Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14]CC)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.[OH-].[Li+]>CO.O1CCCC1.O>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Yield: 97.9 %

Procedure:
ethyl 6-chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carboxylate (3.95 g, 10 mmol) was dissolved in 50 mL methanol and 50 mL tetrahydrofuran. To the resulting mixture was added dropwise a solution of lithium hydroxide (1.26 g, 30 mmol) in water (50 mL). After the completion of the dropwise addition, the resulting mixture is reacted at room temperature for 4 hrs. The reaction was concentrated, and 200 mL water was added. The resulting mixture was adjusted with hydrochloric acid to pH=3. The solid was separated, and dried in vacuum to obtain a yellow solid (3.6 g).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].[CH3:19][CH2:20][C@:21]1([OH:76])[C@H:42]([C:43]([O:45][CH3:46])=[O:44])[C:25]2[CH:26]=[C:27]3[C:40](=[O:41])[C:34]4[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:33]=4[C:31](=[O:32])[C:28]3=[C:29]([OH:30])[C:24]=2[C@@H:23]([O:47][C@@H:48]2[O:53][C@@H:52]([CH3:54])[C@@H:51]([O:55][C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)C(=O)CC4)[C@@H](O)C3)[C@@H:50]([N:73]([CH3:75])[CH3:74])[CH2:49]2)[CH2:22]1>>[CH3:19][CH2:20][C@:21]1([OH:76])[C@H:42]([C:43]([O:45][CH3:46])=[O:44])[C:25]2[CH:26]=[C:27]3[C:40](=[O:41])[C:34]4[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:33]=4[C:31](=[O:32])[C:28]3=[C:29]([OH:30])[C:24]=2[C@@H:23]([O:47][C@@H:48]2[O:53][C@@H:52]([CH3:54])[C@@H:51]([OH:55])[C@@H:50]([N:73]([CH3:75])[CH3:74])[CH2:49]2)[CH2:22]1
Reactant: CC[C@@]1(O)C[C@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]3C[C@H](O)[C@H](O[C@H]4CCC(=O)[C@H](C)O4)[C@H](C)O3)[C@H](C)O2)c2c(cc3c(c2O)C(=O)c2c(O)cccc2C3=O)[C@H]1C(=O)OC
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Agent: [K+]
Product: CC[C@@]1(O)C[C@H](O[C@H]2C[C@H](N(C)C)[C@H](O)[C@H](C)O2)c2c(cc3c(c2O)C(=O)c2c(O)cccc2C3=O)[C@H]1C(=O)OC
Reaction time: 72 h

Procedure:
When the fermentation was carried out at 28° C. with shaking using one of the suitable media at pH 6.9, i.e. 2% glucose, 2% potato starch, 2.5% "Meat", 0.1% KH2PO4, 0.1% MgSO4.7H2O, 0.0007% CuSO4.5H2O, 0.0001% FeSO4.7H2O, 0.0008% MnSO4.4H2O and 0.0002% ZnSO4.5H2O, the pH of the medium dropped to 5.25 to 5.10 in 20 hours and the growth of mycelium increased at 10 hours after inoculation. Thereafter, pH rose to 7.0 to 7.5 on 3 days and aclacinomycin A and B reached a maximum, i.e. 46 mcg./ml. of A and 23 mcg./ml. of B in the broth. In order to isolate aclacinomycin, the antibiotic may be extracted with a suitable solvent either from the cultured broth "in toto" without filtering the mycelium mass or from the mycelium and the culture liquid previously separated by filtration. Most of the antibiotics exist in the filtration cake which consists of the mycelium admixed with the diatomaceous earth. Thereafter, the filtration cake is pulped and stirred in an organic solvent for the extraction of antibiotics. Suitable solvents are alcohols such as methanol, ethanol, butanol, ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, methylene chloride, benzene or aqueous solutions of organic or inorganic acids such as acetic acid, hydrochloric acid, sulfuric acid. Preferred are acetone, ethyl acetate, mixtures of organic solvents such as alcohols and water-immiscible ketones and aqueous solution of inorganic or organic acids.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15].C([BH3-])#N.[Na+].Cl>CO>[C:14]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:28])=[CH:24][CH:25]=1)([O:16][CH3:17])=[O:15]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Yield: 92 %

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one and sodium cyanoborohydride in methanol (reaction time: 5 hours) followed by purification on a silica gel column using methylene chloride/methanol =20:1. This results in a 50:50 diastereomer mixture of the base. This is recrystallised from a mixture of ether/ethyl acetate =65:10. The mother liquor resulting from this is mixed with ethereal hydrochloric acid, and the mixture is evaporated to dryness. The residue resulting from this is recrystallised from a mixture of ether/ethyl acetate/methanol =100:60:1. The mother liquor obtained after the crystals have been removed by filtration is evaporated to dryness, and the base is liberated by shaking with alkali and methylene chloride and purified on a silica gel column using methylene chloride/methanol =20:1 as eluant. This results in diastereomer B as an oil approximately 92-94% pure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1.ClC(Cl)(Cl)[C:35]([N:37]=C=O)=[O:36]>N1C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][N:30]([C:35](=[O:36])[NH2:37])[CH2:29][CH2:28]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCNCC1
Solvent: c1ccncc1
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(N)=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
4-(7-Azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (200 mg, 0.46 mmol) was dissolved in pyridine (5 ml) and cooled to 0° C. Trichloroacetyl isocyanate (55 μl, 0.46 mmol) was added and the mixture stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography eluting with methylene chloride/methanol (90/10) to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-carbamoylpiperazin-1-yl)propoxy]quinazoline (95 mg, 43%) as a white solid.
Reaction SMILES: C(O[CH:4](OCC)/[CH:5]=[CH:6]/[CH3:7])C.[C:11]([C@H:17]([C@@H:19]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[OH:20])[OH:18])([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]>C1C=CC=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH:5](/[CH:4]1[O:20][C@H:19]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C@@H:17]([C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])[O:18]1)=[CH:6]\[CH3:7]
Reactant: C/C=C/C(OCC)OCC
Reactant: CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: C/C=C/C1O[C@H](C(=O)OC(C)C)[C@@H](C(=O)OC(C)C)O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 55.3 %

Procedure:
A solution of (2E)-1,1-diethoxybut-2-ene (32.20 g, 223.27 mmol), (−)-diisopropyl D-tartrate (64.64 mL, 245.60 mmol) and pyridinium tosylate (2.24 g, 8.93 mmol) in 100 mL benzene was heated to 95° C. to distill off the solvent and EtOH produced. After 7 h at 95° C., the reaction was cooled to rt and concentrated in vacuo. Purification by normal phase chromatography (10->30% EtOAc/hexanes) yielded 35.37 g (55%) of diisopropyl (4S,5S)-2-[(1E)-prop-1-enyl]-1,3-dioxolane-4,5-dicarboxylate as an orange oil. 1H NMR (CDCl3, 400 MHz) 6.03 (m, 1H); 5.86 (m, 2H); 5.12 (m, 2H); 4.71 (d, J=3.84 Hz, 1H); 4.63 (d, J=3.84 Hz, 1H); 1.78 (m, 3H); 1.30 (d, J=6.23 Hz, 12H); LC/MS [M+H]+=287.
Reaction SMILES: CS([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[S:8]1)(=O)=O.[OH-].[NH4+].C[NH:39]C>O1CCCC1>[NH2:39][CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[S:8]1
Reactant: CNC
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2C=CC(CCS(C)(=O)=O)Sc3ccccc32)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2C=CC(CCN)Sc3ccccc32)cc1

Procedure:
A mixture of Compound 13 as prepared in Example 10 (0.050 g, 0.09 mM) in tetrahydrofuran (4 ml) was treated as described in Example 12 with ammonium hydroxide (1 ml) substituted for dimethylamine to give a white solid product. m/z (MH+)446
Reaction SMILES: [Si]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([N:16]([C:19]2[C:20]([Cl:30])=[N:21][N:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=2)[CH2:17][CH3:18])=[O:15])[C:9]1=[O:31])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:30][C:20]1[C:19]([N:16]([CH2:17][CH3:18])[C:14](=[O:15])[CH2:13][CH:10]2[CH2:11][CH2:12][NH:8][C:9]2=[O:31])=[CH:23][N:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=1
Reactant: CCN(C(=O)CC1CCN([Si](C)(C)C(C)(C)C)C1=O)c1cn(-c2cccnc2)nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(C(=O)CC1CCNC1=O)c1cn(-c2cccnc2)nc1Cl
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
DIPEA (0.629 mL, 4.41 mmol) was dissolved in THF (20 mL) and cooled to about −78° C. n-Butylithium (1.77 mL, 4.41 mmol) was then added, and the reaction mixture was warmed to about 0° C. for 10 minutes, then re-cooled to about −78° C. Then, 1-(tert-butyldimethylsilyl)pyrrolidin-2-one (0.800 g, 4.01 mmol) was added, and the reaction mixture was warmed to 23° C. and stirred for 1 hour. The reaction was then re -chilled to −78° C., and 2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.600 g, 2.01 mmol) was then added dropwise as a solution in THF (3 mL). The reaction mixture was stirred cold for 30 minutes, then was allowed to slowly warm to room temperature. After 1 hour, the reaction was quenched with a NH4Cl solution and extracted with diethyl ether. The organics were washed with brine, dried over Na2SO4, and concentrated. The resulting oil was purified by flash column chromatography using 0-40% acetone/hexanes as eluent provided the intermediate 2-(1-(tert -butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol). 1H NMR analysis indicated a mixture of molecules present favoring the desired product of about 5:1 over main byproduct. The mixture carried through to the deprotection step without further purification. 2-(1-(tert-Butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol) was dissolved in THF (13 mL) and added was tetrabutylammonium fluoride (TBAF, 1.96 mL, 1.96 mmol). The reaction mixture was stirred for 30 minutes. The reaction product was concentrated onto CELITE® and purified by flash column chromatography using 40-100% acetone/hexanes as eluent providing the title compound (0.204 g, 30% over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].OO.S([O-])([O-])(=[O:29])=S.[Na+].[Na+].C(O)C.O>ClCCl.C(O)(C)(C)C.[O-2].[O-2].[O-2].[O-2].[O-2].[V+5].[V+5]>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: [V+5]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 140.4 %

Procedure:
2-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (1.77 g) was dissolved in dichloromethane (30 ml), to which was added dropwise at 15°-20° C. a solution of hydrogen peroxide in t-butanol (2.75 ml corresponding to 0.2 g of hydrogen peroxide) containing vanadium pentaoxide (5 mg), and then allowed to react at 20°-25° C. for about one hour. After completion of the reaction, an aqueous solution of sodium thiosulfate (0.5 g/30 ml) was added to the reaction mixture, which was stirred vigorously for about 10 minutes, allowed to stand still, and separated into layers. The dichloromethane layer was washed with water (30 ml), and concentrated under reduced pressure; to the residue was added a mixture of ethanol-water (9:1, 10 ml) for crystallization. This solution was ice-cooled, and the crystals were collected by filtration and washed with an ice-cooled mixture of ethanol-water (8:2). The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 10 ml), heated (65°-70° C.) and stirred for dissolution of the crystals, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization, and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2) and dried in vacuo to give white crystals of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (1.64 g). (yield: 93.2%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(N(CC)CC)C>C(O)C>[NH2:20][C:19]1[N:10]([C:4]2[C:3]([F:2])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cnn(-c2c(F)cccc2F)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(2,6-difluorophenyl)hydrazine hydrochloride (12.38 g, 68.56 mmol) in anhydrous ethanol (70 mL) was added 2-(ethoxymethylene)malononitrile (8.791 g, 71.98 mmol) followed by triethylamine (10.01 mL, 71.98 mmol), and the contents stirred at RT for 10 min and then heated to reflux for 1.5 h. The contents were cooled to RT and solvents removed under reduced pressure. The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc. The EtOAc layer was separated, washed with 50 mL of brine, dried and concentrated. The concentrated solid was stirred in 50 mL of hexanes for 5 min, filtered through a flitted funnel, and dried in a vacuum oven at 45° C. for 2 h to afford 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile as a brown solid. This material was used without further purification. MS (ES+): 221.1 (M+H)+. (B): A mixture of 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile (14 g, 64 mmol) in 50 mL of concentrated HCl was refluxed for 10 h. The reaction mixture was concentrated to half of its volume, cooled with an ice bath, pH adjusted to about 10 with 10 N NaOH, and extracted with 3×100 mL of EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford 1-(2,6-difluorophenyl)-1H-pyrazol-5-amine as a brown amorphous solid. This material was used without further purification. MS (ES+): 196.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (346 mg, 74%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[F-:17].[Cs+]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH3:16])[N:3]=[C:2]2[F:17]
Reactant: CCCOc1cc2c(Cl)cccc2c(Cl)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCOc1cc2c(Cl)cccc2c(F)n1
Temperature: 140 °C

Procedure:
To a solution of 1,5-dichloro-3-propoxyisoquinoline (565 mg, 2.206 mmol) in DMSO (5 mL) was added CsF (369 mg, 2.427 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. Crude material purified via silica gel chromatography (90 g column; 0-40% EtOAc:Hex) to get the product 5-chloro-1-fluoro-3-propoxyisoquinoline (440 mg, 83% yield) as a yellow solid. MS: MS m/z 240.05(M++1).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH2:39])=O)=[CH:34][CH:33]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:36]([C:35]5[CH:40]=[CH:41][C:32]([O:31][CH3:30])=[CH:33][CH:34]=5)=[N:38][N:39]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: COc1ccc(C(=O)NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Yield: 36.3 %

Procedure:
The procedure described in example 123 using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (400 mg, 1.25 mmol), triethylamine (0.5 mL, 3.7 mmol) and 4-methoxy benzhydrazide (415 mg, 2.5 mmol) was used to prepare the title compound (175 mg, 37% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.71 (s, 1H), 8.16 (d, 1H), 8.0–8.1 (m, 4H), 7.75 (d, 1H), 7.45 (t, 2H), 7.1 (d, 2H), 3.88 (s, 3H), ES-MS (m/z) 386 [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[CH2:1]([N:8]([CH2:19][CH:18]([OH:20])[CH2:17][O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: ONCc1ccccc1
Solvent: CC(C)O
Product: OC(COc1ccccc1)CN(O)Cc1ccccc1
Yield: 35 %

Procedure:
The procedure of Example 1 is repeated using 3.5 g of N-benzylhydroxylamine and 6.16 g of phenylglycidyl ether in 50 ml of isopropanol. Purification by liquid chromatography affords the title compound in 35% yield as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:17])[CH2:12][NH:13][CH:14]2[CH2:16][CH2:15]2)=[CH:5][C:4]=1[Cl:18]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:17])[CH2:12][NH:13][CH:14]2[CH2:15][CH2:16]2)=[CH:5][C:4]=1[Cl:18]
Reactant: N#Cc1cc(C(=O)CNC2CC2)cc(Cl)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CC2)cc(Cl)c1N

Procedure:
m.p. of the hydrochloride: 175°-177° C., was prepared from 4'-amino-3'-chloro-5'-cyano-2-cyclopropylamino-acetophenone analogous to Example 48.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>ClC(Cl)C>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:7]1[N:6]([N:5]2[C:4](=[O:11])[C:3]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]3[C:1]2=[O:16])[CH:10]=[CH:9][CH:8]=1)=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: O=C(Cl)c1ccccc1F
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(c1ccccc1F)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a mixture of N-phthalimidopyrrole (10 g, 47 mmole) and fused zinc chloride (10 g, 73 mmole) in 80 ml dichloroethane was added o-fluorobenzoyl chloride (7.5 g, 47 mmole). The reaction mixture was stirred at ambient temperature for twenty hours and at 80° for one hour. Thereafter, it was cooled, poured into water and extracted with dichloromethane. The organic extract was washed with water and with saturated sodium chloride solution, and dried over magnesium sulfate. The solution was filtered and evaporated to an oil which yielded a solid upon trituration with ethanol (yield 11 g, m.p. 180°-190°). This material was purified by column chromatography (silica gel, dichloromethane) to give 3 g solid. This material was recrystallized from isopropanol to give 2.6 g (17%) crystals, m.p. 202°-203°.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]2[C:10]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][C:6]=12.[F:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][N:5]3[C:10]([N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[N:7][C:6]=23)[CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Brc1c(-c2ccccc2)nn2c(N3CCCC3)ccnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(-c2c(-c3ccccc3)nn3c(N4CCCC4)ccnc23)ccn1
Temperature: 110 °C
Yield: 31.6 %

Procedure:
3-Bromo-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine (150 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (4 mL). To this solution was added dichlorobis(tripenylphosphine)palladium (II) (60 mg, 0.09 mmol), 2-fluoropyridin-4-ylboronic acid (92 mg, 0.66 mmol), sodium carbonate (185 mg, 1.76 mmol) and a few drops of water. The resulting solution was heated at 110° C. for 24 hours. The resulting mixture was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting black residue was purified by silica gel chromatography (ethyl acetate:hexane 1:1) to give 50 mg (32%) of the title compound as a white solid. 1H NMR (CDCl3):δ 8.17 (d, 1H), 8.08 (d, 1H), 7.60 (m, 2H), 7.41 (m, 4H), 7.24 (broad s, 1H), 5.87 (d, 1H), 4.06 (broad s, 4H), 2.07 (broad s, 4H); 19F NMR (CDCl3):δ −-69.34; MS m/z 360 (M+1).