Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.P(=O)(O)(O)O>O.C(OCC)(=O)C>[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OC1CCCC1
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(C2CCCC2)c(O)c1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A round bottom flask equipped with stirrer bar was charged with resorcinol (150 g, 1.36 moles), cyclopentanol (125 ml, 1.38 moles) and phosphoric acid (85% in water) 500 ml. The flask was fitted with a reflux condenser, purged with nitrogen and the mixture heated at 120° C. (oil bath temperature) for 26 h. After this time, TLC analysis indicated that starting resorcinol was still present. Further cyclopentanol (25 ml, 0.28 moles) was added to the reaction mixture and heating continued for 2.5 hours. On cooling, the mixture was diluted with water (500 ml) and ethyl acetate (600 ml). The organic layer was separated, and the aqueous layer extracted with ethyl acetate (3×500 ml). The combined organic layers were neutralized by careful addition of an excess of saturated aqueous sodium hydrogen carbonate solution, washed with brine (300 ml), dried (magnesium sulfate) and concentrated. The residue was dissolved in toluene (500 ml) and water (20 ml, 1.11 moles, 0.8 eq) added. The solution was stirred for ca. 30 s and cooled in an ice/water batch with periodic stirring. After 4 h the solid was filtered and left to air dry in a crystallizing dish for 16 h to give colored crystals. Recrystallization in toluene afforded the monohydrate form of 4-cyclopentylresorcinol as white plates. An anhydrous toluene solution of 4-cyclopentylresorcinol was prepared via azeotropic distillation. The solution was cooled, and pentane added. Anhydrate A was obtained by filtration. MPt 65-66.5° C. Selected IR Data (υmax/cm−1): 1108.3 s, 1094.7 m, 977.8 s, 971.1 s, 930.4 w, 838.3 m, 826.7 s, 799.8 w, 748.1 w and 628.0 w.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([N+:12]#[C-:13])([CH3:11])([CH3:10])[CH3:9].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.Cl(O)(=O)(=O)=O>>[C:8]([NH:12][C:13]1[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:19]=1[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Nc1ccccn1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: O=Cc1cccs1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2cccs2)nc2ccccn12

Procedure:
Compound (23) was prepared in accordance with general instructions 2 from 2-aminopyridine, tert-butylisonitrile, thiophene-2-carbaldehyde, and perchloric acid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2ccnc(C=O)c2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(c2ccnc(CO)c2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 4-(2-methyl-[1,3]dioxolan-2-yl)-pyridine-2-carbaldehyde (195 mg, 1.01 mmol) was dissolved in MeOH (5 mL). NaBH4 (49 mg, 1.25 mmol) was added portionwise at 0° C. and the reaction mixture was stirred at rt for 1 h. Water was added and the mixture extracted with EA (3×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.41 min; [M+H]+=196.51.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.Br[CH2:27][CH2:28][O:29][CH3:30].[CH2:31]([NH2:35])[CH2:32][CH2:33][NH2:34]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][NH2:35])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:27][CH2:28][O:29][CH3:30])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCCN
Reactant: COCCBr
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(O)ccc3n2)Cc2ccccc21
Product: COCCOc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 30-1 by using 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-ol (prepared in analogy to the one in Example 29), 1-bromo-2-methoxyethane and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 471, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.05 (d, J=8 Hz, 1 H), 7.90-7.83 (d, J=7.6 Hz, 1 H), 7.77-7.68 (q, J=9.2 Hz, 2 H), 7.60-7.52 (m, 2 H), 7.42-7.36 (m, 1 H), 5.95 (s, 1 H), 5.30 (s, 2 H), 4.56-4.45 (m, 2 H), 4.22-4.18 (t, J=2.8 Hz, 2 H), 3.80-3.75 (t, J=2.8 Hz, 2 H), 3.75-3.70 (t, J=4.4 Hz, 2 H), 3.65-3.58 (t, J=6.8 Hz, 2 H), 3.42 (s, 3 H), 3.15-3.09 (t, J=7.6 Hz, 2 H), 2.16-2.05 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.Cl.[O:11]1CCOCC1>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([OH:11])[CH:3]=1
Reactant: Clc1cc(Br)cc(Cl)n1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(Br)cc(Cl)n1
Yield: 76 %

Procedure:
A solution of 4-bromo-2,6-dichloropyridine (1.0 equiv.) in dioxane and aqueous sodium hydroxide (15% by weight solution, 1:1 ratio, 0.55 M) was heated in the microwave for 30 min at 150° C. The solution was cooled to room temperature and neutralized with concentrated HCl (pH=˜6) and extracted with ethyl acetate three times. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was dried under vacuo to give 4-bromo-6-chloropyridin-2-ol as an off-white solid in 76% yield. LCMS (m/z) (M+H)=207.9/209.9, Rt=0.60 min.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([NH:6][C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH3:53][O:54][CH2:55][CH2:56]O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([C:25]([O:27][CH2:56][CH2:55][O:54][CH3:53])=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:32][CH:33]=1
Reactant: COCCO
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OC
Yield: 49.6 %

Procedure:
After dissolving 4-(4-(((4-fluoroanilino)carbonyl)amino) phenoxy)-7-methoxy-6-quinolinecarboxylicacid (84 mg, 0.19 mmol) in dimethylformamide (1 ml), there were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.28 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (38 mg, 0.28 mmol), triethylamine (0.079 ml, 0.56 mmol) and 2-methoxyethanol (0.15 ml) while stirring on ice, and the mixture was stirred overnight at room temperature. The reaction solution was directly subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (47.1 mg, 0.093 mmol, 49.6%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[C:23]4[O:27][CH2:26][O:25][C:24]=4[CH:28]=[CH:29][C:21]=3[O:20][CH2:19][CH2:18][O:17][CH3:16])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: COCCOc1ccc2c(c1B1OC(C)(C)C(C)(C)O1)OCO2
Product: CCOC(=O)c1c[nH]c2c(-c3c(OCCOC)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-(2-methoxy-ethoxy)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A34) the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][C@@H:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]45)=[N:25][C:21]=3[CH:20]=[C:19]([C:43]#[N:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][C@@H:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]45)=[N:25][C:21]=3[CH:20]=[C:19]([C:43](=[N:2][OH:3])[NH2:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (24.3 mg, 0.35 mmol), sodium bicarbonate (44 mg, 0.52 mmol), and water (0.52 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (85.8 mg, 0.175 mmol) dissolved in ethanol (1.2 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C27H34ClN7O2 [M+H]+ 524. found 524.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19](Cl)=[O:20])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].C(N([CH2:27][CH3:28])CC)C.[O:29]1CCCC1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([O:20][CH2:27][CH3:28])=[O:29])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)Cl)cc3c2n1
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]c3cnc(C(=O)OCC)nc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 150 mg of 8-chlorocarbonyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 19) in 5 ml of tetrahydrofuran is combined with a solution of triethylamine in ethanol at 4° C. until a pH of 8 is attained. The mixture is then stirred for 2 hours at room temperature and evaporated. After distribution in ethyl acetate/dilute ammonia solution, the organic phase is separated, dried, filtered, and concentrated. After chromatography over silica gel with methylene chloride/ethanol=10:1 as the eluent, 70 mg of 8-ethoxycarbonyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:2]3[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=3[NH:18][C:19]3=[CH:23][CH:22]=[N:21][N:20]23)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1cc[nH]n1
Reactant: O=C1CCCC(=O)C1
Product: O=C1CCCC2=C1C(c1ccc(F)cc1)n1nccc1N2

Procedure:
1,3-Cyclohexanedione, 4-fluorobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:26]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: ClCCCNc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCCCl)cc3)c2cc1OC
Yield: 37.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 3-Chloropropylaniline (66 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 26 mg of the title compound (yield: 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Br[CH2:12][N+:13]([O-:15])=[O:14].[Cl-:16].C[NH2+]C.[F-].[K+]>C1(C)C(C)=CC=CC=1.ClCCl.O>[Cl:16]/[C:12](/[N+:13]([O-:15])=[O:14])=[CH:7]\[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=[N+]([O-])CBr
Reactant: [Cl-]
Agent: C[NH2+]C
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C(\Cl)[N+](=O)[O-])cc1
Reaction time: 15 h

Procedure:
As in a procedure described in the literature [D. Dauzonne, Synthesis, 1990, 66-70], stir a mixture of 10.0 g (73.5 mmol) 4-methoxybenzaldehyde, 9.0 ml (13.5 g, 96.2 mmol) bromonitromethane, 53.9 g (661.0 mmol) dimethylammonium chloride and 0.6 g (1.0 mmol) potassium fluoride in 150 ml xylene on a water separator at 160° C. for 15 hours. After adding 25 ml water and 100 ml dichloromethane, separate the organic phase and extract the aqueous phase three times with 100 ml dichloromethane each time. Dry the combined organic extracts over sodium sulphate, filter and concentrate by vacuum evaporation. Chromatograph the residue on silica gel (solvent: cyclohexane/dichloromethane 1:1). 9.6 g (59% of theor.) of the target compound is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15].Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>C(#N)C.O>[C:7]1([CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:15]
Reactant: Cc1ccccc1CC(=O)O
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COC(=O)Cc1ccccc1C
Temperature: 25 °C

Procedure:
Potassium carbonate (25 g) was added to a stirred solution of o-tolylacetic acid (7.5 g) in acetonitrile (125 ml). The mixture was stirred for ten minutes at room temperature. Ethyl chloroacetate (6.13 g) was added and the mixture heated at reflux overnight. It was then poured into water, acidified with concentrated hydrochloric acid to pH2 and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated, and purified by column chromatography to give ethoxycarbonylmethyl o-tolylacetate. Potassium carbonate 15 g) was added to a stirred solution of this product (10 g) in dimethylformamide (100 ml). The mixture was stirred at room temperature for 72 hours and then heated at reflux overnight. The mixture was cooled to 0° C. and potassium carbonate (5 g) added, followed by methyl iodide (2.65 ml). The mixture was stirred at room temperature for 24 hours. The mixture was poured into water, extracted with ether and the extract washed with brine, dried and evaporated to give 3-(2-methylphenyl)-4-methoxyfuran-2(5 H)-one, as a gum. This was then treated with N-bromosuccinimide followed by reaction with 2-mecaptobenzothiazole, in a similar manner to that described in Example 1, to give 3-[2-[[(2-benzothiazolyl)thio]methyl]phenyl]-4-methoxyfuran-2(5H)-one m.p. 81°-82°. (Compound 2)
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN=C=NCCCN(C)C.[NH2:56][C@@H:57]([CH3:73])[CH2:58][N:59]1[CH:63]=[CH:62][C:61]([C:64]2[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[C:66]([Cl:72])[CH:65]=2)=[N:60]1>C(Cl)Cl>[C:1]([C:4]1[NH:5][N:6]=[C:7]([C:9]([NH:56][C@@H:57]([CH3:73])[CH2:58][N:59]2[CH:63]=[CH:62][C:61]([C:64]3[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[C:66]([Cl:72])[CH:65]=3)=[N:60]2)=[O:11])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (10.20 g, 66.2 mmol), DCM (195 ml) and DIPEA (11.52 ml, 66.2 mmol) were placed in to the reaction flask under nitrogen atmosphere. HBTU (3.27 g, 8.63 mmol), EDCI (12.68 g, 66.2 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (15 g, 57.5 mmol) were added in this order and the mixture was stirred overnight at RT. The solvent was distilled close to dryness under vacuum, 2-propanol (25 ml) was added and the mixture was distilled to dryness. 2-Propanol (127 ml) was added, heated to reflux, water (23 ml) was added and the mixture was stirred for 15 min. The mixture was cooled to RT, stirred overnight and cooled to 5° C. The precipitate was filtered, washed with 2×10 ml of cold 2-propanol:water (70:30) and dried under vacuum to obtain 18.7 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.17 (d, 3H), 2.50 (s, 3H), 4.21-4.53 (m, 3H), 6.93 (d, 1H), 7.31 (s, 1H), 7.81 (d, 1H), 7.86-8.07 (m, 3H), 8.40-8.54 (bs, 1H), 14.14 (bs., 1H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[I:15]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1.CCOCC.O>[F:6][C:7]1[C:8]([I:15])=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(F)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cccc(F)c1I
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 75.9 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 26 mL, 42 mmol) was added dropwise to a stirred, cooled (-78° C.) solution of 3-fluoroanisole (5.0 g, 40 mmol) in THF (150 mL) and the mixture was stirred at -78° C. for 2.5 h. Iodine (11.1 g, 43 mmol) in THF (50 mL) was added dropwise and the mixture was allowed to warm to room temperature. Water (200 mL), saturated aqueous sodium thiosulfate (100 mL) and ether (300 mL) were added and the layers were separated. The aqueous layer was extracted with ether (200 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (99:1) to give the title compound as a pale yellow oil (7.65 g, 77%). 1H NMR (360 MHz, CDCl3) δ 7.27 (1H, dt, Jd 6.6 Hz, Jt 8.2 Hz), 6.71 (1H, t, J 8.2 Hz), 6.62 (1H, d, J 8.2 Hz), and 3.90 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27]([OH:29])=O)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl-].Cl[CH:46]1[N:50](C)CC[NH+:47]1C.O.[CH3:54][C:55](N(C)C)=[O:56]>ClCCl>[O:56]1[CH:55]=[CH:54][C:46]([NH:50][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([N:17]3[CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[CH2:19][CH2:18]3)=[O:22])[CH:32]=[CH:31][CH:30]=2)=[O:29])=[N:47]1.[O:56]1[CH:55]=[CH:54][C:46]([NH:50][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([N:17]3[CH2:16][C:15]4[CH:14]=[N:13][C:12]5[N:8]([CH2:7][C:6]6[CH:33]=[CH:34][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)[N:9]=[CH:10][C:11]=5[C:20]=4[CH2:19][CH2:18]3)=[O:22])[CH:32]=[CH:31][CH:30]=2)=[O:29])=[N:47]1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)O)c2)CC4)cc1
Reactant: CC(=O)N(C)C
Reactant: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)Nc3ccon3)c2)CC4)cc1
Product: O=C(Nc1ccon1)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid (0.037 g, 80 μmol), isoxa-3-ylamine (8.8 μL, 120 μmol) and Hunig's Base (71 μL, 400 μmol) in dimethylacetamide (1 mL) and dichloromethane (1 mL) was added 2-chloro-1,3-dimethylimidazolinium chloride (DMC, 0.041 g, 240 μmol). The reaction mixture was shaken at room temperature for 16 hours followed by addition of water (2 mL) and dichloromethane (4 mL) were added. The organic layer was separated and the solvent removed under reduced pressure to give the desired product, N-(3-(isoxazol-3-ylcarbamoyl)phenyl)-3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide. LCMS [M+H]: 524. The crude product was used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5](F)=[C:6]([F:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl.[OH-].[NH4+:18]>>[NH2:18][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:13])[C:6]=1[F:14]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Yield: 64 %

Procedure:
Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) was dissolved in concentrated ammonium hydroxide (25 ml) to give instantly a yellow solution. A precipitate began to form within five minutes, after which time the mixture was acidified to pH 0 with concentrated aqueous hydrochloric acid. A yellow precipitate rapidly formed. The mixture was heated to boiling and was filtered hot. The yellow solids were washed with 10% aqueous hydrochloric acid and were suction dried to afford 0.47 g of a yellow powder; 64% yield; 1H-NMR (400 MHz; DMSO) δ 13.32 (s, 1H), 8.36 (d, 1H, J=7.6 Hz), 7.98 (s, 2H); 19F-NMR (376 MHz; DMSO) δ −128.69 to −128.76 (m), −153.60 (d).
Reaction SMILES: [I:1]Cl.[N+:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([O-:5])=[O:4].O>C(O)(=O)C>[I:1][C:11]1[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: ClI
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1I
Yield: 107.6 %

Procedure:
A solution of iodine monochloride (23.54 g) in acetic acid (50 ml) is added dropwise over an hour to a stirred solution of p-nitroaniline (20 g). After stirring for another hour, the dark mixture is poured into water (1 liter), the precipitated yellow solid is collected and dried to afford 41.15 g title product, m.p. 90°-95° C.