Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([CH:16]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=1)[CH2:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:15])[CH3:12].I[CH3:44]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14]([C:16]([CH3:44])([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=1)[CH2:17][CH2:18][P:19](=[O:26])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])=[O:15])[CH3:12]
Reactant: CCCCCCCCc1ccc(CCC(CCP(=O)(OCC)OCC)C(=O)OCC)cc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)C(=O)OCC)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
To a solution potassium bis(trimethylsilyl)amide (0.213 g, 1.068 mmol) in tetrahydrofuran (1 ml) at −78° C. was added (±)-diethyl 3-ethoxycarbonyl-5-(4-(octyl)phenyl)pentylphosphonate (0.250 g, 0.533 mmol) as a solution in 1 ml of tetrahydrofuran. After stirring for 40 minutes at −78° C., iodomethane (0.083 ml, 1.33 mmol) was added. The reaction was stirred for 1 h at −78° C. then allowed to warm to room temperature. The solution was diluted with ethyl acetate (25 ml) and washed with 2N HCl (10 ml) 5% aqueous sodium thiosulfate (10 ml), saturated aqueous sodium chloride (10 ml), dried over magnesium sulfate and concentrated to give a colorless oil (0.211 g): MS m/e 483.4 (M+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:35])=[C:7]([C:16]([NH:18][C:19]([CH2:30][O:31][C:32](=[O:34])[CH3:33])([CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:20][O:21][C:22](=[O:24])[CH3:23])=[O:17])[C:8]([I:15])=[C:9]([C:13]=1[I:14])[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].[OH-].[Na+:37]>O>[C:1]([NH:4][C:5]1[C:6]([I:35])=[C:7]([C:16]([NH:18][C:19]([CH2:25][O:26][C:27](=[O:29])[CH3:28])([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:20][O:21][C:22](=[O:24])[CH3:23])=[O:17])[C:8]([I:15])=[C:9]([C:13]=1[I:14])[C:10]([O-:12])=[O:11])(=[O:3])[CH3:2].[Na+:37]
Reactant: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(COC(C)=O)(COC(C)=O)COC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(C(=O)NC(COC(C)=O)(COC(C)=O)COC(C)=O)c1I

Procedure:
A stirred slurry of 5-acetamido-2,4,6-triiodo-N-[tris(acetoxymethyl)methyl]isophthalamic acid (4.15 g., 5 mol.) in water (20 ml.) was carefully neutralized by dropwise addition of 1 N sodium hydroxide solution (5.00 ml.) so that the pH of the solution never exceeded 7.00. The resulting clear solution (pH 6.98) was concentrated under reduced pressure at room temperature (25°, 20 mm. to 0.1 mm.) and dried overnight in vacuo (0.1 mm.) to yield the salt indicated in the caption as a white powder (4.2 g.). The solubility of this powder in water is greater than or equal to 100% (wt/vol).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH3:26])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[ClH:27]>>[ClH:27].[CH3:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Agent: Cl
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)O)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester obtained in Example 1-(3) (1.11 g), concentrated hydrochloric acid (7.0 mL) was added at room temperature and stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the titled compound (1.08 g) as a light-brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].[CH2:23]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:24][CH2:25][CH3:26]>CC#N.CCOC(C)=O>[CH2:23]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:16])[CH2:29][CH2:28]1)[CH2:24][CH2:25][CH3:26]
Reactant: Cc1cccc2c1ccc(=O)n2CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCC1CCN(CCCn2c(=O)ccc3c(C)cccc32)CC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-5-methyl-1H-quinolin-2-one (0.053 g, 0.23 mmol), KI (0.083 g, 0.5 mmol), K2CO3 (0.069 g, 0.50 mmol) and 4-butylpiperidine (50 μl, 0.30 mmol) in CH3CN (2 mL). The mixture was shaken at 50° C. for 72 h and then diluted with EtOAc (25 mL) and washed with water (15 mL). The water phase was extracted (2×25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 1:4) to give the title compound (0.058 g, 74%). 1H NMR (CD3OD) δ 8.13 (d, J=9.8 Hz, 1H), 7.56-7.46 (m, 2H), 7.15 (brd, 6.8 Hz, 2H), 6.67 (d, J=9.8 Hz, 1H), 4.38 (t, J=7.2 Hz, 2H), 3.10-3.03 (m, 2H), 2.68-2.61 (m, 2H), 2.57 (s, 3H), 2.25-2.15 (m, 2H), 2.04-1.95 (m, 2H), 1.78-1.69 (m, 2H), 1.36-1.16 (m, 9H), 0.89 (t, J=7.0 Hz, 3H); 13C NMR (CD3OD) δ 162.3, 138.7, 136.6, 136.2, 130.4, 123.6, 119.4, 118.9, 112.4, 54.7, 52.9, 39.9, 35.3, 34.5, 30.7, 28.2, 23.7, 22.1, 17.3, 12.6; HPLC-MS (ammonium acetate) [M+H]+=341.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)=[O:19].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[C:18](=[O:19])[C:17]3[C:16](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=2)=[CH:7][C:6]=1[CH3:14]
Reactant: Nc1ccccc1C(=O)Nc1ccc(I)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(I)cc2)cc(C)c1OCCO
Temperature: 155 °C

Procedure:
To a mixture of 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.570 g, 2.96 mmol) and 2-amino-N-(4-iodo-phenyl)-benzamide (1.00 g, 2.96 mmol) in N,N-dimethylacetamide (10 mL) was added sodium hydrogen sulfite (0.470 g, 4.44 mmol) and p-toluenesulfonic acid (0.280 g, 1.48 mmol). The reaction mixture was heated at 155° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with cold water (20 mL) to produce the precipitate. The yellow solid was filtered, washed with cold water (2×20 mL), methanol and dried under vacuum to provide crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give the title compound as white solid. Yield: 0.20 g (13%). MP 101-103° C. 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, 1H), 7.81-7.78 (m, 2H), 7.75 (d, 2H), 7.59-7.48 (m, 1H), 7.01-6.85 (m, 4H), 3.98-3.81 (m, 4H), 2.40 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 513.09 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:9][CH:8]=1.C([O-])=O.[NH4+]>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=1
Reactant: OC/C=C/c1ccc(-c2ncccn2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OCCCc1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A mixture of (2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propen-1-ol (300 mg, 1.41 mmol, prepared as described in Reference Example 65), ammonium formate (445 mg, 7.06 mmol), and 10% Pd/C (100 mg) in methanol (5 mL) was stirred for 1 h at room temperature. Solids were removed by filtration through Celite and washed with additional methanol (20 mL). The filtrate was concentrated and the residue was taken up in ethyl acetate (30 mL), washed with water (20 mL), dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 1:1 dichloromethane/ethyl acetate) provided 240 mg (79%) of the title compound as a colorless oil. MS 215 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].C(NC(C)C)(C)C.[F:15][C:16]([F:20])=[C:17]([F:19])[F:18]>CN(C)C=O>[F:15][C:16]([F:20])([S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:17]([F:19])[F:18]
Reactant: Sc1ccccn1
Reactant: FC(F)=C(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)Sc1ccccn1
Temperature: 50 °C
Yield: 296.6 %

Procedure:
A mixture of 42 grams of 2-pyridinethiol, 1-oxide, 150 ml of dimethylformamide and 36 grams of diisopropylamine in a stainless steel pressure vessel was pressurized with 4.95 grams of tetrafluoroethylene at -20° C. and heated to 50° C. for 6 hours with rocking. After cooling to ambient temperature, the pressure vessel was vented and the resulting reaction solution was poured into 300 ml of ice water. The aqueous reaction mixture was extracted four times, using 300 ml of diethyl ether each time. The combined diethyl ether extracts were washed three times, using 500 ml of cold water each time. After washing the diethyl ether solution once with 500 ml of saturated aqueous sodium chloride solution, the diethyl ether solution was dried over 100 grams of anhydrous sodium sulfate and evaporated under reduced pressure of 300 mm Hg to 49.6 grams of a semisolid. The semisolid was crystallized from 1-chlorobutane to yield 31 grams of 2-(1,1,2,2-tetrafluoroethylthio)pyridine, 1-oxide melting 67.5°-68.5° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[N:6]1[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>CO>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[C:9](=[O:10])[CH:5]([CH2:4][C:3]([OH:23])=[O:2])[N:6]([CH2:20][CH2:21][CH3:22])[C:7]2=[O:19])=[CH:17][CH:16]=1
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)C(=O)C1CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)C(=O)C1CC(=O)O
Yield: 98.6 %

Procedure:
A solution of [1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acid methyl ester (1.67 g, 5.20 mmol) in methanol (40 mL) is treated with aqueous 5 N NaOH (4.4 mL) and heated to reflux 1.5 hour. The reaction mixture is cooled, the solvent removed. The resultant residue is acidified and extracted with EtOAc. The organic layer is dried and dried to afford 1.56 g (98%) [1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acid. 1H NMR. MS (ES−) Calc'd for C16H19N2O4 (M−1) 303. Found m/z 303 (100%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO.O>[C:1](=[N:14][OH:15])([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1cc2ccccc2cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc2ccccc2cn1
Yield: 89 %

Procedure:
A solution of 3-acetyl-isoquinoline (0.65 g), hydroxylamine (0.29 g) and sodium acetate (0.47 g) in a mixture of methanol (20 ml) and water (3 ml) was heated to reflux for 1.5 hours. The reaction was then poured into water and extracted with ethyl acetate. The combined extracts were dried, concentrated and triturated with hexane to give 3-acetyl-isoquinoline oxime (0.63, 89% yield) as a white crystalline solid m.p. 135°-142° C.; 1H NMR: 2.50(3H,s); 7.61(1H,t); 7.70(1H,t); 7.87(1H,d); 7.99(1H,d); 8.11(1H,s); 9.28(1H,s) ppm.
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH3:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12.[C:28]1([C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+]=[N-])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=NN)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>CO.C(Cl)Cl.CCOCC>[NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([O:25][CH:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH3:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1
Agent: NN=C(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CO
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1

Procedure:
In a suspension of 17.48 g of 7-amino-3-[(2-hydroxymethyl5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylic acid in 100 ml of methanol and 300 ml of methylene chloride was added dropwise diphenyldiazomethane as 50 ml of a methylene chloride solution, synthesized from 23.55 g of benzophenonehydrazone, 26 g of mercuric oxide (yellow) and 200 ml of n-hexane while stirring, and the mixture was stirred at room temperature overnight. After the reaction mixture was condensed, ether was added thereto to effect crystallization. The crystals thus formed were collected by filtration and dried to obtain 30.15 g of the title compound. 1H NMR (d6 -DMSO+CDCl3) δ:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13]>ClCCl>[C:12]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:9])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCSc2ccccc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1CCS(=O)c2ccccc2C1
Reaction time: 0.25 h

Procedure:
A solution of 3-chloroperbenzoic acid (1.03 g) in dichloromethane (100 ml) was added dropwise with cooling from 0° C. to -2° C. to a stirred solution of 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.03 g, prepared as Example 7 above) in dichloromethane (50 ml). The reaction mixture was stirred for 15 minutes, then washed with water, dried and the solvent was removed by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (9:1) as eluent gave 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethyl acetate. Yield 0.67 g (m.p. 156°-157° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:16]1([CH3:26])[C:17]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[C:16]1([CH3:26])[C:17]([S:22]([O:13][C@H:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1

Procedure:
(S)-1-Benzyl-3-pyrrolidinol (44.32 g), 132.88 g of toluene and 166.95 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 500-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.0° C. Then, 104.94 g of toluenesulfonyl chloride was added in divided portions at an interval of about 5 g/10 minutes over 3 hours and 10 minutes at a flask inside temperature of 5 to 10° C. Water (37 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of (S)-1-benzyl-3-pyrrolidinol toluenesulfonate was thus obtained in a yield of 85.5 mole percent.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[OH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH2:16]1.N1CCCCC1>ClCCCC>[OH:24][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:14])[C:16]1=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N:3]([CH2:12][CH3:13])[CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: O=C1CC(O)c2ccccc21
Reactant: CCN(CC)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCCCCl
Product: CCN(CC)c1ccc(C=C2C(=O)c3ccccc3C2O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
A mixture of 56.6 g.(0.32 mole) of p-diethylaminobenzaldehyde, 47.36 g. (0.32 mole) of 3-hydroxy-1-indanone and 7 ml. of piperidine was then heated with magnetic stirring to 80°-100° C. for 1.5 hours (the mixture is a melt at the reaction temperature). The mixture was cooled in ice water, 90 ml. of 1-chlorobutane and seed was added. The product tended to come out as a gum; the solution was therefore heated, cooled (seeded) and muddy brown solid separated. The product was collected by filtration and the brown solid washed until bright orange; 43.62 g. 44% yield, m.p. 139°-141°, m.p. recrystallized material (1-chlorobutane) 142°-143° C. An extra 11% yield was obtained through concentration and refiltration of the filtrate; the latter fraction washed up as cleanly as the first. The IR spectrum and elemental analysis are those expected of the titled merocyanine derivative.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([C:18]([O:20]C)=O)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:22][NH2:23]>>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([C:18]([NH:23][CH3:22])=[O:20])[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CN
Reactant: COC(=O)C1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Product: CNC(=O)C1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of methyl 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidine-3-carboxylate (6.5 mg, 0.02 mmol) in methylamine (2M in MeOH, 1 ml) was heated to 65° C. for 2.5 h. After cooling to room temperature the solvent was removed in vacuo and the residue purified by FCC on silica to afford the title compound as colourless oil (4 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:33])[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[C:20]2[C:19]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][C:17]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:16][C:15]=2[C:14]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:13][CH:12]=1)=[O:9].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].O.O.O.C([O-])(=O)C.[Na+].[N+](C1C=CC(C([O:85][C:86](=O)[C:87]2[CH:92]=[CH:91][C:90]([N+:93]([O-:95])=[O:94])=[CH:89][C:88]=2[S:96]([OH:99])(=[O:98])=[O:97])=O)=C(S(O)(=O)=O)C=1)([O-])=O>O>[N+:93]([C:90]1[CH:91]=[CH:92][C:87]([C:86]([NH:1][C:2]2[CH:3]=[C:4]([CH3:33])[CH:5]=[CH:6][C:7]=2[C:8]([NH:10][C:11]2[C:20]3[C:19]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][C:17]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:16][C:15]=3[C:14]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:13][CH:12]=2)=[O:9])=[O:85])=[C:88]([S:96]([OH:99])(=[O:97])=[O:98])[CH:89]=1)([O-:95])=[O:94]
Reactant: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(N)c1
Reactant: O=C(OC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(NC(=O)c2ccc([N+](=O)[O-])cc2S(=O)(=O)O)c1
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a stirred solution of 6.5 g of 8(3-amino-p-toluamido)-1,3,5-naphthalenetrisulfonic acid, trisodium salt (prepared in Example 1) and 2.4 g of sodium acetate trihydrate in 43.0 ml of water is added 3.07 g of 4-nitro-2-sulfobenzoic acid anhydride. The mixture is stirred for 30 minutes then is filtered. The filtrate is acidified with 0.98 ml of concentrated hydrochloric acid and evaporated in vacuo. The residue is dissolved in 20 ml of hot water which is added to 130 ml of absolute ethanol forming a gelatinous precipitate. The material is collected and washed with 80% aqueous ethanol, ethanol and ether and is dried to yield 4.2 g of 8-[3-(4-nitro-2-sulfobenzamido)-p-toluamido]-1,3,5-naphthalenetrisulfonic acid, tetrasodium salt.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].CS(O[C@@H:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)=O.FC(F)(F)S([O-])(=O)=O>[OH-].[Na+].O1CCCC1>[CH2:18]([O:17][C:15](=[O:16])[C@@H:14]([CH3:20])[N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2])[CH3:19]
Reactant: CCOC(=O)[C@H](C)OS(C)(=O)=O
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 24 h
Yield: 134.8 %

Procedure:
A suspension of bis(2-chloroethyl)amine hydrochloride (0.392 g; 2.1 mmol) in 5N aqueous sodium hydroxide (3 mL) is extracted with ether (2×10 mL) and the combined extracts are washed with a minimum amount of water and saturated brine. The ethereal solution is dried quickly over magnesium sulfate and filtered. Tetrahydrofuran (2 mL) is added to the filtrate, and ether is carefully removed under reduced pressure on a rotavapor unit without heating. The residue is mixed with a solution of ethyl (S)-2-[(methylsulfonyl)oxy]-propionate (0.5 g; 2 mmol) in tetrahydrofuran (1 mL). After stirring the reaction mixture for 24 hrs at room temperature, there is no visible precipitate. The volatiles are removed under reduced pressure and the remaining viscous oil is dissolved in ether (8 mL), and the slightly turbid solution is filtered after 60 minutes. The filtrate is treated dropwise with n-heptane to induce crystallization; the final ratio of n-heptane/ether is 1:3. The crystalline salt is collected by filtration and washed quickly with a small portion of ether. There is obtained 0.653 g (yield 83.3%) of N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester, trifluoromethanesulfonate; mp 73-74.5° C.; 1H NMR (300 MHz, CDCl3) δ 1.35 (t, J=7.1 Hz, 3H), 1.76 (d, J=7.2 Hz, 3H), 3.87 (m, 2H), 4.00 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.57 (q, J=7.2 Hz, 1H), 9.02 (b, 1H).
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].[H-].[Na+].[C:20](OC)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>O1CCCC1.C(OCC)(=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]2[O:1][N:2]=[C:3]([N:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)[N:4]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Reactant: COC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3cccnc3)n2)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
tert-Butyl 4-(N-hydroxyamidino)-piperazine-1-carboxylate (320 mg) prepared in Example 36 was dissolved in 3 ml of tetrahydrofuran, 36 mg of sodium hydride was added thereto, the mixture was stirred at 60° C. for 15 minutes, a solution of 360 mg of methyl nicotinate in 2 ml of tetrahydrofuran was added thereto and the mixture was heated to reflux for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and a saturated saline solution and dried over sodium sulfate. The residue prepared by evaporation of the solvent was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=1:1) to give 39.7 mg of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:11][C:10]1[C:3]2[C:2](=[C:1]([CH3:13])[CH:6]=[CH:5][CH:4]=2)[CH2:7][CH2:8][N:9]=1
Reactant: CC(=O)NCCc1ccccc1C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2c(C)cccc21
Yield: 59 %

Procedure:
In close analogy to the procedure described above, N-(2-o-tolyl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.