Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C#C)C=CC=CC=1.Cl[CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li]CCCC.BrCCCCl.[I-:31].[Na+]>C1COCC1>[I:31][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCC#Cc1ccccc1
Reactant: [I-]
Agent: ClCCCBr
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C#Cc1ccccc1
Solvent: C1CCOC1
Product: ICCCC#Cc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 80.8 %

Procedure:
To a solution of THF (200 mL) into reaction flask was added (5-chloropent-1-ynyl)benzene Phenylacetylene (10 g, 97.91 mmol). Then the reaction mixture was cooled to −78° C. in a dry ice bath. nBuLi (95.95 mmol, 38.39 mL) was added dropwise and allowed to react for 0.5 h at −78° C. At −78° C., 1-bromo-3-chloropropane was added. Stirred for 5 hours during which the reaction was allowed to warm up to room temperature. Then reaction was refluxed at 90° C. for 3 hours. The solvent was distilled off, then water (150 mL) and ether (150 mL) was added. The crude product was extracted, ether was distilled off and the resulting crude mixture was dissolved in acetone. Sodium iodide (22.92 mmol, 3.44 g) was added into the solution. The reaction mixture, with reflux condenser attached, was heated to 70° C. for two days. Acetone was distilled off using short path distillation apparatus. Ether (150 mL) and water (150 mL) was added and carried out extraction. Ether was then dried over magnesium sulfate and distilled off resulting in 5.00 g of product (yield 98%). No further purification was carried out. 1H NMR (500 MHz, CDCl3) □2.072 (m, 2H, CH2); 2.605 (t, 2H, CH2); 3.697 (m, 2H, CH2); 7.276 (m, 2H, Phenyl); 7.389 (m, 2H, phenyl); 7.484 (m, 1H, phenyl).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:46]=[S:47]1(=[O:71])[NH:60][C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[C:51]([CH2:61][CH2:62][O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH:52]=2.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:60]3[C:59]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:53]4[C:48](=[CH:49][CH:50]=[C:51]([CH2:61][CH2:62][O:63][Si:64]([CH2:67][CH3:68])([CH2:69][CH3:70])[CH2:65][CH3:66])[CH:52]=4)[S:47]3(=[O:71])=[O:46])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: CC[Si](CC)(CC)OCCc1ccc2c(c1)-c1ccccc1NS2(=O)=O
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccccc4-c4cc(CCO[Si](CC)(CC)CC)ccc4S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthrene (429 mg, 1.1 mmol) in anhydrous tetrahydrofuran (7.3 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography , eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-[9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-1-methyl-carbapen-2-em-3-carboxylate.
Reaction SMILES: COC[O:4][C:5]1[C:27]([CH3:28])=[CH:26][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[C:14](=[O:22])[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:6]=1[CH3:29].Cl>CC(O)C.C1COCC1>[OH:4][C:5]1[C:27]([CH3:28])=[CH:26][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[C:14](=[O:22])[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:6]=1[CH3:29]
Reactant: COCOc1c(C)cc(/C=C/c2cccc(C(=O)Sc3ccccc3)c2)cc1C
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cc(/C=C/c2cccc(C(=O)Sc3ccccc3)c2)cc(C)c1O
Reaction time: 18 h

Procedure:
To a solution of (E)-S-phenyl 3-(4-(methoxymethoxy)-3,5-dimethylstyryl)benzothioate (80 mg, 0.198 mmol) in i-PrOH and THF (½ mL) was added 0.5 mL of concentrated HCl. The reaction mixture was stirred overnight (about 18 hours). After removal of solvent under reduced pressure, the residue was dissolved in EtOAc. The solution was washed with brine and dried with Na2SO4. The solution was filtered and concentrated. The compound was purified by column chromatography (9:1 Hexane:EtOAc) to afford (E)-S-phenyl 3-(4-hydroxy-3,5-dimethylstyryl)-benzothioate in quantitative yield. Azo-linked compounds of Formula I are prepared following usual syntheses for preparing aromatic or heteroaromatic azo compounds. A typical scheme is shown in Scheme 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[C:3]=1[CH2:16]O.P(Br)(Br)[Br:19]>ClCCl>[Br:19][CH2:16][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]1
Reactant: BrP(Br)Br
Reactant: CCN1CCN(c2cccc(Cl)c2CO)CC1
Solvent: ClCCl
Product: CCN1CCN(c2cccc(Cl)c2CBr)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [2-chloro-6-(4-ethylpiperazin-1-yl)phenyl]methanol (6.31 g, 24.8 mmol) in anhydrous dichloromethane (200 mL) was added dropwise phosphorus tribromide (5 mL, 52.7 mmol). The mixture was stirred at room temperature for 3 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 1-[2-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine. The product was used without further purification.
Reaction SMILES: [Br:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)C[C@@H](Br)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C[C@@H](Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
2(R)-Bromo-4-metylpentanoic acid (28.5 g, 146 mmol), benzyl alcohol (18.1 ml, 175 mmol) and 4-dimethylaminopyridine (1.90 g, 14.6 mmol) were dissolved in CH2Cl2 (140 ml), and added with EDC (35.6 g, 175 mmol) under ice-cooling and stirring The mixture was stirred under ice-cooling for 1 hour and further at room temperature overnight and washed for separation with water, a saturated aqueous solution of NaHCO3 and then a saturated aqueous solution of NaCl two times respectively. The organic layer was dried over an hydrous MgSO4, evaporated under reduced pressure and purified by column chromatography (silica gel; 700 g, elution with the mixed solvent; n-hexane:AcOEt=40:1), giving the title compound (32.0 g, 77%) of a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2)cs1
Product: Clc1nc(-c2ccccc2)cs1
Yield: 57 %

Procedure:
4-Phenyl-3H-thiazol-2-one (5 g, 28.2 mmol) was dissolved in POCl3 (30 mL), and the mixture was refluxed overnight. The mixture was concentrated in vacuum, and the residue was purified by column chromatography to give 2-chloro-4-phenylthiazole (3.1 g, 57%).
Reaction SMILES: [CH3:1][N:2]1CCOCC1.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][NH:2][C:25](=[O:26])[C@@H:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1
Reactant: CN1CCOCC1
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of N-methylmorpholine (0.217 ml) and isobutyl chloroformate (0.256 ml) in tetrahydrofuran (5 ml) is added to a solution of (2R)-2-(tert-butoxycarbonylamino)-3-(4-methylbenzylthio)propionic acid (reference compound No. 3-1, 700 mg) in tetrahydrofuran (15 ml) under a nitrogen atmosphere and freezing medium (ice-sodium chloride) cooling, and the mixture is stirred for 15 minutes. Then, a 40% aqueous N-methylamlne solution (0.756 ml) is added thereto under a freezing medium (ice-sodium chloride) cooling, and the mixture is further stirred for two hours. A 5% aqueous sodium hydrogencarbonate solution is added to the system of reaction, and the whole is extracted with ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][C:46]4[CH:51]=[CH:50][C:49]([CH2:52][CH3:53])=[CH:48][CH:47]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:52]([C:49]1[CH:50]=[CH:51][C:46]([CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:54]=[CH:55][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])=[CH:47][CH:48]=1)[CH3:53]
Reactant: CCc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 35.2 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(4-ethylphenethyl)-1-piperidinecarboxamide (0.295 g, 0.369 mmol) -was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.078 g, 0.13 mmol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Br:11]Br>C(Cl)Cl>[Br:11][C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: BrBr
Solvent: ClCCl
Product: O=c1[nH]c2ccc(Br)cc2o1
Reaction time: 19.5 h

Procedure:
To a mixture of 3H-benzooxazol-2-one (20 g, 0.15 mol) in DCM (500 mL) was added bromine (8.34 mL, 0.16 mol). After stifling at room temperature for 19.5 h, the orange precipitate that had formed was filtered off and washed with DCM until the orange color was washed out. The filtrate was concentrated to approximately 33% of its original volume and filtered and washed as before. The combined solids weighed 28.36 g and contained ca. 8-9% starting material.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>O1CCCC1>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[N:17]=[C:18]4[NH:23][C:25](=[O:26])[NH:22][C:19]4=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(c1ccc(N)c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Solvent: C1CCOC1
Product: CN(c1ccc2[nH]c(=O)[nH]c2n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
A solution of (R)—N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (35 mg, 0.11 mmol,) and 1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) in tetrahydrofuran (3.0 mL) was stirred at reflux for 1 h. The volatiles were removed and the residue was purified by chromatography to give the title compound. MS (m/z): 351 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.CN(CCN(C)C)C.C([Li])CCC.CCCCCC.[CH3:34][C:35]([CH3:41])([CH2:38][CH:39]=[CH2:40])[CH:36]=[O:37]>C1COCC1>[CH3:34][C:35]([CH3:41])([CH2:38][CH:39]=[CH2:40])[CH:36]([OH:37])[CH:6]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[C:5]1[CH:12]=[CH:13][CH:14]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(Cn2ccnc2)c1
Reactant: C=CCC(C)(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC(C)(C)C(O)C(c1cccc(OC)c1)n1ccnc1
Yield: 6.4 %

Procedure:
7.52 g (40 mmol) of 1-(3-methoxybenzyl)-imidazole and 4.65 g (40 mmol) of TMEDA in 80 ml of absolute THF were metallized using 53.5 ml of 1.5 molar n-butyllithium/hexane solution according to the procedure described in Example 19, and the product was reacted with 5.00 g of 90% purity (≅40 mmol) 2,2-dimethyl-4-pentenaldehyde. Work-up was effected analogously to that in Example 19. The extract residue (12.2 g) was chromatographed as described in Example 19 on a silica gel S/CH2Cl2 column (φ 3.5 cm, height 40 cm), and the combined fractions which contained the compound desired (amount 6.3 g) were subsequently chromatographed a second time on a silica gel S/CH2Cl2 column (φ 2.4 cm, height 88 cm). A group of fractions (2.5 g) from the second chromatography crystallized from a hexane/diisopropyl ether 3:1 solution. After isolation of the substance, 0.77 g (≅6.3% yield) of pure 3,3-dimethyl-1-(1-imidazolyl)-1-(3-methoxyphenyl)5-hexen-2-ol of melting point 83° C. were obtained. C18H24N2O2 (300.41) calculated: C 71.97 H 8.05 N 9.33% found: C 68.9 H 8.0 N 8.6%.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=O)[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([Cl:22])[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C

Procedure:
Part B. A solution of the pyridone from Part A (6.72 g, 25.9 mmol) in phosphorus oxychloride (52 mL, 25.5 mmol) was stirred at ambient temperature for 3 d. The reaction mixture was poured into a mixture of ice (150 g) and dichloromethane (200 mL). After the ice had melted, 100 mL more dichloromethane was added, and the pH of the mixture was adjusted to 7 with solid NaHCO3. The mixture was separated, and the aqueous phase was extracted with dichloromethane. The extracts were combined, dried over sodium sulfate, filtered and evaporated to afford the product (4-benzylamino-2-chloro-6-methyl-3-nitropyridine) as a bright yellow crystalline solid (6.45 g, 23.2 mmol, 90%). TLC RF 0.76 (ethyl acetate). 1H NMR (300 MHz, CDCl3): d 7.43-7.26 (5H, m), 7.04 (1H, br), 6.47 (1H, s), 4.48 (2H, d, J=5.5 Hz), 2.40 (3H, s). MS(NH3 -CI): m/e 281 (5), 280 (35), 279 (17), 278 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:24])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22]O)[CH:14]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:46][CH:45]=1>C(#N)CC>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:24])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22][N:53]2[CH2:52][CH2:51][N:50]([C:47]4[CH:46]=[CH:45][C:44]([Cl:43])=[CH:49][CH:48]=4)[CH2:55][CH2:54]2)[CH:14]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncc(CO)cc3NC(=O)C2C1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)N1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
7-Hydroxymethyl-10-oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2-carboxylic acid tert-butyl ester (22.0 mg, 0.598 mmol) was suspended in propionitrile (1.5 mL) and (cyanomethyl)trimethylphosphonium iodide (174.0 mg, 0.718 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (313 ul, 1.794 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (139 mg, 0.598 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and purified on silica column (24 g, 25% THF in ethyl acetate). The fractions were combined and concentrated to afford 250.9 mg (82%) of the title compound as a brown solid in 80% purity. [M+H] calc'd for C26H33ClN6O3, 513; found, 513.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(NCCCCCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 77.5 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.6 g of 5-amino-1-pentanol and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 8 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.38 g of 5-(4-nitro-3-methylphenylamino)pentan-1-ol (17) were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][N:4]=1.[Se](=O)=O>O1CCOCC1.ClCCl>[C:3]1([CH:2]=[O:1])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: OCc1nccc2c1CCCC2
Agent: O=[Se]=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=Cc1nccc2c1CCCC2
Temperature: 82.5 °C
Yield: 90.1 %

Procedure:
1-Hydroxymethyl-5,6,7,8-tetrahydroisoquinoline (4.14 g, 25.4 mmole) is dissolved in 75 ml dioxane in a 200 ml one neck round bottom flask under nitrogen. The solution is treated with selenium dioxide (1.56 g, 14.0 mmole) and the reaction mixture is warmed to 80-85° C. for 2.5 h. The mixture is cooled to room temperature, is diluted with 125 ml dichloromethane and is filtered through celite. The filter cake is washed well with fresh dichloromethane and the filtrate is concentrated in vacuo to an amber oil. The crude material is chromatographed over 200 g silica gel (230-400 mesh), eluting with 1:5:4 acetone/chloroform/hexane while collecting 50 ml fractions. Fractions 11-18 are combined and concentrated to give 3.69 g (90%) of 5,6,7,8,-tetrahydroisoquinoline-1-carbaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.O.[NH2:30][NH2:31]>C(Cl)(Cl)Cl>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([NH:30][NH2:31])[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Reactant: NN
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(NN)n2)cc1OC

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (10.0 g) in chloroform (100 ml) was added hydrazine hydrate (3.66 ml). The mixture was refluxed for 6 hours. The reaction mixture was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-hydrazino-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (3.46 g).
Reaction SMILES: [OH-].[K+].[CH:3]1([CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O.C(O)C>[CH:3]1([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([OH:16])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C(=O)O)C1CCCC1
Temperature: -10 °C
Yield: 96 %

Procedure:
KOH (3.42 g, 61.0 mmol) in water (10 mL) was slowly added (over 1 h) to diethyl 2-cyclopentylmalonate (12.12 g, 53.09 mmol) in ethanol (30 mL) at 0° C. The resultant mixture was stirred at 0° C. for 2 h and at rt over night. The mixture was freezing-dried, and the residue partitioned between Et2O and water. The aqueous layer was washed with Et2O. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduce pressure to recover unreacted diethyl cyclopentylmalonate (1.94 g, 8.5 mmol). The aqueous layer was cooled to −10° C. and the pH was adjusted to 1 using HCl (conc.). The water layer was extracted with Et2O (6×50 mL), dried (MgSO4) and concentrated under reduce pressure to give the title compound (10.2 g, 96%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.21-1.38, 1.47-1.75, 1.76-1.97, 2.37-2.55, 3.24, 4.14-4.31. Total no of protons: 15.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:13][Si](C=[N+]=[N-])(C)C>C1COCC1>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][Br:1]
Reactant: O=C(O)Cc1ccccc1CBr
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1CBr
Temperature: 0 °C
Reaction time: 14 h
Yield: 32 %

Procedure:
To an ice-cold solution of (2-bromomethylphenyl)acetic acid (1 g, 4.4 mmol) in THF (2.4 mL) was added trimethylsilyldiazomethane (3 mL of a 2 M solution in hexanes, 6 mmol), and the reaction mixture was stirred for 14 h. The reaction was quenched with AcOH, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 98:2 to 94:6 methylene chloride/hexanes) afforded methyl(2-bromomethylphenyl)acetate as a light yellow solid (0.34 g, 32%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 4H), 4.59 (s, 2H), 3.81 (s 2H), 3.71 (s, 3H).
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:13][C:14](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:7]([N:13]=[C:14]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCNC(=N)N
Reactant: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in part A of Example 18, and using 4.5 g. of sodium, 38.4 g. of n-hexylguanidine sulfate, and 25.4 g. of n-hexyl isocyanate, there was obtained 11.1 g. of 1-n-hexylamidino-3-n-hexylurea having the structural formula ##EQU62## as a white crystalline solid which melted at 75-78°C. The solubility of this base in water at 25°C. was less than 0.25 per cent. In 95 per cent ethyl alcohol at 25°C. it was soluble to the extent of 5 per cent (w/v); a precipitate formed when the 5 per cent alcoholic solution was diluted with four volumes of water.