Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.CCOC(C)=O>[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: C=CC=CC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)C=CC=Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Reaction time: 96 h
Yield: 26.7 %

Procedure:
A solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (480 mg, 1.2 mmol), 5-(5,5-dimethyl-1,3-hexadiene (200 mg, 1.8 mmol), Pd(OAc)4 (25 mg), tris(o-tolyl)phosphine (125 mg), and triethylamine (2.5 mL) in acetonitrile (5 mL) was sealed in a tube and headed at 100° C. for 4 days. The solution was then diluted with EtOAc, and the mixture was extracted with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 100:5-100:15 to afford the title compound (135 mg, 43% yield). MS (CI/NH3) m/z 421 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.08 (s, 9H), 1.48 (s, 9H), 1.89 (m, 2H), 2.00 (m, 2H), 3.38 (m, 2H), 3.95 (m, 1H), 4.13 (m, 1H), 4.23 (m, 1H), 5.99 (m, 1H), 6.22 (m, 1H), 6.71 (m, 1H), 6.95 (m, 1H), 7.74 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[CH:18]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)Oc1cc(F)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C)c2c1C
Temperature: 110 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (112 mg), 4-fluoro-2-isopropoxyaniline (77.9 mg) and p-toluenesulfonic acid monohydrate (15 mg) were dissolved in dioxane (3.0 ml). The reaction was heated at 110° C. under microwave irradiation. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and extracted with water. The organic phase was dried and concentrated in vacuo. The residue was triturated with diisopropyl ether and filtered.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18].O>C(O)CCC>[N+:12]([O-:15])([OH:14])=[O:13].[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH:1][C:17]([NH2:18])=[NH:16]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: N#CN
Solvent: CCCCO
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Temperature: 0 °C

Procedure:
To 2-amino-4-nitro toluene 1 (0.033 mol) in n-butanol (29 mL) is added nitric acid (2.1 g, 65% in water) followed by cyanamide solution in water (2 mL, 0.047 mmol). The resulting mixture is heated at reflux for 25 h. After cooling to 0° C., filtration and washing with 1:1=ethanol:diethyl ether (30 mL), 2-methyl-5-nitrophenyl guanidine nitrate 2 is obtained. To 2-methyl-5-nitrophenyl guanidine 2 (0.0074 mol) in isopropanol (15 ME) is added 3 (0.0074 mol) and sodium hydroxide flakes (0.008 mol). The resulting mixture is heated at reflux for 12 h. After cooling to 0° C., the product is collected by filtration and washed with isopropanol (6 mL) and methanol (3 mL) to afford 4. 1H NMR (400 MHz, d6-DMSO) δ 9.31 (s, 1H), 9.24 (s, 1H), 8.78 (m, 1H), 8.70 (m, 1H), 8.61 (m, 1H), 8.47 (m, 1H), 7.88 (m, 1H), 7.55 (m, 3H), 2.39 (s, 3H). MS (m/z) (M+1)+: 278.2.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1.N12CCCN=C1CCCCC2>CN(C)C=O>[CH:13]1([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1OC1CCCC1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
A mixture of N-hydroxypthalimide (10.00 g, 61.3 mmol), cyclopentylbromide (8.21 mL, 76.63 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (13.75 mL, 76.6 mmol) were combined under an Argon atmosphere in dimethylformamide (50 mL). The mixture was heated to 55° C. and stirred vigorously for 1.5 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. After separating the phases, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate, saturated aqueous brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with hexane, filtered, and dried under high vacuum to provide 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (11.37 g, 80%). H1-NMR (chloroform-D3): 1.61 (m, 2H), 1.77 (m, 2H), 1.97 (m, 4H), 4.91 (m, 1H), 7.73 (m, 2H), 7.82 (m, 2H). MS(ESI): 254 (M+Na).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].CCOCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:30][CH2:29][C:28]([O:27][CH3:26])=[O:31])=[O:24]
Reactant: COC(=O)CN
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc2ccccc2n1C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
DMAP (1.222 g, 0.01 mol) and EDAC (2.680 g, 0.014 mol) were added as solids to a solution of 1-methylindole-2-carboxylic acid (1.752 g, 0.01 mol) and glycine methyl ester hydrochloride (1.256 g, 0.01 mol) in methylene chloride (30 mL) and DMP (5 mL) under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and then for 3 hours at room temperature. The reaction mixture was partitioned with ethyl acetate and 5% KHSO4 solution and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) solution and brine, dried over sodium sulfate, and concentrated to give a purple powder as crude product. Trituration of the powder with ether afforded the title product (1.734 mg, 70%). TLC: (methanol/methylene chloride 1:9): Rf=0.61, 1H NMR (CDCl3): δ7.65 (dt, J=8.0, 1.1, 1H), 7.41-7.31 (m, 2H), 7.16 (dd, J=6.6, 1.4, 1H) 6.96 (d, J=0.5, 1H), 6.67 (bs, 1H), 4.25 (d, J=5.2, 2H), 4.05 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:7][O:8][CH2:9][Cl:10]>C1(C)C=CC=CC=1>[Cl-:10].[CH3:1][N+:2]1([CH2:7][O:8][CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCC1
Reactant: COCCl
Solvent: Cc1ccccc1
Product: COC[N+]1(C)CCCC1
Product: [Cl-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 30.0 g quantity of N-methylpyrrolidine (reagent, product of Tokyo Kasei Co., Ltd.) was dissolved in 120 g of toluene, followed by replacement with nitrogen. Chloromethyl methyl ether (31.2 g, reagent, product of Tokyo Kasei Co., Ltd.) was added dropwise to the solution at 5° C. over a period of 1 hour. The mixture was stirred at 5° C. for 1 hour, then gradually heated to a higher temperature, and stirred at room temperature for 10 hours to complete the reaction. The reaction mixture was filtered, and the resulting solid product was washed with 150 g of toluene and 150 g of acetone. The washed product was dried in a vacuum to obtain 53.7 g of the desired product (white solid).
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:14][C:15]1[C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:36]([NH:43][C:44](=[O:54])[NH:45][C@H:46]([CH2:51][CH:52]=[CH2:53])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[S:23]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:54])[CH2:51][CH:52]=[CH2:53])[CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:29][CH:30]=3)=[O:4])[C:20]=2[N:21]=[CH:22]1
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2scnc12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2(50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCl (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mL) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 744 (M+H), 766 (M+Na)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
to a solution of 4-nitrophenol (75 g, 0.54 mol) in glacial acetic acid (700 ml) was added bromine (40 ml). The solution was stirred at room temperature under an atmosphere of nitrogen for 24 hours. The solvent was evaporated under reduced pressure and the residue was recrystallized from dichloromethane to give the title compound. 1H NMR (250 MHz, CDCl3) δ 8.45 (1H, d, J 2.7 Hz), 8.16 (1H, dd, J 9.0 Hz and 2.6 Hz), 7.13 (1H, d, J 9.1 Hz), and 6.18 (1H, s).
Reaction SMILES: [N:1](=[C:3]([CH:6]([CH3:8])[CH3:7])[C:4]#N)[OH:2].[OH-:9].[Na+].N.[OH2:12]>>[N:1](=[C:3]([CH:6]([CH3:8])[CH3:7])[C:4]([OH:12])=[O:9])[OH:2]
Reactant: [OH-]
Reactant: CC(C)C(C#N)=NO
Reactant: O
Agent: N
Agent: [Na+]
Product: CC(C)C(=NO)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 3.36 g of 2-oximino-3-methylbutyronitrile, 7 ml of 50% NaOH and 3 ml of water is refluxed under a slow stream of nitrogen until cessation of ammonia evolution. This is allowed to cool to RT. The mixture is then diluted with water and washed with ether to remove the neutrals. The aqueous layer is acidified (HCl) and extracted into ether to give 2-oximino-3-methylbutanoic acid, m.p.=153° (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]2[NH:10][N:11]=[CH:12][C:4]=12.C([O-])(=O)C.[Na+].[I:18]Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.C(OCC)(=O)C.CO>[I:18][C:12]1[C:4]2[C:5](=[N:6][C:7]([NH2:9])=[N:8][C:3]=2[O:2][CH3:1])[NH:10][N:11]=1
Reactant: ClI
Reactant: COc1nc(N)nc2[nH]ncc12
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1nc(N)nc2[nH]nc(I)c12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4-Methoxy-pyrazolo[3,4-d]pyrimidin-6-ylamine (6.75 g, 40.87 mmol) was suspended in an aqueous solution containing sodium acetate (6.0 g, 44.09 mmol) and iodine monochloride (9.12 g, 56.17 mmol) and stirred at 100° C. in a sealed reaction vessel for 24 h. The resulting mixture was cooled to room temperature and treated with a solution of sodium metabisulfite (3.6 g, 18.94 mmol) in 24 mL of water. The solid that formed was filtered, rinsed with water and dried: 6.93 g (58%) yield; TLC (10% methanol in ethyl acetate), Rf=0.57; 1H NMR (DMSO-d6) δ 13.08 (1H, br s, N−1 proton), 10.58 (1H, s, N−5 proton), 6.60 (2H, br s, 6-amino).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14](OC)=[O:15]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:14](=[O:15])[CH2:13][O:12][CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: COCC(=O)OC
Solvent: COC(C)(C)C
Product: COCC(=O)NC(C)c1ccc(Cl)cc1
Reaction time: 4.5 h

Procedure:
At room temperature, a solution of 7.8 g (0.05 mol) of racemic 1-(4-chloro-phenyl)-ethylamine in 35 ml of methyl tert-butyl ether is mixed with stirring with 8.32 g (0.08 mol) of methyl methoxyacetate and then with 0.39 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at room temperature and the progress of the reaction is monitored by gas chromatographic sample analysis. After 4.5 hours, the conversion is 55%. At this stage, the reaction is terminated by filtering off the enzyme. In the filtrate that remains, the (S)-enantiomer of 1-(4-chloro-phenyl)-ethylamine has an ee value of 98.1%, while the (R)-enantiomer of N-(1-(4-chlorophenyl)-ethyl]-methoxyacetamide obtained has an ee value of 96%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([Cl:22])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.O.O>[Cl:22][C:21]1[C:16]2[CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[NH:23][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound Intermediate 1 (2.60 g, 7.77 mmol) in 10 ml DCM, 30 ml TFA/water 95:5 were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and basified by addition of 2N sodium hydroxide and extracted with DCM. The organic layer was washed with brine (2×), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica (cyclohexane/EtOAc 1:1 to EtOAc) to afford the compound Intermediate 2 as a beige solid.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4].O1CCOCC1.C(OCC)C>C(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[O:5]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: BrBr
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Br)s1
Reaction time: 1 h

Procedure:
A solution of bromine (2.9 ml, 56.5 mmol) in 30 ml of CH2Cl2 was added dropwise to a solution of 2-acetyl-5-bromothiophene (10 g, 49 mmol), dioxane (55 ml) and ethyl ether (55 ml). The stirring was continued for 1 h and then the reaction medium was poured into a water/ice mixture and extracted with ethyl ether. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7](#[N:10])[CH:8]=[CH2:9]>>[C:7]([CH2:8][CH2:9][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])#[N:10]
Reactant: NCCCCN
Reactant: C=CC#N
Product: N#CCCNCCCCN
Temperature: 100 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
To 1,4-diaminobutane (84.6 g) cooled with ice, acrylonitrile (50.9 g) was added dropwise. After the addition had been completed, the reaction mixture was stirred for 20 minutes under ice cooling, at 40° C. for one hour and at 100° C. for three hours in this order. The resultant mixture was purified by distillation under reduced pressure to obtain as colorless oil 1-(N-2-cyanoethyl)amino-4-aminobutane (66 g).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N+:15]([C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)([O-:17])=[O:16].O[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCCC(C)C.CCOC(C)=O>[N+:15]([C:18]1[CH:19]=[N:20][N:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:22]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc([N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
DIAD (3.92 mL, 19.90 mmol) was added dropwise to a stirred solution of 4-nitro-1H-pyrazole (1.5 g, 13.27 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.67 g, 13.27 mmol) and triphenylphosphine (5.22 g, 19.90 mmol) in THF (30 mL) cooled to 0° C. under a nitrogen atmosphere. The resulting solution was stirred at 0° C. for 10 minutes then allowed to warm to room temperature and stirred overnight. The mixture was diluted with isohexane (80 mL) and EtOAc (20 mL) and then stirred vigorously. The mixture was filtered and the solid washed with isohexane (20 mL). The combined filtrates were evaporated and the residue was purified by chromatography on silica, eluting with a gradient of 20-50% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford tert-butyl 4-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (3.63 g, 92% yield); 1H NMR spectrum: (300 MHz, DMSO) 1.42 (9H, s), 1.79-1.84 (2H, m), 2.01-2.05 (2H, m), 2.87-2.98 (2H, m), 4.40-4.47 (1H, m), 8.28 (1H, s), 8.95 (1H, s). b) A mixture of tert-butyl 4-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (3.63 g, 12.25 mmol) and 10% palladium on carbon (0.326 g, 0.31 mmol) in EtOH (200 mL) were stirred under an atmosphere of hydrogen for 18 hours. The mixture was filtered through Celite and the filtrate loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (2.100 g, 64% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.41 (9H, s), 1.65-1.74 (2H, m), 1.89-1.92 (2H, m), 2.81-2.93 (2H, m), 3.75 (2H, s), 3.99 (2H, d), 4.09-4.16 (1H, m), 6.91 (1H, s), 7.06 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=211.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C-:14]#[N:15].[K+]>CN(C=O)C.O>[Br:13][C:11]1[CH:12]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: BrCc1cc(Br)c2ncccc2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(Br)c2ncccc2c1
Temperature: 100 °C

Procedure:
To a solution 6-bromomethyl-8-bromoquinoline (described in International Patent Publication WO 94/22852) (1.0 eq) in DMF:H2O (2:1, 0.66M) was added potassium cyanide (2.5 eq). After heating at 100° C. for 1 h, the resulting mixture was quenched with H2O and extracted with EtOAc (2 x). The combined organic extracts were washed with water (3×), brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc, 3:1) yielded the desired compound as a white solid.
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.C([C:18]1C=C(C)C=C(C(C)(C)C)[C:19]=1[OH:29])(C)(C)C.CCCCO[C@H](CO)CC.OCC[O:43][C:44](=[O:47])[CH:45]=[CH2:46]>>[C:44]([OH:47])(=[O:43])[CH:45]=[CH2:46].[NH2:8][C:9]([O:29][CH2:19][CH3:18])=[O:10]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: C=CC(=O)OCCO
Agent: CCCCO[C@@H](CC)CO
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 5 h

Procedure:
To a reaction vessel equipped with a stirrer, 104.3 gm of 2,4-tolylene diisocyanate, 1 gm of dibutyltindilaurate, and 0.3 gm of 2,6-di-t-butyl-4-methylphenol as a polymerization inhibitor were added. To this, 856.0 gm of polytetramethylene glycol of a number average molecular weight of 2,000 (commercial product PTG2000 manufactured by Hodogaya Chemical) was added while maintaining the temperature in the 40° to 50° C. range, and reacted for 2 hours. Next, 2-hydroxyethylacrylate was added, after which the mixture was continuously stirred for 5 hours at 50° to 60° C. to complete the reaction. A urethane acrylate [B-2] of a number of average molecular weight of about 5,840 was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=C(C(O)=O)[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].[C:13](=O)([O-])[O-].[K+].[K+].CI.[C:21]([O:24][CH2:25]C)(=[O:23])[CH3:22].CCCCCC>CC(C)=O>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][C:22]=1[C:21]([O:24][CH3:25])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CCOC(C)=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(C=O)ccc1OC
Reaction time: 12 h

Procedure:
Combine 5-formylsalicylic acid (5.0 g, 30.1 mmol), potassium carbonate (16.6 g, 120.4 mmol), and methyl iodide (34.06 g, 240 mmol) in acetone (20 mL). Heat to reflux. After 12 hours, cool and extract five times with ethyl acetate. Combine the organic layers and extract with brine. Dry over MgSO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate/hexane 1/1 to give methyl 2-methoxy-5-formylbenzoate: Rf=0.44 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=O)[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.C([O-])(=O)C.[N+:25]([CH3:28])([O-:27])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=[CH:28][N+:25]([O-:27])=[O:26])[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Agent: CC(=O)[O-]
Product: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2Cc2ccccc2-1

Procedure:
600 mg (2.27 mmol) of the compound obtained in Step E dissolved in 25 ml of nitromethane are heated at 120° C. for 3 hours in the presence of 440 mg (5.67 mmol) of animmonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation of the organic phase yields the title compound in the form of a yellow solid.