Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][C:8]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[CH:22][CH:23]=2)[CH:31]=[CH:35][CH:34]=[CH:33]1
Reactant: CCOC(=O)C(NC(=O)CCc1ccc(N)cc1)C(=O)OCC
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(NC(=O)CCc1ccc(-n2cccc2)cc1)C(=O)OCC
Temperature: 65 °C

Procedure:
4,6 g of diethyl 4-aminobenzylacetamidomalonate in 104 ml of acetic acid are placed in a three-necked flask which is maintained under nitrogen. 7.02 g of sodium acetate are added, followed by 1.87 ml of 2,5-dimethoxytetrahydrofuran. The mixture is heated at 65° C. for 1 h 15 min, then cooled down and extracted with 100 ml of dichloromethane and 100 ml of distilled water. The aqueous phase is separated off after settling and then washed with 3 times 100 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water and then with 100 ml of a saturated solution of NaCl, separated off after settling and then dried over magnesium sulphate; the phases are filtered and then evaporated to dryness under reduced pressure (50 kPa) in order to yield 6.2 g of a solid which is purified by flash chromatography (eluent CH2Cl2/acetone 75/25 by volume). This results in 3.57 g of diethyl 4-(1-pyrrolyl)benzylacetamidomalonate in the form of a beige solid which melts at 110° C.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1COCC1>[CH2:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
At 0° C., 1.32 g (33 mmol) of 60% NaH was added to a solution containing 5.2 g (30 mmol) of 1,4-dioxaspiro[4,5]decan-8-ylmethanol dissolved in 75 ml of THF. After stirring for 10 minutes, benzyl bromide (50 mmol) was added and the mixture was stirred for 18 hours at room temperature. Then, the reaction solution was neutralized with 1N aqueous hydrochloric acid solution, and concentrated under reduced pressure. The residue was dissolved in ether, washed twice with water and once with brine, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography to obtain 8-(benzyloxymethyl)-1,4-dioxaspiro[4,5]decane (6.0 g, 77%) as a colorless clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4]N=1.NC1ON=C(C(C)(C)C)C=1>C(#N)C>[C:5]([CH2:6][C:2]#[N:1])(=[O:4])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)no1
Agent: CC(C)(C)c1cc(N)on1
Solvent: CC#N
Product: CC(C)(C)C(=O)CC#N

Procedure:
This invention relates to a method for optimizing the yield of 3-amino-5-(t-butyl)isoxazole over the yield of the isomeric 5-amino-3-(t-butyl)isoxazole. The method is carried out in a stepwise manner utilizing in a first step the reaction of a lower alkyl pivalate with acetonitrile in the presence of a base to yield pivalyl acetonitrile, which pivalyl acetonitrile is then reacted with hydroxylamine under carefully controlled conditions of pH to yield a preponderance of 3-amino-5-(t-butyl)isoxazole.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:6][CH:5]=1.C1COCC1.O.[OH-].[Li+].Cl>O>[CH:10]1([C:8]2[C:7]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:22])=[O:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
5-Cyclohexyl-6-(2,2,2-trifluoroethoxy)nicotinic acid methyl ester (95 mg, 299 μmol) was combined with THF (4 mL) and water (2 mL) to give a light yellow solution. Lithium hydroxide hydrate (25.1 mg, 599 μmol) was added under argon. The reaction mixture was stirred at ambient temperature over night; poured into 6 mL 2 M HCl solution and extracted with i-propyl acetate (2×60 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give the title compound (92 mg, quant.) as white solid that was used in the subsequent reactions without further purification; MS (ESI) 302.0 (M−H)−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:29]2[CH2:32][CH2:31][CH2:30]2)(O)[CH2:23][Si](C)(C)C)[N:16]=3)=[C:9]([F:33])[CH:8]=1.[H-].[K+]>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[CH2:23])[N:16]=3)=[C:9]([F:33])[CH:8]=1
Reactant: C[Si](C)(C)CC(O)(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1
Temperature: 65 °C

Procedure:
1-(2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)-1-cyclobutyl-2-(trimethylsilyl)ethanol (355.8 mg, 0.731 mmol) in THF (10.0 mL) was carefully added dropwise to potassium hydride (30 wt % in mineral oil; 293 mg, 2.193 mmol) (washed with hexanes (1×5 mL) to remove mineral oil) at 0° C. The resulting solution was heated at 65° C. for 3 h, and excess potassium hydride was then quenched by the sequential addition of water (4 mL) and sat. aq. NH4Cl (4 mL). THF was removed in vacuo, and the resulting mixture was diluted with EtOAc (100 mL) and sequentially washed with sat. aq. NH4Cl and brine. The combined aqueous layers were extracted with EtOAc, and all organic layers were then combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-30% EtOAc/hexanes) furnished 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclobutylvinyl)-thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 396.1; Observed: 397.1 (M++1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][CH2:18][CH2:19][C:20]3[CH:35]=[CH:34][C:23]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[C:30]([O:32]C)=[O:31])=[CH:22][CH:21]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCCN1Cc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCN1Cc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.5 mL 1 M NaOH solution are added to a solution of 33 mg (0.07 mmol) methyl 1-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-pyrrolidine-2-carboxylate (Example 2.14) in 5 mL MeOH and the reaction mixture is stirred for 4 h at RT. The mixture is evaporated down i.vac., combined with 5 mL water, extracted with 10 mL EtOAc and the aqueous phase is saturated with NaCl, during which time the product is precipitated. It is evaporated down again i.vac., the residue is combined with EtOH, filtered and the solvent is eliminated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].O>CS(C)=O>[N+:14]([C:9]1[CH:8]=[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Temperature: 100 °C
Yield: 64.7 %

Procedure:
28.4 g (0.33 mol, 5.5 eq) of piperazine is dissolved in 50 ml of DMSO. 6.4 ml (60 mmol) of 2-fluoronitrobenzene is added. The mixture is heated at 100° C. for 60 hours. After cooling, the reaction mixture is transferred into 530 ml of water. The precipitate formed is filtered and the filtrate extracted with Et2O. After drying on MgSO4 and concentration under vacuum, the crude product is purified by column chromatography (eluent CH2Cl2/MeOH 9:1) to produce 8.04 g of the expected compound in the form of an orange oil which crystallizes at room temperature (yield: 65%).
Reaction SMILES: C(#N)C.[C:4]([C:8]1[CH:9]=[C:10]([S:19][CH2:20][C@H:21]2[O:26][C:25](=[O:27])[CH2:24][C@H:23]([OH:28])[CH2:22]2)[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:34]>>[C:15]([C:12]1[CH:11]=[C:10]([S:19][CH2:20][C@@H:21]([OH:34])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:26])=[O:27])[CH:9]=[C:8]([C:4]([CH3:7])([CH3:5])[CH3:6])[C:13]=1[OH:14])([CH3:16])([CH3:18])[CH3:17]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)c1cc(SC[C@@H]2C[C@@H](O)CC(=O)O2)cc(C(C)(C)C)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)c1cc(SC[C@@H](O)C[C@@H](O)CC(=O)O)cc(C(C)(C)C)c1O
Temperature: -20 °C

Procedure:
To 1.6 ml of a solution of acetonitrile containing 150 mg (0.409 mmol) of (4R,6S)-6-[[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]methyl]-4-hydroxytetrahydropyrane-2-one was added 0.98 ml of 1N lithium hydroxide with stirring in an atmosphere of argon at -20° C. After 30 minutes thereto was added 3.9 ml of 0.1 M solution of citric acid, and an organic solvent was distilled away under reduced pressure at a temperature not more than 25° C. In ether was dissolved the residue and the mixture was washed with saturated brine solution, dried and distilled away under reduced pressure to give 157 mg of (3R,5S)-6-[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]-3,5-dihydroxyhexanoic acid. Thereto was added 3.9 ml (0.389 mmol) of 0.1 N sodium hydroxide which was ice-cooled, washed with ether and freeze-dried to give 151 mg of the desired compound (yield: 89%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][N:18]=1)[CH3:15].CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:23]([C:22]2[C:17]([S:16][CH2:14][CH3:15])=[N:18][CH:19]=[N:20][CH:21]=2)=[O:24])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1ncncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ncncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 1.04 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 1.00 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid, 1.57 g of EDCI hydrochloride, 73 mg of HOBt and 5 ml of pyridine was stirred at 60° C. for 4 hours. Water was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.94 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-Ethylsulfanylpyrimidine-5-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[CH:1]1([O:7][CH2:8][CH2:9][CH:10]=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCOC1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCOC1CCCCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.5 %

Procedure:
The obtained 3-cyclohexyloxypropan-1-ol (11.5 g, 72.9 mmol) was dissolved in dichloromethane (240 ml), and then molecular sieve 4 Å (58 g) and pyridinium chlorochromate (23.8 g, 0.11 mol) were added thereto in the ice bath followed by stirring under a nitrogen atmosphere for 1 hour and 40 minutes. The reaction solution was diluted with ether, and then the solution was filtered through Celite. The Celite was washed with diethyl ether, and this filtrate was added to the previous filtrate. The total filtrate was evaporated in vacuo, and the residue was purified roughly by chromatography on a silica gel column (elution solvent; n-hexane:ethyl acetate=20:1-10:1) to give a crude 3-cyclohexyloxypropionaldehyde (8.6 g).
Reaction SMILES: Cl.[O:2]=[C:3]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)=[O:7].O=[C:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.[BH3-]C#N.[Na+]>CO>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([N:28]2[CH2:29][CH2:30][CH:25]([N:10]3[CH2:11][CH2:12][C@@H:8]([C:6]([NH:5][CH2:4][C:3](=[O:2])[NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=4)=[O:7])[CH2:9]3)[CH2:26][CH2:27]2)=[CH:40][CH:39]=1
Reactant: COC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)[C@@H]1CCNC1)Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(N2CCC(N3CC[C@@H](C(=O)NCC(=O)Nc4cccc(C(F)(F)F)c4)C3)CC2)cc1
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of (3R)—N-(2-oxo-2-{[3-(trifluoromethyl)phenyl]amino}ethyl)pyrrolidine-3-carboxamide hydrochloride (130 mg, 0.370 mmol) in MeOH (1 mL) was added methyl 4-(4-oxopiperidin-1-yl)benzoate (95 mg, 0.407 mmol) and NaBH3CN (70 mg, 1.11 mmol). After overnight, the mixture was washed with EtOAc and NaHCO3 (sat. aq.), the organic phase was dried over MgSO4, concentrated, and subjected to flash chromatography (EtOAc) to generate the title compound as a white solid (45% yield, 2 steps). 1H-NMR (CDCl3) δ: 1.55-1.75 (m, 2H), 1.85-2.06 (m, 3H), 2.10-2.22 (m, 1H), 2.24-2.40 (m, 1H), 2.42-2.62 (m, 2H), 2.81-3.02 (m, 5H), 3.65-3.85 (m, 5H), 4.05-4.20 (m, 2H), 6.81 (d, J=8.9 Hz, 2H), 7.20-7.40 (m, 2H), 7.65-8.00 (m, 5H), 9.57 (s, 1H). MS m/z: 533 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH3:21]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][CH2:20][CH3:21])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2cccc(Cl)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a solution of 1,5-dichloroisoquinolin-4-ol (0.5 g, 2.33 mmol) in acetonitrile (15 ml) was added K2CO3 (0.96 g, 7.01 mmol) followed by ethyl iodide (0.72 g, 4.67 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1,5-dichloro-4-ethoxyisoquinoline (0.3 g, 53%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.26-8.24 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.78-7.76 (d, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 1H), 4.26-4.21 (m, 2H), 1.57 (t, J=7 Hz, 3H); MS: MS m/z 242.6 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18](NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.Br[C:28]1[C:29](Cl)=[C:30]([N+]([O-])=O)C(N)=N[CH:33]=1.CCN(C(C)C)C(C)C.Cl.C1(N2CCNCC2)C=CC=CC=1>C(O)(C)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:30]=[CH:29][CH:28]=[CH:33][CH:18]=3)[CH2:13][CH2:12]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: Cl
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(c3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 91 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (300 mg, 1.19 mmol), DIPEA (3.5 eq, 4.16 mmol, 0.72 mL), isopropanol (7 mL) and 1-phenylpiperazine hydrochloride (1.1 eq, 1.31 mmol, 260 mg). After 18 h the precipitate was filtered and washed with cold water (2×3 mL) to give the product (407 mg, 91%) as an orange solid; 1H-NMR (500 MHz, DMSO-d6) 3.20 (br s, 4H, piperazine N(CH2)2), 3.30 (hidden by DMSO peak, 4H, piperazine N(CH2)2), 6.83 (t, J=7.5 Hz, 1H, phenyl H-4), 6.98 (d, J=8.4 Hz, 2H, phenyl H-2 & H-6), 7.04 (br s, 2H, NH2), 7.25 (t, J=7.9 Hz, 2H, phenyl H-3 & H-5), 8.21 (s, 1H, pyridine H-6);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[N+:12]([C:15]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>COCCOC.O>[F:11][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:12]([O-:14])=[O:13])[CH:21]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2ccc([N+](=O)[O-])c(F)c2)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 45.3 %

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol), 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (660 mg, 2.50 mmol) and K2CO2 (940 mg, 6.81 mmol) were suspended in DME-H2O (4:1, 15 mL) and purged with nitrogen. The solution was degassed by sonication before Pd(dppf)Cl2 (185 mg, 10 mol %) was added. The mixture was heated to 130° C. for 10 min under microwave irradiation. The cooled mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resulting black solid was absorbed onto silica and purified by column chromatography (4:1 to 1:1 petrol-EtOAc) to give the product as an orange solid (285 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](C)[CH:18]=3)[N:13]([CH2:21][C:22]([OH:24])=[O:23])[C:12]=2[CH3:25])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OC(=O)CN1C2C(=CC(C)=CC=2)C(S(C2C=CC([Cl:50])=CC=2)(=O)=O)=C1C)C>>[Cl:50][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[C:12]([CH3:25])[N:13]2[CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(c1)c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O
Reactant: CCOC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2ccc(Cl)cc2n1CC(=O)O

Procedure:
The title compound was prepared by the method of example 2 part (d) using the product from part (c).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)(=[O:26])=[O:25])(=[O:17])=[O:16])[CH:5]=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH2:12].[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1>CN(C)C=O>[ClH:34].[CH3:1][C:2]1[CH:3]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)(=[O:25])=[O:26])(=[O:17])=[O:16])[CH:5]=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH:12][C:40]([NH2:41])=[NH:35]
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(C)CC2)c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A mixture of 3-[5-methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine (113 mg, 0.23 mmol), as prepared in the previous step, and 1H-pyrazole-1-carboxamidine hydrochloride (62 mg, 0.42 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at room temperature under nitrogen (balloon) for 18 hours. The solution was concentrated under high vacuum with heating and the residue was purified by flash chromatography (10% to 20% methanol in dichloromethane), then dissolved in dichloromethane, filtered and concentrated to give the title compound (105 mg, 80%) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.20 (m, 2H), 7.83 (td, 1H, J=7.7, 1.3 Hz), 7.70 (td, 1H, J=7.7, 1.2 Hz), 6.59 (m, 2H), 6.52 (m, 1H), 6.28 (m, 3H), 4.04 (t, 2H, J=5.8 Hz), 3.96 (t, 2H, J=5.8 Hz), 3.43 (m, 4H), 2.33 (s, 3H), 2.23 (s, 3H), 2.00 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C22H31N5O7S2: 542.2 (M+H), 564.2 (M+Na). Found: 542.3, 564.3.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:23])[CH:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH2:24]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:25][CH3:26]>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:23])[CH:13]([O:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCCCCCCCC(Br)C(=O)Nc1cccc2cnccc12
Reactant: CCCc1ccc(O)cc1
Product: CCCCCCCCC(Oc1ccc(CCC)cc1)C(=O)Nc1cccc2cnccc12

Procedure:
N-(isoquinolin-5-yl)-2-bromodecanoic amide, prepared according to the procedures described in Examples 3 and 25, was coupled with 4-propylphenol according to the procedure described in Example 6 to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1.[CH3:21]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Oc2cnc(Cl)c3ccccc23)nc1
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(Oc2ccc(C#N)cn2)c2ccccc12
Temperature: 80 °C

Procedure:
To a solution of 6-(1-chloroisoquinolin-4-yloxy)nicotinonitrile (Preparation 17) (300 mg, 1.1 mmol) in DMF (8 mL) under argon was added trimethylboroxine (148 μL, 1.1 mmol) followed by K2CO3 (442 mg, 3.2 mmol) and palladium tetrakistriphenylphosphine (123 mg, 0.1 mmol). The mixture was purged with argon for 5 min and then heated to 80° C. for 16 h. Solvent was removed in vacuo. The residue was partitioned between EtOAc (100 mL) and water (40 mL), the organic phase was washed with water (40 mL), NaHCO3 (40 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (2% MeOH: DCM) to give the title compound: RT=2.40 min; m/z (ES+)=262.4 [M+H]+.