Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:7]=2[C:6]([OH:18])=[C:5]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=1)#[CH:2].S(=O)(=O)(O)[OH:27]>CC(C)=O.S([O-])([O-])(=O)=O.[Hg+2]>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:7]=2[C:6]([OH:18])=[C:5]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=1)(=[O:27])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: CC(C)=O
Product: CC(=O)c1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A mixture of [(4-ethynyl-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid (52 mg, 0.15 mmole), mercury sulfate (44 mg, 0.15 mmole), concentrated sulfuric acid (19 mg, 0.19 mmole) in 80% aqueous acetone (1.6 ml) was refluxed for 2 h before it was cooled to room temperature and concentrated. The residue was washed with water and filtered. The remaining solid was dissolved in 0.5 N NaOH (15 ml) and extracted with dichloromethane (2×20 ml). The remaining aqueous layer was acidified with 1N HCl (8 ml) to pH=2. The suspension was extracted with ethyl acetate (20 ml) and dichloromethane (20 ml). The organic layer was combined, concentrated and purified by column chromatography on a C18 column with a gradient of water and acetonitrile in formic acid to give the title compound as a yellow solid (24 mg): MS: (+) m/z 372.24 (M+1), MS: (−) m/z 370.27 (M−1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[OH:33].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.O1CCCC1>[F:1][C:2]([F:30])([F:31])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][OH:33])=[CH:23][CH:24]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: O=C([O-])O
Reactant: C=Cc1ccc(Oc2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [BH3-]C#N
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(CCO)cc1
Yield: 7.6 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propyl-1-(4-vinylphenoxy)benzene (242 mg, 539 mmol) in chloroform (5 mL), sodium hydrogen carbonate (181 mg) and m-chloroperbenzoic acid (60%) (310 mg) were added at room temperature and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and a colorless oil was obtained. To a tetrahydrofuran solution (2 mL) of this substance, boron trifluoride diethyl ether complex (40 μL) and sodium cyanoborohydride (40 mg) were added at 0° C. under an argon atmosphere, and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (76 mg, yield 30%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH:16]([CH3:18])[CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: CC(=O)C(=O)OC(C)C
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CC(C)OC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and isopropyl pyruvate (prepared by following General Procedure AO above using isopropanol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: CCC/C=C/C=[CH:7]/[C:8]([O:10][C@@H:11]1[C@@:49]2([OH:51])[O:50][C@H:19]([CH2:20][CH:21]([C@H:62]([OH:64])[CH3:63])[O:22][C:23]([CH2:25][C@H:26]([OH:61])[CH2:27][C@H:28]3[O:33][C@@:32]([OH:54])([CH2:34][C@H:35]4[O:45][C@@H:44]([CH:46]=[CH:47][C:48]2([CH3:53])[CH3:52])[CH2:43]/[C:37](=[CH:38]\[C:39]([O:41][CH3:42])=[O:40])/[CH2:36]4)[C:31]([CH3:56])([CH3:55])[C@@H:30]([O:57][C:58]([CH3:60])=[O:59])[CH2:29]3)=[O:24])[CH2:18]/[C:12]/1=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[O:9].[CH3:65][CH2:66][CH2:67]CCC.CC(C)=O>C(OCC)(=O)C>[CH3:63][C@@H:62]([OH:64])[C@@H:21]1[O:22][C:23](=[O:24])[CH2:25][C@H:26]([OH:61])[CH2:27][C@H:28]2[O:33][C@:32]([OH:54])([C:31]([CH3:55])([CH3:56])[C@@H:30]([O:57][C:58]([CH2:60][CH:66]([CH3:67])[CH3:65])=[O:59])[CH2:29]2)[CH2:34][C@H:35]2[O:45][C@H:44]([CH2:43]/[C:37](/[CH2:36]2)=[CH:38]\[C:39]([O:41][CH3:42])=[O:40])[CH:46]=[CH:47][C:48]([CH3:52])([CH3:53])[C@:49]2([OH:51])[O:50][C@H:19]([CH2:18]/[C:12](/[C@@H:11]2[O:10][C:8]([CH3:7])=[O:9])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])[CH2:20]1
Reactant: CCCCCC
Reactant: CCC/C=C/C=C/C(=O)O[C@H]1/C(=C/C(=O)OC)C[C@H]2CC([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H]3C[C@H](OC(C)=O)C(C)(C)[C@](O)(C[C@@H]4C/C(=C/C(=O)OC)C[C@H](C=CC(C)(C)[C@]1(O)O2)O4)O3
Agent: CCC/C=C/C=C/C(=O)O[C@H]1/C(=C/C(=O)OC)C[C@H]2CC([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H]3C[C@H](OC(C)=O)C(C)(C)[C@](O)(C[C@@H]4C/C(=C/C(=O)OC)C[C@H](/C=C/C(C)(C)[C@]1(O)O2)O4)O3
Agent: COC(=O)/C=C1/C[C@H]2C[C@]3(O)O[C@H](C[C@@H](O)CC(=O)O[C@@H]([C@@H](C)O)C[C@H]4C/C(=C\C(=O)OC)[C@H](OC(C)=O)[C@@](O)(O4)C(C)(C)/C=C/[C@@H](C1)O2)C[C@H](OC(=O)CC(C)C)C3(C)C
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C1/C[C@H]2C[C@]3(O)O[C@H](C[C@@H](O)CC(=O)O[C@@H]([C@@H](C)O)C[C@H]4C/C(=C\C(=O)OC)[C@H](OC(C)=O)[C@@](O)(O4)C(C)(C)C=C[C@@H](C1)O2)C[C@H](OC(=O)CC(C)C)C3(C)C

Procedure:
From a succession of silica gel column chromatographies and gel permeation (Sephadex LH-20) chromatography, an active fraction (0.38 g) was isolated as a white amorphous powder with PS ED50 =1.6×10-3 μg/ml and which contained bryostatins 4-7 by TLC (7:3 n-hexane:acetone and 2:3 n-hexane:ethyl acetate). By using dry column (2×60 cm) silica gel chromatographic methods with n-hexane:acetone (5:1→1:1) and n-hexane:ethyl acetate (2:1→1:2), six fractions were selected for further purification. The first fraction contained bryostatin 4. The second, third and fifth fractions were subjected to HPLC using Partisil-10M-9-ODS-2 (C-18 reversed phase) with a 1:1→9:1 methanol:water gradient (flow rate of 2 ml/min). The second fraction (15 mg) yielded pure bryostatin 5 (14.1 mg), melting at 169°-172° C. (needles from CH2Cl2 --CH3OH); FAB MS m/z 866 for C44H66O17 :[α]27D+106.92 (c=0.028, CH3OH); uv (CH3OH) λmax 226 nm (ε 36,300); and ir (KBr) 3465, 2980-2935, 1740, 1725, 1660-1640, 1440, 1385, 1370, 1290, 1230, 1165, 1100, 1080, 1060, and 1000 cm-1.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1>C(O)(=O)C.[Zn]>[O:10]1[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:7]=2[CH:8]=[CH:9]1
Reactant: Clc1nccc2occc12
Agent: [Zn]
Solvent: CC(=O)O
Product: c1cc2occc2cn1
Yield: 73.1 %

Procedure:
To a solution of 4-chlorofuro[3,2-c]pyridine (10.0 g, 65.1 mmol) in acetic acid (130 mL) was added zinc (10.0 g, 153 mmol), and the mixture was heated under reflux for 2 hr and filtered. The filtrate was concentrated under reduced pressure. The residue was basified with 1M aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (5.67 g, yield 73%).
Reaction SMILES: C[C:2]([O-:5])(C)C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][N:31]([CH3:46])[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>C1COCC1>[CH3:30][N:31]([CH3:46])[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[CH2:37][CH2:36][CH:35]([CH:2]=[O:5])[CH2:34][CH2:33]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C1(c2cccc(F)c2)CCC(C=O)CC1
Reaction time: 2 h

Procedure:
KOtBu (2.15 g, 19.2 mmol) dissolved in abs. THF (25 mL) was added in drops to a solution of (methoxymethyl)triphenylphosphonium chloride (6.58 g, 19.2 mmol) in abs. THF (25 mL) at 0° C. in argon. The resulting red solution was mixed after 30 min at 0° C. with a solution of 4-dimethylamino-4-(3-fluorophenyl)cyclohexanone (3.0 g, 12.76 mmol) in abs. THF (25 mL) and stirred overnight at RT. The solvent was removed in a vacuum, the residue mixed with 1M sulphuric acid (50 mL) and stirred for 2 h. The precipitate precipitated out during this was separated and the filtrate (pH 1) washed with ether (6×30 mL). The aqueous solution was adjusted to pH 11 with 5N NaOH and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18].[CH3:19][O:20][NH2:21]>>[ClH:18].[CH3:19][O:20][N:21]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: CON
Agent: Cl
Product: CON=C(c1ccccc1)c1cc2ccncc2[nH]1

Procedure:
Phenyl (1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-methyloxime hydrochloride was prepared from phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) and O-methylhydroxylamine hydrochloride following the procedure described for Example 104 (geometry of the oxime double bond undefined).
Reaction SMILES: [C:1]([N:5]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16]SC)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=[C:33]([C:37]([O:39]O)=[O:38])C=1>C(Cl)Cl>[C:1]([N:5]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][O:39][C:37](=[O:38])[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1CSC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1COC(C)=O
Reaction time: 0.08 h

Procedure:
3-Methoxy-2-methylsulfanylmethyl-benzoic acid N′-tert-butyl-N′-(3,5-dimethyl-benzoyl)-hydrazide in CH2Cl2 was stirred at room temperature with 1.0 eq of m-chloroperbenzoic acid. The reaction was complete within 5 min as indicated by TLC. The reaction mixture was washed with saturated NaHCO3 and the organic layer was stripped under vacuum. The residue was mixed with 1-2 mL of 1:1 ether:hexane and the solution was removed with a pipette, leaving the product which was then dried under vacuum.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=2)[NH:11][C:10](=[O:20])[CH:9]=1)[C:4]([OH:6])=[O:5].Br>>[ClH:1].[NH2:2][CH:3]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][C:10](=[O:20])[CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc2[nH]c(=O)cc(CC(N)C(=O)O)c2c1
Agent: Br
Agent: Cl
Product: NC(Cc1cc(=O)[nH]c2ccc(O)cc12)C(=O)O
Yield: 57.7 %

Procedure:
To 4 g of 2-amino-3-(6-methoxy-2-quinolon-4-yl)propionic acid hydrochloride was added 50 ml of 48%-hydrobromic acid and the mixture was refluxed for 4 hours. After cooling of the reaction mixture, the crystals precipitated were collected by filtration and were dissolved in an aqueous solution of sodium hydroxide. Then the solution was acidified with hydrochloric acid and the crystals precipitate were collected by filtration. Recrystallized from dimethylformamide-water to obtain 2.2 g of 2-amino-3-(6-hydroxy-2-quinolon-4-yl)propionic acid hydrochloride in the form of white powdery product.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[CH:23]1[C:24]2[C:19](=[C:18]([NH:15][C:16]([NH:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][CH:11]=3)=[O:17])[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1
Reactant: NCc1ccc(N2CCOCC2)cc1
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: O=C(NCc1ccc(N2CCOCC2)cc1)Nc1cccc2cnccc12

Procedure:
The product from Example 66B (285 mg, 1.48 mmol) in diethyl ether (10 mL) was treated with the product from Example 61A. The mixture was filtered and the filter cake purified by chromatography (95:5 CH2Cl2—MeOH, eluant) to provide that title compound as a white solid. The corresponding di-hydrochloride salt was prepared using methanolic HCl to afford a yellow solid (505 mg, 78%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.67 (s, 1H), 8.52-8.55 (m, 1H), 8.32 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.23 (d, J=8.8 Hz, 2H), 6.92-6.96 (m, 3H), 4.26 (d, 5.4 Hz, 2H), 3.72-3.75 (m, 4H), 3.06-3.12 (m, 4H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3]O.[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:15])=C[CH:14]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:15][C:12]1[N:11]=[N:10][C:9]([Cl:8])=[CH:14][C:3]=1[C:2]([CH2:5][OH:6])([CH3:1])[CH3:7]
Reactant: CC(C)(CO)CO
Reactant: Clc1ccc(Cl)nn1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)(CO)c1cc(Cl)nnc1Cl
Reaction time: 0.33 h

Procedure:
To a 5-liter flask were added 341 g. of 2,2-dimethyl-1,3-propanediol, 500 ml. of water, 223 g. of 3,6-dichloropyridazine, 100 ml. of sulfuric acid in 900 ml. of water and 51 g. of silver nitrate. To the mixture was then added, dropwise, with an insulating mantle around the flask, 600 g. of ammonium persulfate dissolved in 1 liter of water. The addition was carried out in about 20 minutes, while the temperature rose from 33° to 86°. When the addition was complete, the insulating mantle was removed and the flask was placed in a water bath to cool it. When the temperature had reached 40°, 1200 ml. of dichloromethane was added and the mixture was stirred for 10 minutes more and filtered through a polypropylene filter pad. The solids were washed with 500 ml. of dichloromethane, and the layers of the combined filtrate were separated. The aqueous layer was extracted with 1 liter of dichloromethane, and the combined organic layers were extracted with 1 liter of water, and dried over sodium sulfate. The solvent was removed under vacuum, to leave 385 g. of a gummy solid. Most of the solid was removed and dissolved in 1200 ml. of toluene at 85°. It was then cooled to 0° and filtered, and the solids were washed with cold toluene and dried under vacuum to obtain 152 g. of the desired intermediate product, 97% pure by nuclear magnetic resonance analysis, m.p. 133°-136°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1
Yield: 68.9 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (40 mg, 0.13 mmol) obtained in Example 1, (3), and 2-nitrobenzenesulfonyl chloride (42 mg, 0.19 mmol) were stirred at 80° C. in anhydrous pyridine (1 mL). After the disappearance of the starting materials was confirmed, a post-treatment was performed in a conventional manner to obtain the title compound (45 mg, yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:39]>>[CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:39]=2)[CH2:14][N:13]([CH2:29][C:30]([F:31])([F:33])[F:32])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 1 h

Procedure:
{1-[5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2,2,2-trifluoro-ethyl)-imidazolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (148 mg, <257 mmol) was dissolved in m-xylenes (4.0 mL) and heated at 135° C. Solid ammonium acetate (150 mg, 1.9 mmol) was added and the reaction was stirred at 135° C. After 60 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[4-(4-Bromo-phenyl)-1′-(2,2,2-trifluoro-ethyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (15.1 mg) as the TFA salt: LCMS-ESI+: calc'd for C21H25BrF3N5O3: 532.3 (M+). Found: 532.1/534.2 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([C:19]#[N:20])[N:12]=2)=[CH:7][CH:6]=1)[CH3:2].[Li+].[I-]>N1C(C)=CC(C)=CC=1C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:19]#[N:20])[N:12]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(C#N)n2)cc1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1ccc(-c2ccc(O)c(C#N)n2)cc1
Temperature: 120 °C

Procedure:
A solution of 4-(6-cyano-5-methoxy-pyridin-2-yl)-benzoic acid ethyl ester from Example 13d in collidine is treated with LiI and heated at 120° C. for 24 h. The reaction mixture is evaporated, the residue is taken into water and neutralized with 1 N HCl. The resulting precipitate is collected and dried to give 4-(6-cyano-5-hydroxy-pyridin-2-yl)-benzoic acid ethyl ester.
Reaction SMILES: C(OC(=O)CN1C2C=CC=CC=2N(CC2N(CCC(C)C)C3C=CC(C(=N)N)=CC=3N=2)C1=O)(C)(C)C.O[NH:38][C:39]([C:41]1[CH:68]=[CH:67][C:44]2[N:45]=[N:46][N:47]([CH2:48][C:49]3[N:53]([CH2:54][CH2:55][CH:56]([CH3:58])[CH3:57])[C:52]4[CH:59]=[CH:60][C:61]([C:63](=[NH:66])[NH:64]O)=[CH:62][C:51]=4[N:50]=3)[C:43]=2[CH:42]=1)=[NH:40]>>[C:63]([C:61]1[CH:60]=[CH:59][C:52]2[N:53]([CH2:54][CH2:55][CH:56]([CH3:57])[CH3:58])[C:49]([CH2:48][N:47]3[C:43]4[CH:42]=[C:41]([C:39]([NH2:40])=[NH:38])[CH:68]=[CH:67][C:44]=4[N:45]=[N:46]3)=[N:50][C:51]=2[CH:62]=1)(=[NH:64])[NH2:66]
Reactant: CC(C)CCn1c(Cn2nnc3ccc(C(=N)NO)cc32)nc2cc(C(=N)NO)ccc21
Agent: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)N)ccc21
Product: CC(C)CCn1c(Cn2nnc3ccc(C(=N)N)cc32)nc2cc(C(=N)N)ccc21

Procedure:
3-[5-Carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3H-benzotriazole-5-carboxamidine was prepared as described for {3-[5-carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester using N-Hydroxy-3-[5-(N-hydroxycarbamimidoyl)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3H-benzotriazole-5-carboxamidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.O1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(Br)(CC)C>O>[CH:10]([N:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:7]=[N:6]1)([CH2:11][CH3:12])[CH3:9]
Reactant: COc1cn[nH]c1
Reactant: C1CCOC1
Solvent: O
Solvent: CCC(C)Br
Product: CCC(C)n1cc(OC)cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
A mixture of 23.6 g (0.21 mol) of potassium tert.-butylate, 19.6 g (0.2 mol) of 4-methoxypyrazole (for the preparation, see Archiv der Pharmazie 300 (1967), pages 704-708), 100 ml of tetrahydrofuran and 28.7 g (0.21 mol) of sec.-butyl bromide was stirred at 70° C. for 18 hours. 300 ml of water were then added and the mixture was extracted 3 times with 100 ml of chloroform each time. The combined organic phases were dried over sodium sulphate and evaporated in vacuo. 13.2 g (42% of theory) of 1-sec.-butyl-4-methoxypyrazole were obtained from the residue, by vacuum distillation, in the form of a colorless oil with a boiling point of 60° C./0.2 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:24]([CH3:23])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)=[O:22])=[CH:18][CH:19]=1
Reactant: CNc1cccc(C)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1cccc(N(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-methylphenyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-methyl-N-(3-methylphenyl)amine using method M. NMR; δH [2H6]—DMSO 7.85,(1H, dd), 7.64,(1H, d), 7.49,(1H, d), 7.34,(2H, d), 7.25,(2H, d), 7.15,(1H, t), 7.04,(1H, s), 7.00-6.94,(2H, m), 3.38,(3H, s), 2.55,(3H, s), 2.20,(3H, s), 2.19,(3H, s). LCMS; retention time 3.50 min, MH+ 398.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[SH:21]>CC(C)=O>[CH3:5][C:4](=[CH:3][CH2:2][S:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[CH3:13])[CH3:6]
Reactant: CC(C)=CCBr
Reactant: Cc1ccc(C)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCSc1cc(C)ccc1C
Yield: 100.3 %

Procedure:
80 ml of acetone, 9.1 g (0.06 mol) of 1-bromo-3-methyl-2-butene and 8.0 g (0.058 mol) of anhydrous potassium carbonate were added to 8.0 g (0.058 mol) of 2,5-dimethyl-thiophenol, and the mixture was refluxed under heat for 1 hour. After the completion of the reaction, a formed salt was removed by filtration, and the acetone was distilled off under reduced pressure. Then, ethyl acetate was added to the residue, and the mixture was washed with a saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, and then the ethyl acetate was distilled off to give 12 g (yield 100%) of 2-methyl-4-(2,5-dimethylphenyl)thio-2-butene.