Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2](Br)[C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1.[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:37][CH2:2][C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1
Reactant: [F-]
Reactant: CCCc1nc(C(Br)Br)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCc1nc(CF)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 27 %

Procedure:
A mixture of 4′-{[2-(dibromomethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g), tetrabutylammonium fluoride (1.0 M, 3.3 mL) and tetrahydrofuran (10 mL) were stirred at 80° C. for 12 hr. The solvent was evaporated from the reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 27%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][C:11]([N:14]([C:22]2[CH:38]=[CH:37][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][CH:23]=2)C(OC(C)(C)C)=O)=[CH:10][CH:9]=1>ClCCl>[N:8]1[CH:13]=[CH:12][C:11]([NH:14][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCCCCOc1ccc(N(C(=O)OC(C)(C)C)c2ccncc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCOc1ccc(Nc2ccncc2)cc1

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred solution of ethyl 6-[4-[N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino]phenoxy]- hexanoate (260 mg) dissolved in dichloromethane (3 ml). After 18 hours the solvents were removed in vacuo and the residual gum dissolved in dichloromethane. This solution was treated with a saturated solution of sodium hydrogen carbonate. The organic phase was washed with water, dried and evaporated. Trituration of the residue with hexane gave the title compound, 120 mg, as a white solid: m.p. 104°-106° C.; NMR (CDCl3) δ8.22(2H,d), 7.12(2H,d), 6.90(2H,d), 6.64(2H,dd), 5.82(1H,s), 4.13(2H,q), 3.97(2H,t), 2.34(2H,t), 1.80(2H,m), 1.70(2H,m), 1.53(2H,m), 1.27(3H,t); m/e 329 (M+H)+ ; calculated for C19H24N2O3.0.25H2O:C, 68.6; H, 7.4; N, 8.4. found: C, 68.8; H, 7.3; N, 8.2%.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[N:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=2)[C:16]1=[O:44].CO>O1CCOCC1.C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:24]=[N:23][NH:22][CH:21]=2)[C:16]1=[O:44]
Reactant: Cc1ccncc1N1CCN(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2cn[nH]c2)C1=O
Yield: 63.9 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 4-bromo-1-trityl-1H-pyrazole (369.3 mg, 0.8465 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in chloroform) afforded 250 mg of 1-(4-Methyl-pyridin-3-yl)-3-(1-trityl-1H-pyrazol-4-yl)-imidazolidin-2-one (60% yield). Dioxane hydrochloride (10 mL) was added to a stirred solution of 1-(4-methyl-pyridin-3-yl)-3-(1-trityl-1H-pyrazol-4-yl)-imidazolidin-2-one (250 mg, 0.51484 mmol) in dioxane under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours with TLC monitoring (10% MeOH in DCM). The solvent was distilled from the reaction mixture and washed with ether. The precipitate was collected and dried under reduced pressure to afford 80 mg of the product (55% yield).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH2:37][CH2:38][CH3:39])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[CH:10][C:11]=3[CH2:36][CH2:37][CH2:38][CH3:39])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cc(OC(C)(C)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ8.04 (d, J=8.3 Hz, 2H), 7.68-7.62 (m, 4H), 7.46 (t, J=6.6 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 6.74 (s, 3H), 4.21 (t, J=6.1 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.52-1.43 (m, 8H), 1.32-1.24 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); MS (ES) m/e 514 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][CH:15]2[CH2:18][N:17]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH2:16]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][CH:15]3[CH2:18][N:17]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(CC1CN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Temperature: 130 °C
Yield: 45 %

Procedure:
In a round bottom flask equipped with reflux condenser, a mixture of N-(4-bromophenyl)-2-{[1-(cyclopropylcarbonyl)-3-azetidinyl]acetyl}hydrazinecarboxamide (4.71 g, 5.48 mmol) and potassium carbonate (3.79 g, 27.4 mmol) in water (400 mL) was stirred at reflux (oil bath temp=130° C.) for 14 h. The reaction was cooled to room temperature. The reaction mixture was concentrated in vacuo and then taken up into ethyl acetate (250 mL) and water (100 mL). The pH of the mixture was adjusted to ˜5-5.5 (pH paper) using 1N aq HCl solution and then the layers were separated. The aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-10% methanol/ethyl acetate) followed by drying in a vacuum oven (70° C.) overnight provided the title compound as a white solid (0.93 g, 38.7%). MS(ES)+ m/e 377.0, 379.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11])([CH3:8])[C:3](OCC)=[O:4].Cl.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][C:2]1([CH3:8])[O:9][C:10](=[O:11])[N:23]([C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:26][CH2:25]2)[C:3]1=[O:4]
Reactant: CCOC(=O)C(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)N([C@H]2CC[C@H](C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of the compound (1.3 g) obtained in step 1, benzyl trans-4-aminocyclohexanecarboxylate monohydrochloride (1.1 g), potassium carbonate (0.88 g) and DMF (30 mL) was stirred at 60° C. for 6 hr. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→25% ethyl acetate/hexane) to give benzyl trans-4-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)cyclohexanecarboxylate (1.2 g, 81%) as a white powder.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[OH-].[K+].[CH2:21]([SH:23])[CH3:22].Cl>CN(C)C=O.C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([S:23][CH2:21][CH3:22])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCS
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCSc1nc2c(cc1F)c(=O)c(C(=O)O)cn2CC
Temperature: 60 °C
Yield: 182.6 %

Procedure:
A suspension of 0.54 g (2 mmol) 1-ethyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 10 ml N,N-dimethyl formamide was stirred at 60° C. and treated all at once with a solution of 0.56 g potassium hydroxide (10 mmol) and 1 ml (0.85 mmol) ethanethiol in 5 ml absolute ethanol. After 15 minutes the mixture was poured into 40 mmol 0.4 N hydrochloric acid containing ice. The precipitate was filtered, washed with ethanol and ether to afford 0.46 g of the title compound. A sample for analysis was crystallized from acetic acid, mp 219°-221° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=O)[CH3:2].[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:17]>CC(O)C>[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:17]=[CH:8][C:7]1[C:6](=[CH:5][C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[CH:11][CH:10]=1)[OH:12]
Reactant: CN(N)c1ccccc1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Solvent: CC(C)O
Product: CCN(CC)c1ccc(C=NN(C)c2ccccc2)c(O)c1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 4-(diethylamino)salicylaldehyde (10 g, 52 mmol, obtained from Aldrich) dissolved in 80 ml of 2-propanol, and N-methyl-N-phenylhydrazine (6.8 ml, 63 mmol, obtained from Aldrich) was added to a 250 ml round bottom flask equipped with a reflux condenser and a magnetic stirrer. The reaction mixture was refluxed until 4-(diethylamino)salicylaldehyde completely reacted. After the termination of the reaction, the reaction mixture was cooled to room temperature. The crystals formed were filtered and washed repeatedly with cold 2-propanol and dried under vacuum to yield 12.9 g (84%) of 4-(diethylamino)salicylaldehyde N-methyl-N-phenylhydrazone. The melting point was found to be 75.5–76.5° C. (recrystallized from 2-propanol). The 1H-NMR spectrum (100 Mhz) of the product in CDCl3 was characterized by the following chemical shifts (in ppm): 11.53 (s, 1H, OH); 7.63 (s, 1H, N═CH); 7.50–6.80 (m, 6H, Ar); 6.26 (m, 2H, Ar); 3.37 (m, 7H, CH2CH3, NCH3); 1.18 (t, 6H, CH2CH3, J=7.0 Hz). An elemental analysis yielded the following results in weight percent: C, 72.61; H, 7.88; N, 14.20, which compared with calculated values for C18H23N3O in weight percent of: C, 72.70; H, 7.80; N, 14.13.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[C:36]2([CH3:43])[CH3:42]>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[C:36]3([CH3:42])[CH3:43])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1C(=O)c2c(N)cccc2C1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4(C)C)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2,3,3-trimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 148A). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (br s, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.38-7.45 (m, 1H), 7.32 (br s, 1H), 7.07-7.16 (m, 2H), 6.84 (s, 1H), 6.31 (br s, 1H), 3.91 (quin, J=7.3 Hz, 4H), 3.77 (s, 3H), 3.13 (s, 3H), 3.06 (d, J=21.2 Hz, 2H), 1.27 (s, 6H), 1.16 (t, J=7.1 Hz, 6H). MS (ES+): m/z 608.24 [MH+] HPLC: tR=1.31 min (UPLC, analytical).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([C:25]2[N:26]=[CH:27][N:28]([CH2:30][C:31]#[CH:32])[CH:29]=2)(C(OC)=O)[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C>Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([C:25]2[N:26]=[CH:27][N:28]([CH2:30][C:31]#[CH:32])[CH:29]=2)[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: C#CCn1cnc(C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)(C(=O)OC)C(=O)OC)c1
Agent: Cl
Product: C#CCn1cnc(C(Cc2ccc(N)nc2)C(=O)O)c1
Yield: 86.3 %

Procedure:
A solution of 40 mg (0.09 mmol) of the compound from example 31a in 1.4 ml of 50% concentrated hydrochloric acid was heated at 95° C. for 9 h. Freeze-drying after cooling afforded 21 mg of the title compound as bishydrochloride.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:31][CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)(=O)=O)=CC=CC=1>>[CH2:34]1[CH2:35][CH2:36][CH2:37][CH:33]1[CH:32]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[CH3:31]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccccc1S(=O)(=O)OCCC1CCCC1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2C(C)C2CCCC2)c1
Yield: 28.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (2-cyclopentyl)ethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound (105 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1>O1CCCC1>[CH3:25][C:24]1[C:19]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][CH2:12][C:13]#[N:14])=[N:20][CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[CH:23]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ncc([N+](=O)[O-])cc1C
Yield: 48.9 %

Procedure:
2-(2-Cyanoethyl)malonic acid diethyl ester (148.3 g) was reacted with sodium hydride (15.3 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (100 g) was added and the internal temperature was raised to 100° C. (some tetrahydrofuran was distilled off) over 14 hrs. The reaction mixture was partitioned between water and chloroform, the chloroform extract was dried, treated with charcoal and filtered through a silica bed and then evaporated to dryness. Crystallisation of the residue from ethanol gave 4-(3-methyl-5-nitropyrid-2-yl)-4,4-bis(carbethoxy)-butyronitrile (99 g) m.p. 64°-65.5° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8]O)[CH3:6].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8][Cl:16])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)Cc1ccccc1F
Solvent: Cc1ccccc1
Product: CN(CCCl)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(N-(2-fluorobenzyl)-N-methylamino)-ethanol (Step B, 7.51 g, 41 mmol) in dry toluene (50 ml) was added thionyl chloride (16 ml). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The crude mixture was diluted with chloroform and washed with aq NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to provide the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[CH:20]=[CH:21][C:22]=1[NH2:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(OCc2ccccc2)c1

Procedure:
A solution of (3-benzyloxy-4-nitrophenoxy)-tert-butyldimethylsilane in EtOAc (50 mL) is hydrogenated over 5% Pt/C (630 mg) at 1 atm for 18 h. The catalyst is filtered off through Celite and the solvent removed under reduced pressure to afford the title compound as an oil: 1H NMR (CDCl3δ7.26 (m, 5H), 6.48 (d, J=8.3 Hz, 1H), 6.29 (d, J=2.5 Hz, 1H), 6.19 (dd, J=8.3, 2.5 Hz, 1H), 4.93 (s, 2H), 0.83 (s, 9H), 0.00 (s, 6H); (M+1)+=330.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+]([O-])=O.[H][H].Cl>CO.[Pd].CC(O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:13]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=N)N)C(=O)O

Procedure:
Boc-hArg(NO2)-Amp (1.5 g) was dissolved in HPLC grade MeOH (120 mL) and to the clear solution was added the Pd/C catalyst (10%, Aldrich). A small stir bar was placed in the flask and the reaction mixture was stirred under a slow stream of hydrogen overnight after incorporating the 5-6 N HCl in 2-propanol solution (1.5 mL). After the overnight reaction, the solution was filtered and the solvent evaporated. The white crystalline product was dried under vacuum to give 1.61 g of the Boc-hArg-Amp intermediate product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:20][CH3:21])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[C:8]([NH2:22])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:23]1([CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:11]([O:20][CH3:21])=[N:10][C:9]3[C:13]2=[N:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]=3[NH2:22])[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCN3CCC3)c2n1
Temperature: 50 °C
Yield: 7.2 %

Procedure:
2-(Butyloxy)-9-(4-chlorobutyl)-8-(methyloxy)-9H-purin-6-amine (100 mg, 0.305 mmol), azetidine (0.021 ml, 0.305 mmol) and N,N-diisopropylethylamine (0.107 ml, 0.610 mmol) were dissolved in DMF (2 ml) and heated at 50° C. for 48 hours. LCMS indicated the reaction to be incomplete and additional azetidine (0.021 ml, 0.305 mmol) and N,N-diisopropylethylamine (0.107 ml, 0.610 mmol) were added and the reaction mixture heated at 50° C. for a further 48 hours. The mixture was then partitioned between DCM (4 ml) and water (4 ml) and the layers separated using a hydrophobic frit. The aqueous phase was re-extracted with DCM (4 ml) and the combined organic extracts were concentrated and the residue purified by MDAP (Method A). The product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a clear gum (7.6 mg).
Reaction SMILES: OO.[CH2:3]([CH:11]1[C:15](=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:14](=[O:26])[CH:13]=[CH:12]1)[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[Cl-:29].[NH4+].Cl.C(=O)([O-])O.[Na+]>CO.CC(C)=O>[Cl:29][C:13]1[C:14](=[O:26])[C:15](=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:11]([CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:12]=1
Reactant: CCCCCC=CCC1C=CC(=O)C1=CCCCCCC(=O)OC
Reactant: [Cl-]
Agent: Cl
Agent: O=C([O-])O
Agent: OO
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCC=CCC1C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Yield: 54 %

Procedure:
0.3 ml of 30% aqueous hydrogen peroxide was added to a solution of 75 mg (226 micromol) of 4-(2-octenyl)-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone in 3 ml of methanol under ice cooling and stirring, and then 70 microliters of 1N sodium hydroxide was added. The mixture was stirred at 0° C. for 20 minutes. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with hexane. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered and concentrated to give an oily product. The product was dissolved in 3 ml of acetone, and 0.5 ml of concentrated hydrochloric acid was added. The mixture was stirred for one hour. A saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 10 g; eluent, cyclohexane:ethylacetate=10:1) to give 45 mg (yield 54%) of 2-chloro-4-(2-octenyl)-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone.
Reaction SMILES: NC1C=CC(CC2CC(C(OCC)=O)C2)=CC=1.[C:18]1([CH:24]2[CH2:27][C:26](=[C:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH:24]2[CH2:25][CH:26]([CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C)=C1CC(c2ccccc2)C1
Agent: CCOC(=O)C1CC(Cc2ccc(N)cc2)C1
Product: CCOC(=O)C(C)C1CC(c2ccccc2)C1

Procedure:
Following the general procedure described for ethyl 3-(4-aminobenzyl)cyclobutanecarboxylate (Intermediate 931i), replacing ethyl 3-(4-nitrobenzyl)cyclobutanecarboxylate with ethyl 2-(3-phenylcyclobutylidene)propanoate the title compound was obtained without chromatography; 1H NMR δ (CDCl3): 1.08-1.10 (0.75H, d), 1.12-1.15 (3.25H, d), 1.22-1.30 (3H, m), 2.17-2.64 (6H, m), 3.34 (0.25H, m), 3.48-3.54 (0.75H, m), 4.09-4.18 (2H, m), 7.15-7.36 (5H, m); MS m/e MH+ 233.