Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C:18]3[C:13](=[C:14]([OH:28])[C:15]([C:20]([NH:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH:17]=3)[C:12]3[C:29]([OH:46])=[C:30]4[C:41](=[O:42])[C:40]5[C:35](=[C:36]([OH:45])[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=5)[C:33](=[O:34])[C:31]4=[CH:32][C:11]=3[C@@H:10]2[OH:47])[C@H:5]([OH:48])[C@@H:4]([O:49][C@@H:50]2[O:55][CH2:54][C@@H:53]([OH:56])[C@H:52]([OH:57])[C@H:51]2[OH:58])[C@H:3]1[NH2:59].Cl.Cl>O>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C:18]3[C:13](=[C:14]([OH:28])[C:15]([C:20]([NH:22][CH:23]([C:25]([OH:27])=[O:26])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH:17]=3)[C:12]3[C:29]([OH:46])=[C:30]4[C:41](=[O:42])[C:40]5[C:35](=[C:36]([OH:45])[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=5)[C:33](=[O:34])[C:31]4=[CH:32][C:11]=3[C@@H:10]2[OH:47])[C@H:5]([OH:48])[C@@H:4]([O:49][C@@H:50]2[O:55][CH2:54][C@@H:53]([OH:56])[C@H:52]([OH:57])[C@H:51]2[OH:58])[C@H:3]1[NH2:59]
Reactant: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)N[C@H](C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](N)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O
Agent: Cl
Solvent: O
Product: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)NC(C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](N)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O

Procedure:
Benanomicin B hydrochloride (130 mg) was dissolved in 10 ml of water, followed by addition of 10 ml of concentrated hydrochloric acid. The resultant mixture was sealed in a glass tube. After effecting the hydrolysis reaction at 110° C. for 12 hours, the resultant precipitate was collected by filtration. The precipitate was extracted three times with 10 ml of dioxane, so that 47.5 mg of benanomicinone (aglycone of benanomicin B) was obtained. The residue which remained after the extraction was purified by a preparative silica gel thin layer chromatography (on silica gel "Art. 5744", trade name, product of Merck & Co., Inc.; as developed with a mixed solvent of butanol-acetic acid-pyridine=6:1:4), whereby Fraction 1 containing dexylosylbenanomicin B and Fraction 2 containing benanomicinone were obtained separately. Fraction 1 was adsorbed on 20 ml of an adsorbent "DIAION HP-20". After washing the adsorbent with water (60 ml), the adsorbent was eluted four times with 40 ml of methanol. The eluate was concentrated to dryness, the residue obtained was dissolved in 3 ml of water, and the resultant solution was adjusted to pH 2 with 0.1 N hydrochloric acid. When concentrating the solution to dryness, 17.8 mg of a purified dexylosylbenanomicin B hydrochloride was obtained. Similarly, Fraction 2 was purified chromatogrophically using the adsorbent "DIAION HP-20", when 9.5 mg of benanomicinone was recovered.
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][CH3:7])C.Cl.C1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[N:23]=[C:22]([C:37]([NH:39][NH2:40])=[O:38])[CH:21]=1>C(OCC)(=O)C.O>[CH:4](=[N:40][NH:39][C:37](=[O:38])[C:22]1[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)[N:23]=1)[C:5]#[C:6][CH3:7]
Reactant: CC#CC(OCC)OCC
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC#CC=NNC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C

Procedure:
2-butyne-1-al diethyl acetal (0.27 g, 0.000993×2 mol) was mixed with a 2N aqueous hydrochloric acid solution (about 3 ml) and 5 ml of benzene, and then the resultant mixture was stirred at about 70° C. for about 2 hours. After cooling to room temperature, the obtained mixture was mixed with 4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.325 g, 0.000993 mol), and the resultant mixture was stirred at room temperature for 45 minutes. The obtained reaction solution was distributed in ethyl acetate-water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]([CH3:25])[C:21](OC)=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CCCCCC.C(OCC)(=O)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C@H:20]([CH3:25])[CH2:21][OH:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H](CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.25 h
Yield: 109.1 %

Procedure:
Under argon atmosphere, Methyl(S)-3-(t-butyldiphenylsilyloxy)-2-metylpropionate (47) (1.0 g, 2.7 mmol) was dissolved in 50 ml of dry toluene, 1M DIBAL-H/hexane (5.7 ml, 5.7 mmol) was added to the resultant solution at 0° C., and the mixture was stirred for 15 min. Subsequently, the reaction mixture was further stirred for 45 min after the temperature was returned to room temperature. Ethyl acetate was added to the reaction mixture to decompose the excess DIBAL-H, and the resultant mixture was extracted with 0.5N HCl. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated. The obtained crude product was purified by column chromatography (30 g, 4-10% AcOEt-hexane) to obtain a colorless oily product (48) (968 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>CCO.N1CCCCC1>[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[N:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: O=Cc1cccc(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1cccc(O)c1
Yield: 55 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in EtOH (10 mL) and 3-hydroxybenzaldehyde (559 mg, 1 eq.) and piperidine (10 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((3-hydroxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (800 mg, 55% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[N:4]=1.C(O[C:19](=[O:30])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]O)[CH2:23][CH2:22]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)=[O:30])[CH2:26][CH2:25]3)=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc2ccc(O)cc2n1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Product: COc1ccc2ccc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)cc2n1

Procedure:
The title compound is prepared as a white lyophilizated powder following Scheme 1 and in analogy to Example 2 using 2-methoxy-quinolin-7-ol, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].ClCCl>O>[SH:2][CH2:3][CH2:4][NH:5][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)Cl
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)NCCS
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 22.7 g of 2-mercaptoethylamine hydrochloride (0.2 mol) and 44.3 g of potassium carbonate (0.32 mol) were introduced at room temperature in solution in 130 ml of water. The solution was warmed to 40° C. and 12.0 g of valeryl chloride (0.1 mol) were added dropwise over the course of 15 minutes. The batch was stirred at 40° C. for 3 hours and then cooled to room temperature. 70 ml of dichloromethane were added and a phase separation was carried out. The organic phase was washed with 50 ml of 20% strength ammonium chloride solution, dried over sodium sulfate and freed of its solvent under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:22][CH2:23][CH3:24])[CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:23]([O:22][CH:4]([O:3][CH2:1][CH3:2])[CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])[CH3:24].[C:4]([O-:22])(=[O:3])[CH3:5]
Reactant: CCOC(OCC)C(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: CCOC(OCC)C(Cc1ccccc1N)c1ccccc1

Procedure:
A solution of 1-(3,3-diethoxy-2-phenylpropyl)-2-nitrobenzene (11.74 g, 30.5 mmol) (79a) in acetic acid (30 mL) was hydrogenated under hydrogen atmosphere (40 psi) in the presence of Pd/C (100 mg) for 16 h. At the end of this period the reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with acetic acid. Upon concentration under reduced pressure the title compound was obtained (11.36 g). 1H NMR (300 MHz, CDCl3) δ 0.86 (t, 3H, J=10 Hz), 1.30 (t, 3H, J=7 Hz), 2.27 (dd, 1H, J=11 Hz, J=14 Hz), 3.08 (dd, 1H, J=3 Hz, J=14 Hz), 3.62 (dt, 1H, J=11, 15 Hz), 3.84 (m, 3H), 4.27 (q, 1H, J=7 Hz), 6.36 (m, 2H), 6.61 (d, 1H, J=8 Hz), 6.87-7.26 (m, 5H). MS APCI, m/z=356 (M+1). LC/MS: 2.11 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C@H:9]([NH2:16])[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:21]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C@@H:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[NH:16][CH2:18][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-amino-4-(S)-cyclohexyl-butyric acid tert-butyl ester (5 g, 20 mmol) and 4-formyl-5-nitro-2-phenoxypyridine (6 g, 24 mmol) in methylene chloride (100 mL) was stirred at room temperature overnight. NaBH(OAc)3 (0.8 gm, 4 mmol) was added, and the solution was stirred at room temperature for 5 hours. Additional NaBH(OAc)3 (7 g, 33 mmol) was added and the solution was stirred at room temperature for another one hour. The solution was then poured into EtOAc (100 mL). The organic layer washed with aqueous NaCl, dried over MgSO4 and evaporated to yield a residue which was purified by column chromatography (10% EtOAc/Heptane) to yield 4-(S)-cyclohexyl-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-butyric acid tert-butyl ester as a brown oil.
Reaction SMILES: [Na].[C:2]1([CH:8]([C:12]([NH2:14])=[O:13])[C:9]([NH2:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](OCC)=O.O>C(O)C>[C:2]1([C:8]2[C:12]([OH:13])=[N:14][CH:15]=[N:11][C:9]=2[OH:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C(C(N)=O)c1ccccc1
Reactant: CCOC=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Oc1ncnc(O)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Sodium metal (0.92 g, 40 mmol) was dissolved by stirring in ethanol (30 mL) at room temperature under argon over 40 min. To the resulting solution at room temperature was added 2-phenylmalonamide (3.56 g, 20 mmol) and ethyl formate (1.9 mL, 24 mmol). The resulting suspension was heated at 50° C. under argon 16 h. After cooling the reaction mixture to room temperature, water (100 mL) was added and the mixture was stirred for 1 h. Solid was removed by filtration. The filtrate was acidified to pH˜4 with 1 M aqueous HCl. The resulting precipitate was collected by filtration and further washed with water (20 mL×2), then Et2O (10 mL×2). After drying under vacuum for 3 h, the title compound (2.6 g) was obtained as a light yellow solid. HPLC/MS: retention time=0.76 min, [M+H]+=189.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([NH:10][C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>C1COCC1>[Br:3][C:4]1[C:5]([N:10]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN(C(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1)c1ncccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 117 mg, 4.88 mol) was added in portions over 10 min to a solution of benzyl 4-{2-[(3-bromopyridin-2-yl)amino]-2-oxoethyl}-3,6-dihydropyridine-1(2H)-carboxylate (1.91 g, 4.43 mol) in THF (15 mL) at 0° C. After 0.5 h, 2-(trimethylsilyl)ethoxymethyl chloride (0.861 mL, 4.88 mol) was then added slowly, keeping the temperature of the reaction mixture below 10° C. After 4 h, sodium hydride (60 mg) and 2-(trimethylsilyl)ethoxymethyl chloride (0.45 ml) were added and the reaction allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 40 to 70% ethyl acetate:hexanes to give the title compound (1.51 g). MS: m/z=560.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=1.C(=O)([O-])O.[Na+].Br[CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[CH3:1][N:2]([CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=1
Reactant: CCOC(=O)Cc1cccc(NC)c1
Reactant: CCOC(=O)c1ccccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1cccc(N(C)Cc2ccccc2C(=O)OCC)c1
Yield: 68.3 %

Procedure:
The starting material employed above had been synthesized in the same manner as described in Example 1. That is, N-methyl-3-ethoxycarbonylmethylaniline (20.7 g), sodium hydrogencarbonate (19 g), water (30 ml) and ethyl 2-bromomethylbenzoate (27.5 g) were used to produce N-methyl-N-(2-ethoxycarbonylbenzyl)-3-ethoxycarbonylmethylaniline (26 g) as a light yellow oil. Then, N-methyl-N-(2-ethoxycarbonylbenzyl)-3-ethoxycarbonylmethylaniline (26 g) so produced, sodium hydroxide (40 g), water (450 ml) and ethanol (150 ml) were used to prepare N-methyl-N-(2-carboxybenzyl)-3-carboxymethylaniline (14.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)=[CH:11][C:10]([C:24](O)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([F:23])[CH:14]=3)=[CH:11][C:10]([C:24]([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: O=CO
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(C(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 97A in analogy to the synthesis of the compound of Example 23 with the addition of 0.1% formic acid in the preparative HPLC. 60 mg (51% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2ccc(C(=O)Cl)cc2)c1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
The 4-(4-methylpyrazol-1-yl)benzoyl chloride (0.72 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.60 g) and diisopropylethylamine (0.48 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.75 g), m.p. 179-181° C.; MS m/z: 369 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(OC(=O)[NH:39][CH2:40][CH2:41][NH2:42])(C)(C)C.Cl>>[ClH:1].[NH2:39][CH2:40][CH2:41][NH:42][C:12](=[O:14])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:31])([F:30])[F:32])[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21
Agent: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl, the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][SH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH2:6][CH2:5]1.[CH:27]([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28]>>[CH:27]([NH:29][CH:30]([CH2:31][CH2:32][S:33][CH3:34])[C:35](=[O:36])[S:19][CH2:18][C:17](=[O:20])[C@:16]1([OH:24])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:26])[C:9](=[CH:8][C:7](=[O:25])[CH2:6][CH2:5]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1)=[O:28]
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CS
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 26.7 %

Procedure:
The title compound (0.38 gm) was prepared from 11β,17-dihydroxy-pregna-4-ene-3,20-dione-21-thiol (1.00 gm) and N-formyl-L-methionine (1.41 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [F:1][C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[C:3]([F:14])([F:13])[C:4]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:12])[NH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([N:33]2[CH2:32][CH2:31][N:30]([C:28](=[O:29])[CH2:27][N:6]3[C:7]([CH3:12])=[C:8]([N+:9]([O-:11])=[O:10])[C:4]([C:3]([F:13])([F:14])[C:2]([F:1])([F:19])[C:15]([F:17])([F:18])[F:16])=[N:5]3)[CH2:35][CH2:34]2)=[CH:41][CH:40]=1
Reactant: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1[N+](=O)[O-]
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])c(C(F)(F)C(F)(F)C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4, Rf=0.81) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.92–7.02 (m, 2H), 6.82–6.9 (m, 2H), 5.04–5.14 (m, 2H), 3.64–3.82 (m, 4H), 3.06–3.18 (m, 4H), 2.6–2.66 (d, 3H). 13C NMR (400 MHz, CDCl3): 160.4, 146, 144.2, 119.2, 118.2, 52, 50.8, 50.6, 46, 42, 12.2.
Reaction SMILES: [CH3:1][OH:2].[Na].Cl[C:5]1[N:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:17]=[C:13]2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1>C(O)(=O)C>[CH3:1][O:2][C:5]1[N:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:17]=[C:13]2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Reactant: CO
Agent: [Na]
Solvent: CC(=O)O
Product: COc1nc2c(c3nc(-c4ccccc4F)cn13)CCCC2

Procedure:
To 10 mL anhydrous methanol was added 100 mg of sodium, and the mixture was stirred to ensure all the sodium had dissolved. Next, 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg) was added and the mixture refluxed for 1 h. To this mixture was added 2 mL of acetic acid and the solvent was then removed under reduced pressure. The resulting solid was recrystallized from ethanol and collected to yield 5-Methoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 37), m.p. 160°-161° C.