %

Procedure:
[2-(2,5-Dioxo-imidazolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (14.6 g, 60 mmol) was dissolved in THF (1.5 L) and treated with 1.0 M LiAlH4 in THF (77 mL, 77 mmol) added dropwise. The initial vigorous effervescence subsided and the solution became opaque white. The mixture was stirred for 16 h and then quenched (i. 2.0 mL of water; ii. 2.0 mL of 4 M aqueous NaOH; iii. 10 mL of water). The mixture was filtered and the resulting filtrate concentrated to give 12.1 g of solid. This was dissolved in 100 mL of hot EtOAc and applied (hot) to 250 g of silica pre-washed with EtOAc. The product was isolated by elution with EtOAc→2% MeOH/EtOAc→5% MeOH/EtOAc as a white solid (7.85 g, 53%). The compound has poor solubility in a number of organic solvents.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH:10]=[C:9]([O:11]C)[CH2:8][C:7]([O:13]C)=[CH:6]1.Cl>O1CCCC1.O>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH2:6][C:7](=[O:13])[CH2:8][C:9](=[O:11])[CH2:10]1
Reactant: CNCCC1C=C(OC)CC(OC)=C1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNCCC1CC(=O)CC(=O)C1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
To a stirred solution of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (5.5 g, 27.9 mmol) in 20 ml of tetrahydrofuran was added 10 ml of 6 N hydrochloric acid in one portion. The warm solution was heated for 15 min. at 50° C. and concentrated to give a light yellow oil. The crude oil was dissolved in 25 ml of water, and the solution was mixed with 50 g of Dowex 50×8 resin (previously washed with 2 N HCl and deionized water) in a sintered glass funnel. After a few minutes, the aqueous solution was drawn out by suction, and the resin rinsed with four 50 ml-portions of water, and then with eight 35 ml-portions of 2 M aqueous pyridine. Pyridine fractions 3-8 were pooled and concentrated to give 3.9 g of 5-[(2-methylamino)ethyl]-cyclohexane-1,3-dione. An analytical sample crystallized from water and had mp 171°-4° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[C:8]([NH2:38])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCCCC1

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (7.58 g, 22.0 mmol). 3-Chloroperoxybenzoic acid (9.1 g of 50% pure material, 26.4 mmol) was added in five portions during the oxidation step, and the amination with ammonium hydroxide (55 mL) and p-toluenesulfonyl chloride (6.3 g, 33 mmol) proceeded overnight. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration and washed with a small amount of acetonitrile. A portion of the brown solid was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 85:15) to provide 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a brown solid, mp 215–216° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([NH:30][CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Reactant: CN(C)CCCN
Product: CN(C)CCCNc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1

Procedure:
The title compound was prepared as described for Example 21, using 3-cyano-(4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline (65 mg, 0.206 mmol) and N1,N1-dimethyl-propane-1,3-diamine (200 mg, 1.96 mmol) and yielded 68 mg (83%). 1H NMR (CDCl3): 7.98 (m, 2H), 7.81 (dd, J=7.5, 1.8 Hz, 1H), 7.55 (m, 4H), 7.31 (s, 1H), 6.63 (d, J=9.0 Hz, 2H), 5.78 (s, broad, 1H), 3.34 (m, 2H), 2.51 (t, J=6.3 Hz, 2H), 2.31 (s, 6H), 1.85 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[CH:24](=O)[CH2:25][CH3:26]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:24][CH2:25][CH3:26])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCC=O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Product: CCC=Nn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 210 and using 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg) and propionaldehyde. A colorless powder (120 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[C:5](Cl)=[N:4][N:3]=1.[NH2:18][NH2:19]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[C:5]([NH:18][NH2:19])=[N:4][N:3]=1
Reactant: NN
Reactant: Clc1nnc(Cl)c2c(-c3ccccc3)noc12
Solvent: C1COCCO1
Solvent: CCO
Product: NNc1nnc(Cl)c2c(-c3ccccc3)noc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4,7-dichloro-3-phenylisoxazolo[4,5-d]pyridazine (25.5 g, Desimoni, G.; Et al. Tetrahedron 1967, 23, 681) in 1,4-dioxane (200 mL) and ethanol (50 mL) at 0° C. was added hydrazine (7.0 g) slowly. The reaction mixture was allowed to slowly warm to room temperature. After 20 hours, the reaction mixture was concentrated and the solid obtained was washed with water and filtered. The material was purified by column chromatography on silica gel (methanol:dichloromethane=5:95) to afford first the regioisomer of the title compound followed by the later eluting title compound (4.50 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH3:13])[C:10]#[N:11].[CH2:14](N)[CH2:15][NH2:16]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[NH:16][CH2:15][CH2:14][N:11]=1)[CH2:12][CH3:13]
Reactant: CCC(C#N)c1cccc(F)c1F
Reactant: NCCN
Product: CCC(C1=NCCN1)c1cccc(F)c1F

Procedure:
rac-2-[1-(2,3-Difluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,3-difluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 225.0 ((M+H)+.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[NH:8][CH2:7]1)=[O:5])[CH3:2].[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([CH2:28]O)=[CH:23][N:22]=1>>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([CH2:28][C:12]2[C:13]([O:16][CH3:17])=[C:14]3[C:9](=[C:10]([O:18][CH3:19])[CH:11]=2)[NH:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:15]3)=[CH:23][N:22]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: CCOC(=O)C1CNc2c(OC)ccc(OC)c2C1
Product: CCOC(=O)C1CNc2c(OC)cc(Cc3cnc(N)nc3N)c(OC)c2C1
Yield: 49 %

Procedure:
Ethyl-1,2,3,4-tetrahydro-5,8-dimethoxy-3-quinolinecarboxylate (0.38 g, 1.43 mmol) was reacted with 2,4-diamino-5-hydroxymethylpyrimidine as in Example 17, and the product worked up as before. The product was purified on a silica gel column eluted with methylene chloride:methanol/19:1 to give 0.27 g (49%) of the title compound, mp 186°-188° (absolute ethanol). Anal. Calcd. for C19H25N5O4 : C, 58.90; H, 6.50; N, 18.08. Found: C, 58.95; H, 6.52; N, 18.08.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:27])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[CH3:27][C:11]1([NH2:10])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC1(N)CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-methyl-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester (0.37 g, 0.95 mmol) in acetonitrile (4.0 mL) at room temperature was added iodotrimethysilane (0.2 mL, 0.125 mmol). The reaction mixture was stirred at 50° C. for 30 minutes, concentrated under reduced pressure and purified by flash chromatography with 2% methanol in dichloromethane to provide the titled compound. MS (CI) m/z 260 (M+1)+; 1H NMR (300 MHz, methanol-d4) δ ppm 8.31 (d, 1H), 7.67 (d, d 1H), 6.87 (d, 1H), 4.83 (m, 2H), 3.79 (m, 2H), 3.63 (m, 2H), 1.63-1.54 (m, 4H), 1.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([CH3:20])[C:14](=[O:19])[CH2:15][CH2:16][S:17][CH3:18])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.B1([O-])O[O:22]1.O.O.O.O.[Na+].C([O-])(O)=O.[Na+].ClCCCl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([CH3:20])[C:14](=[O:19])[CH2:15][CH2:16][S:17]([CH3:18])=[O:22])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: [O-]B1OO1
Reactant: CSCCC(=O)N(C)c1cnc(-c2cncc(F)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CN(C(=O)CCS(C)=O)c1cnc(-c2cncc(F)c2)s1
Temperature: 65 °C
Yield: 43.6 %

Procedure:
To N-[2-(5-fluoro-pyridin-3-yl)-thiazol-5-yl]-N-methyl-3-methylsulfanyl-propionamide (Compound 30, 44 mg, 0.14 mmol) in glacial acetic acid (1.5 mL) was added sodium perborate tetrahydrate (23 mg, 0.14 mmol), and the mixture was heated at 65° C. for 2 h. The reaction mixture was carefully poured into a separatory funnel containing saturated aqueous NaHCO3 resulting in gas evolution. When the gas evolution had ceased, DCE was added and the layers were separated. The aqueous layer was extracted twice with DCE, and all the organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as white solid (20 mg, 45%): mp 152-154° C.; 1H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 8.59 (s, 0.3H), 8.49 (s, 0.7H), 7.98 (d, J=9.3 Hz, 1H), 7.73 (s, 0.3H), 7.62 (s, 0.7H), 3.64 (s, 2.1H), 3.36 (s, 0.9H), 3.40-2.70 (m, 4H), 2.69 (s, 2.1H), 2.61 (s, 0.9H); ESIMS m/z 328.1 (M+1), m/z 326.1 (M-1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O.CO>[CH2:1]([O:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([CH2:10][OH:9])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Benzyl bromide (7.8 mL, 66 mmol) was added to a suspension of 4-hydroxymethylbenzoic acid (10 g, 66 mmol) and cesium carbonate (11 g, 33 mmol) in a mixed solvent (DMF (100 mL)-methanol (30 mL)-water (30 mL)), and then the mixture was stirred at room temperature for 2 hours. Water (500 mL) was added thereto, the whole was extracted with ethyl acetate (500 mL), and then the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) twice and water (300 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with hexane, and dried at 35° C. under reduced pressure to give 13 g of the title reference compound as a white solid. (Yield 81%)
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([O:13]CC)[O:10]CC)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>O>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:10])([OH:13])[OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Temperature: 120 °C
Yield: 90 %

Procedure:
A mixture of diethyl (4-nitrobenzyl)phosphonate (1,700 mg, 2.56 mmol) and 5 mL concentrated HCl was heated at 120° C. for 6 hours. The cooled mixture was then diluted with water, the suspended solid isolated by filtration, washed with water and dried in vacuo to afford 500 mg of (4-nitrobenzyl)phosphonic acid (II) which was used without further purification. This material was mixed with oxalyl chloride (5 mL) and heated at 65° C. under nitrogen for 12 hr after which time the mixture was concentrated in vacuo to afford crude (4-nitrobenzyl)phosphonic dichloride (III). This dichloride was dissolved in dry methylene chloride (5 mL), cooled in ice under nitrogen and treated with n-butanol (1.05 mL, 11.5 mmol) and DIPEA (0.88 mL, 5.07 mmol). After 1 hr at room temperature the mixture was concentrated in vacuo and chromatographed over silica gel eluting with EtOAc:hexane 30-70% to yield 498 mg of dibutyl (4-nitrobenzyl)phosphonate (IV, R=nBu) yield: 66%). A solution of this phosphonate ester in methanol (5 mL) was hydrogenated in the presence of 5% Pd/C (32 mg) for 2 h The suspension was filtered and the filtrate concentrated in vacuo to afford 368 mg of dibutyl (4-aminobenzyl)phosphonate (yield: 82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(Br)cc2)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccc(Br)cc2)nc1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A mixture of 0.248 g of 2-(p-bromophenyl)-5-methyl-pyridine, 0.196 g of N-bromosuccinimide, 20 mg of dibenzoyl peroxide and 5 ml of carbon tetrachloride was heated to reflux for 2.5 hours while gassing with nitrogen. The reaction mixture was subsequently left to cool to room temperature and suction filtered. The residue was rinsed with carbon tetrachloride. The filtrate was concentrated in a vacuum, there being obtained 0.360 g of crude 2-(p-bromophenyl)-5-bromomethyl-pyridine as brownish crystals.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>O>[C:22]1(=[O:31])[N:1]([CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)CC(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a stirred solution of d,l-leucine (3.31 g, 25.0 mmol) and sodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is added N-carboethoxyphthalimide (5.65 g, 25.0 mmol). After 1 hour at room temperature, the reaction slurry is filtered, the filtrate stirred, and the pH adjusted to 1-2 with 4N hydrochloric acid. The mixture is stirred overnight, the resulting slurry is filtered, and the solid washed with water and dried in vacuo (60° C., <1 mm) to afford 5.32 g (81%) of the 2-phthalimido-4-methylpentanoic acid as a white powder: mp 134°-137° C.; 1H NMR (DMSO-d6, 250M Hz) δ 12.50 (br s, 1H), 8.00-7.80 (m, 4H), 4.79 (dd, 1H, J=4.3), 2.28-2.10 (m, 1H), 1.94-1.77 (m, 1H), 1.51-1.34 (m, 1H), 0.89 (d, 3H, J=4.4), 0.86 (d, 3H, J=4.5); 13C NMR (DMSO-d6) δ 170.8, 167.4, 134.8, 131.1, 123.3, 50.2, 36.7, 24.6, 23.0, 20.8. Anal. Calculated for C14H15NO4. Theoretical: C, 64.36; H, 5.74; N, 5.36. Found: C, 64.18; H, 5.73; N, 5.98.
Reaction SMILES: [N:1]([CH:4]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:13]=[CH:12][N:11]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[N+]=[N-].CO.CCOC(C)=O>CCOC(C)=O.[Pd]>[CH2:8]([CH:5]([CH2:6][CH3:7])[CH:4]([NH2:1])[C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[N:13]=[CH:12][N:11]=1)[CH3:9]
Reactant: CCC(CC)C(N=[N+]=[N-])c1ncnn1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(CC)C(N)c1ncnn1Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a suspension of 5% Pd/C in EtOAc was added a solution of 5-(1-azido-2-ethylbutyl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole in EtOAc and the mixture was shaken on a Parr apparatus for 2 h under 3 atm of H2. The mixture was filtered through Celite, washed several times with EtOAc, concentrated in vacuo, and purified by column chromatography (SiO2, EtOAc, then, MeOH/EtOAc, 1:9, then 1:4) to yield 68% of the amine.