Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:21])([OH:20])[OH:19].N>C(O)C>[CH:1]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:19])([OH:21])[OH:20])[OH:11])=[O:3]
Reactant: O=CO
Reactant: O=P(O)(O)CCCCCNO
Agent: N
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)CCCCCP(=O)(O)O
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Formic acid (1.19 g.) was added dropwise to acetic anhydride (1.33 g.) at ambient temperature with stirring. After the stirring was continued at the same temperature for 30 minutes, 5(N-hydroxyamino)pentylphosphonic acid (1.83 g.) was added to the mixture. The reaction mixture was stirred at ambient temperature for an hour and 45 minutes, and then concentrated under reduced pressure to give an oily residue. The residue was dissolved in ethanol (30 ml) and to the solution was added dropwise conc. aqueous ammonia (2 ml.) to give crystals. After the mixture containing crystals was stirred at ambient temperature for an hour, the crystals were separated by filtration and dried to give crystalline monoammonium salt of 5-(N-formyl-N-hydroxyamino)pentylphosphonic acid (2.10 g.). A part (1.8 g.) of the crystals was dissolved in water (6 ml.) to give insoluble materials, which were removed by filtration and washed with water. The filtrate and the washing were combined and ethanol (30 ml.) was added thereto under heating at 60° C. to give purified crystals (1.62 g) of the same compound as mentioned above. M.p. 170°-175° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14]1[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: OC1CCOCC1
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc(OC2CCOCC2)c1C
Temperature: 55 °C

Procedure:
A 100 mL round bottom flask was charged with methyl 5-chloro-3-hydroxy-2-methylbenzoate (500 mg, 2.492 mmol), tetrahydro-2H-pyran-4-ol (318 mg, 3.12 mmol), triphenylphosphine (1307 mg, 4.98 mmol) and tetrahydrofuran (20 mL). The reaction was maintained for 15 min, at which time DIAD (1.454 mL, 7.48 mmol) was added in one portion. The resulting solution was heated at 55° C. for 24 h and then concentrated in vacuo. Purification of the residue by column chromatography (10-50% EtOAc/hexanes) gave methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzoate as an orange-oil, which was used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.42 (d, J=2.02 Hz, 1H), 6.98 (d, J=2.02 Hz, 1H), 4.51 (tt, J=3.73, 7.39 Hz, 1H), 3.99 (ddd, J=3.66, 7.01, 11.31Hz, 2H), 3.91 (s, 3H), 3.64 (ddd, J=3.28, 7.77, 11.43 Hz, 2H), 2.38-2.45 (m, 3H), 1.99-2.10 (m, 2H), 1.74-1.92 (m, 2H). MS(ES) [M+H]+ 285.0
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21]([C:28]([O:30]C)=[O:29])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21]([C:28]([OH:30])=[O:29])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(C)C)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
In toluene/ethanol/water (=10/1/1, 20.4 ml) was dissolved methyl 7-bromo-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (0.48 g) and potassium carbonate (0.47 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (0.10 g), and the mixture was heated to reflux for 14 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=20/1→8/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.44 g). Methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.44 g) was dissolved in THF (8.8 ml)/methanol (8.8 ml). To the solution was added 1N sodium hydroxide (4.4 ml), and the mixture was stirred at 50° C. for 4 hours. After cooled to room temperature, pH was adjusted to approximate. 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (12/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (320 mg).
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]/[CH2:4][OH:5].[H-].[Na+].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[Na+].[Cl-]>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:5][CH2:4]/[CH:3]=[CH:2]/[CH2:1][OH:6])=[CH:13][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OC/C=C/CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC/C=C/CO)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 20.5 %

Procedure:
A solution of 11.8 g (133.4 mmol) of trans 2-butene-1,4-diol in 100 ml of DMF was treated with 6.4 g (147 mmol) of sodium hydride dispersion on oil (55%), stirred at 0° C. for 45 min., and treated dropwise with 25.1 g (160 mmol) of 4-methoxybenzylchloride. The mixture was stirred during 5 hrs at RT and then poured into a saturated aqueous solution of NaCl. Extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration, evaporation of the solvent and chromatography on silica gel with heptane/AcOEt 9:1 gave 5.7 g (21%) of trans 4-(4-methoxy-benzyloxy)-but-2-en-1-ol. Light yellow oil. MS: 207 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:28]([OH:33])(=[O:32])[CH:29]([CH3:31])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:29]([C:28]([OH:33])=[O:32])[CH3:31])=[O:5]
Reactant: CC(O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)O)c(F)c1

Procedure:
A flask containing 10.0 g 2-fluoro-4-(hexadecylamino)benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 2-fluoro-4-(hexadecylamino)benzoate separates as off-white crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[C:16]2[S:15][CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:17]([O-])([O-])=[O:18].[Na+].[Na+]>CN(C=O)C>[CH3:6][O:7][C:8]1[C:16]2[S:15][CH:14]=[CH:13][C:12]=2[C:11]([CH:17]=[O:18])=[CH:10][CH:9]=1
Reactant: COc1cccc2ccsc12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C=O)c2ccsc12
Temperature: 100 °C

Procedure:
Phosphorous oxychloride (0.518 g, 17.7 mmol) was added to DMF (1.04 mL) under argon at rt. After 30 min 7-methoxybenzothiophene (0.5 g, 3.04 mmol) was added and the reaction was heated to 100° C. for 3.5 h. The reaction was cooled to rt and poured into a saturated Na2CO3 solution, extracted with ether (100 mL) and the organic phase dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=3.34 min; m/z (ES+)=193.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH3:8])=[C:6]([OH:9])[O:5][N:4]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>O>[F:11][C:2]([F:1])([F:10])[C:3]1[C:7]([CH3:8])=[C:6]([O:9][CH2:23][C:24]([O:26][CH3:27])=[O:25])[O:5][N:4]=1
Reactant: Cc1c(C(F)(F)F)noc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)COc1onc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To 1.00 g (6 mmole) of 3-trifluoromethyl-4-methyl-5-hydroxyisoxazole were added 10 ml of dry acetone and 1.00 g (7.2 mmole) of anhydrous potassium carbonate and the resulting mixture was stirred at room temperature for one hour. After addition of methyl bromoacetate (1.10 g, 7.2 mmole), the mixture was refluxed for 30 hours. The reaction mixture was mixed with water (100 ml) and, extracted with diethyl ether. The diethyl ether phase was dried with anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was purified by chromatography on silica gel to give 0.73 g of the title compound as colorless viscous liquid, yield 53.6%.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][C@@H:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]45)=[N:25][C:21]=3[CH:20]=[C:19]([C:43]#[N:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][C@@H:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]45)=[N:25][C:21]=3[CH:20]=[C:19]([C:43](=[N:2][OH:3])[NH2:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: NO
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (24.3 mg, 0.35 mmol), sodium bicarbonate (44 mg, 0.52 mmol), and water (0.52 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (85.8 mg, 0.175 mmol) dissolved in ethanol (1.2 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C27H34ClN7O2 [M+H]+ 524. found 524.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][C:13]2[CH:12]=[CH:11][C:10]3[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6][C:5]=3[C:4]=2[CH2:3]1.[Cl:17][S:18](O)(=[O:20])=[O:19]>>[Cl:17][S:18]([C:12]1[C:13]2[CH2:14][N:2]([CH3:1])[CH2:3][C:4]=2[C:5]2[NH:6][C:7](=[O:16])[C:8](=[O:15])[NH:9][C:10]=2[CH:11]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: CN1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Product: CN1Cc2c(S(=O)(=O)Cl)cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
A solution of 1,7,8,9-tetrahydro-8-methyl-2H-pyrrolo[3,4-f]quinoxaline-2,3(4H)-dione in chlorosulfonic acid was stirred at 120° C. for 3 hours, whereafter it was cooled and poured on ice. This afforded a crystalline precipitate of the product, which was filtered off and washed with water, mp>300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]2[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:18](=[O:20])[O:19][C:5]=2[CH:4]=1>CN(C)C=O.[Ni]>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[O:19][C:18](=[O:20])[C:13]3[CH2:14][N:15]([CH2:4][C:3](=[O:2])[CH3:8])[CH2:16][CH2:17][C:12]=3[C:6]=2[CH:7]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Agent: [Ni]
Solvent: CN(C)C=O
Product: COc1cc2oc(=O)c3c(c2cc1N)CCN(CC(C)=O)C3
Yield: 115.3 %

Procedure:
1,2,3,4-Tetrahydro-8-methoxy-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (13.0 g) in N,N-dimethylformamide (130 ml) is hydrogenated over Raney Nickel (2 g). The Raney Nickel is filtered off. The solvent is evaporated to give a light brown solid. The solid is triturated with methanol, washed with methanol, and dried to give the product (8.2 g), mp 178°-180° C.
Reaction SMILES: CO[C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:6]([O:7][CH3:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C(O)(=O)C.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[N+:11]([C:10]1[CH:9]=[C:6]([O:7][CH3:8])[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[NH:24][CH2:23][CH2:21][OH:22])([O-:13])=[O:12]
Reactant: COc1cc([N+](=O)[O-])c(OC)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(NCCO)c([N+](=O)[O-])c1

Procedure:
1 g of 2,6-dinitro-hydroquinone dimethyl ether (B. Relchert and W. Turkewitsch, Arch. der Pharmazie 276, 397, 406 (1938)) was stirred in 15 ml of ethanol amine for one hour at room temperature, whereupon the mixture was poured on ice and neutralized with acetic acid. The precipitated red crystals were filtered with suction. 0.9 g (78 percent of the theoretical yield) of the product was obtained; it has a melting point of 104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)OC1C=CC=CC=1)#[N:26]>>[C:25]([NH:27][C:28]([NH:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)=[N:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:22])#[N:26]
Reactant: COc1ccc(CN(CCN(C)CCCN)c2ccccn2)cc1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: COc1ccc(CN(CCN(C)CCCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.52 g (1.6 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil that crystallises from ether at -20° C.; MS (+FAB method): m/z (rel. int. [%])=610 ([M+H]+, 1), 121 (100); IR (KBr): 2161 cm-1 (C≡N); m.p.: 54° C. (ether).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[F:25]C1C=C(C=CC=1OCC1C=CC2C(=CC=CC=2)N=1)C(O)=O>>[F:25][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[C:4]([N:3]([O:2][CH3:1])[CH3:24])=[O:23]
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting 3-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid provided the title compound. MS: (M+H m/z=341.2).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.[OH-].[Na+]>COCCOCCOC>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCNCCCl
Reactant: CC(C)(C)c1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: CC(C)(C)c1ccccc1N1CCNCC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A solution of 2-tert-butylaniline (35.7 g, 0.240 mol) and di(2-chloroethyl)amine hydrochloride (47.0 g, 0.264 mol) in diethylene glycol dimethyl ether (350 mL) was refluxed for 12 h. Then the mixture was cooled to room temperature, and 2 M NaOH solution (50 mL) was added. The mixture was extracted with ether, the combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude product as a colorless oil. The product was purified by re-crystallization in petroleum ether to afford 1-[2-(tert-butyl)phenyl]piperazine (22.6 g, 43%) as a white solid. To the mixture of [2-(tert-butyl)phenyl]piperazine and ethyl acetate was added dropwise 4 M HCl solution in ethyl acetate (50 mL), keeping stirring for 0.5 h. Then the resulting solid was collected by filtration to give 1-[2-(tert-butyl)phenyl]piperazine dihydrochloride (30 g, quant.) as a white solid, which was re-crystallized in ethanol to give 1-(2-tert-butylphenyl)piperazine dihydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[C:1]([C:5]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([Cl:29])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)Cl
Reaction time: 2 h

Procedure:
To a stirred slurry of 2-(2,4-di-t-butyl phenoxy) propionic acid (27.8 g, 0.100 mol) in CH2Cl2 (280 mL) with 2 mL of DMF, oxalyl chloride (17.0 g, 0.134 mol) was added dropwise. The solution resulted after several minutes was stirred for 2 hr. TLC indicates no starting material. The solution was filtered through a glass wool plug to remove some debris and the filtrate was concentrated in vacuo, residue was washed with CH2Cl2 (50 mL) and was concentrated once more to give a gelatinous mixture, which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]([CH3:16])[C:3]1=[O:17].C([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])(OC(C)(C)C)=O>>[NH2:25][C@H:26]([C:28]([C:2]1([NH2:1])[N:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]([CH3:16])[C:3]1=[O:17])=[O:29])[CH3:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C1=NC(N)C(=O)N(C)c2ccccc21
Product: CC(C)C1=NC(N)(C(=O)[C@H](C)N)C(=O)N(C)c2ccccc21

Procedure:
Following General Procedure D using 3-amino-2,3-dihydro-5-isopropyl-1-methyl-1H-1,4-benzodiazepin-2-one and N-Boc alanine (Novabiochem), the title compound was prepared as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][CH3:16])=[O:14])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)n1ncc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Product: COC(=O)n1ncc2c(N)cccc21
Temperature: 80 °C

Procedure:
Methyl 4-nitro-1H-indazole-1-carboxylate 1.66 g, 7.5 mmol) and 10% Pd/C were combined in ethanol (20 mL) and exposed to a hydrogen atmosphere. The reaction mixture was heated at 80° C. for 20 minutes, allowed to cool to room temperature, and filtered through Celite. The filtrate was evaporated to provide title compound. 1H NMR (300 MHz, DMSO-d6) δ 6.1 (s, 2H), 6.41 (dd, 1H), 7.21 (m, 2H), 8.42 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].N1C=CC=CC=1>C(#N)C>[Cl:12][CH2:13][CH2:14][C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:16]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(CCCl)Nc1ccc(C(=O)O)c(O)c1
Reaction time: 0.33 h

Procedure:
7.5 g of 4-Aminosalicyclic acid was dissolved in 300 ml of acetonitrile at about 60° C. 12 ml of 3-chloropropionyl chloride was added dropwise and followed by addition of 5 ml of pyridine, the resulting mixture was refluxed for three hours. The mixture, which became clear after approximately 20 minutes of refluxing, was cooled and evaporated to dryness under reduced pressure. A gummy oil was dissolved in isopropanol-water and refrigerated for several days. A small amount of solid thus produced was filtered off. The filtrate was evaporated to dryness and approximately 16.8 g of crude 4-(3-chloropropionamido) salicyclic acid was produced. A lens treated with this compound was found to be clear with excellent UV blockage up to about 320 nm. ##STR9##
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:27]([C:25]2[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=2)(=[O:29])=[O:28])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 1-methylimidazole-4-sulfonyl chloride (524 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(1-methylimidazole-4-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (730 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:32]([O:39][C:40](=[O:41])[N:11]([CH2:10][CH:9]([OH:16])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]([CH3:14])[CH3:15])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -1.5 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester (2) (24.50 g, 72.80 mmol, 1 equiv) and triethylamine (7.37 g, 72.80 mmol, 1 equiv) were dissolved in dichloromethane (500 mL). The solution was cooled to −1.5° C., followed by the dropwise addition of benzylchloroformate (12.40 g, 72.80 mmol, 1 equiv). The solution was stirred at 0° C. for 24 h. Due to the incompleteness of the reaction, benzylchloroformate (2.40 g, 14.07 mmol) and triethylamine (1.44 g, 14.23 mmol) were added to the solution. The solution was stirred at room temperature for 24 h. The solution was diluted with 2% Na2CO3 solution (300 mL) and the mixture was stirred for 10 min. The organic layer was separated, washed with water (2x) and saturated sodium chloride solution (1×). The organic layer was dried on MgSO4, filtered, and evaporated to dryness to obtain the desired product as a yellow colored oil (34.30 g, 72.80 mmol, quantitative). LRMS (ES+): m/z 471 [M+H]+.