Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11]>CO.O>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1ccccc1
Yield: 86.2 %

Procedure:
10.0 mmol of Benzaldehyde was dissolved in 30 ml of 30% solution of CH3OH and H2O, and added into a triangular flask equipped with magnetic stirrer. 10.0 mmol of hydroxylamine hydrochloride was added under stirring. After hydroxylamine hydrochloride was dissolved, 5.0 mmol of dry and porphyrized sodium carbonate was slowly added. The reaction was carried out at room temperature. After the completion of the reaction monitored by TLC, methanol was removed from the system under reduced pressure. 30 ml H2O and dichloromethane (3×30 ml) were added to extract the mixture. The organic layers were combined, and then dried over anhydrous sodium sulfate. The solvent was removed to afford a crude product of benzaldehyde oxime in 86.2% yield. The crude material was directly used in the next reaction without separation and purification.
Reaction SMILES: [O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:21]([NH2:23])=[O:22])=[C:15]([N+:17]([O-])=O)[CH:16]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.COCCO.[Ni]>[O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:21]([NH2:23])=[O:22])=[C:15]([CH:16]=1)[NH2:17])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: COCCO
Solvent: CO
Product: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N

Procedure:
33.7 g of 5-phenoxysulfonyl-2-ureidonitrobenzene in 250 ml of methanol and 250 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After uptake of hydrogen is complete, the catalyst is filtered off with suction, washed with dimethylformamide and the solution is evaporated under reduced pressure, induced to crystallize with methanol, and the crystals are filtered off with suction and washed with methanol, melting point 180° C., decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:22][N:21]=2)=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1c[nH]cc1C(=O)c1cccnc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH]cc1-c1n[nH]c2ncccc12
Temperature: 80 °C
Yield: 16.3 %

Procedure:
A mixture of 4-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester (170 mg, 0.6 mmol) and hydrazine hydrate (0.8 g) in ethanol (10 mL) was heated at 80° C. for 24 hours. The reaction was concentrated, the residue was recrystallized to give 25 mg (16%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:17]([NH:25][C@@H:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:27]([OH:31])[C:28](O)=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:28](=[O:29])[C@H:27]([OH:31])[C@@H:26]([NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:3][CH:4]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: O=C(N[C@@H](c1ccccc1)[C@@H](O)C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)[C@H](O)[C@@H](NC(=O)c2ccccc2)c2ccccc2)cc1

Procedure:
Analogously to Example 1, Process step 1, 33 mg (0.15 mmol) of tert-butyl (4-aminobenzyl)carbamate and 43 mg (0.15 mmol) of (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionic acid were dissolved in 1 ml of DCM and 1 ml of DMF and treated successively with 78 μl of DIPEA (0.45 mmol), 22.5 mg of HOAt (0.165 mmol) and 76.9 mg (0.165 mmol) of PyBrop. Without further work-up, the batch obtained was filtered and then purified using HPLC. The product-containing fractions were lyophilized.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Cl[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:29][CH:28]=2)[CH2:24][NH:25][CH3:26])=[CH:19][CH:18]=1>>[CH3:26][NH:25][CH2:24][CH:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)=[CH:29][CH:28]=1)[C:20]1[CH:19]=[CH:18][C:17]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:21]=1
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: CNCC(c1ccc(-c2cccnc2)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 1 but substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and coupling to {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine*, the title compound was obtained. LC/MS: (PS-B3) Rt 2.42 [M+H]+ 355. 1H NMR (Me-d3-OD) δ 1.94 (AcOH, s), 2.72 (3H, s), 3.73 (2H, d), 4.46 (1H, t), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d), 7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d). * This starting material can be made by the method described in Example 21.
Reaction SMILES: [C:1]1([C:11]([O:13]C)=[O:12])[C:10]2[CH:9]=[CH:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([C:11]([OH:13])=[O:12])[C:10]2[CH:9]=[CH:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1C=CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c1C=CCC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5,6-dihydronaphthalene-1-carboxylate (0.276 g, 1.466 mmol) in methanol (30 ml) was added 1N aqueous sodium hydroxide solution (8.80 ml, 8.80 mmol) and the mixture was stirred at 70° C. for 8 hrs. The reaction solution was diluted with water, acidified with dilute hydrochloric acid and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was crystallized from hexane to give the objective substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[S:26]([O:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:4]1)([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1(CO)CN(C(=O)OC(C)(C)C)CCO1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
E3 (3.2 g, 11.62 mmol) was dissolved in pyridine (75 mL), p-toluenesulfonyl chloride (2.66 g, 13.95 mmol) was added in 4 portions in ca. 10 minutes and the solution was stirred for 15 h at RT. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed with 1 N HCl and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash column chromatography (heptane:EtOAc 100:0 to 40:60) yielding the title compound (4.0 g, 80%). MS (ES) C19H27NO8S requires: 429. found: 452.1 [M+Na]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:25][C:26]2([OH:39])[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH3:9].[OH-].[Na+]>ClCCl.O>[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:25][C:26]2([OH:39])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH3:9]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere a mixture of trifluoroacetic acid (40 mL) and dichloromethane (200 mL) was chilled in an ice bath. A solution of tert-butyl 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate (20 g, Example 4 Parts A through E) in dichloromethane (200 mL) was slowly added. The reaction mixture was allowed to warm to ambient temperature, stirred for 6 hours, and then concentrated under reduced pressure to provide a dark amber oil. The oil was dissolved in water (200 mL), the pH was adjusted to 13 with 50% sodium hydroxide, and the mixture was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 15.2 g of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol as a tan frothy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:32][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NC1CCCCC1
Product: O=S(=O)(Nc1cccc2nc(NC3CCCCC3)ccc12)c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=400.3 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 4-fluorobenzenesulfonyl chloride and cyclohexylamine.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:35]I>C1COCC1>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:34])[C@H:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH3:35])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: COc1ccccc1CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
As shown in step 5-ii of Scheme 5, to a solution of sodium hexamethyldisilazide (NaHMDS, 5.06 g, 26.2 mmol) in THF (100 mL) under an atmosphere of nitrogen at −78° C. was added (4S)-4-benzyl-3-[2-(2-methoxyphenyl)acetyl]oxazolidin-2-one (7.11 g, 21.9 mmol) and the reaction was stirred for 1.5 hours. Methyl iodide (3.08 g, 1.35 mL, 21.7 mmol) was then added dropwise and stirring continued at −78° C. for 4 hours, then the reaction was warmed to room temperature over 18 hours. The reaction was cooled to −20° C. and quenched with NH4Cl (sat). The organics were removed under reduced pressure and the aqueous layer was extracted with DCM (3×). The organic extracts were combined and washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (5 to 25% EtOAc in hexanes) to give (4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)propanoyl]oxazolidin-2-one as a white solid with a de of 9:1 (SIR). The solid was then purified via supercritical fluid chromatography (SFC) on an IC column (10% MeOH/CO2 isocratic gradient) to give (4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)propanoyl]oxazolidin-2-one (Compound 2015, 3.14 g, 41.8% yield) with an enantiomeric excess of 99.9% by analytical SFC: 1H NMR (300 MHz, CDCl3) δ 7.41-7.20 (m, 7H), 6.96 (dd, J=13.8, 6.6 Hz, 1H), 6.93-6.84 (m, 1H), 5.30 (q, J=7.1 Hz, 1H), 4.68 (qd, J=6.7, 3.5 Hz, 1H), 4.22-4.11 (m, 2H), 3.84 (s, 3H), 3.35 (dd, J=13.3, 3.2 Hz, 1H), 2.82 (dd, J=13.3, 9.7 Hz, 1H), 1.64-1.46 (m, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([C:13](=[O:15])[CH3:14])[C:6]=1[CH3:16])(=[O:3])[CH3:2].[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.N1[CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([CH3:16])=[C:7]2[C:8](=[CH:9][C:10]=1[CH3:11])[O:12][C:17]1([CH2:20][CH2:19][CH2:18]1)[CH2:14][C:13]2=[O:15])(=[O:3])[CH3:2].[OH:4][C:5]1[C:6]([CH3:16])=[C:7]2[C:8](=[CH:9][C:10]=1[CH3:11])[O:12][C:23]1([CH2:26][CH2:25][CH2:24]1)[CH2:14][C:13]2=[O:15]
Reactant: O=C1CCC1
Reactant: C1CCNC1
Reactant: CC(=O)Oc1c(C)cc(O)c(C(C)=O)c1C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1c(C)cc2c(c1C)C(=O)CC1(CCC1)O2
Product: Cc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution 3-acetyl-4-hydroxy-2,6-dimethylphenyl acetate (13 g) and cyclobutanone (4.5 g) in toluene (150 mL) was added pyrrolidine (5.4 mL, 4.6 g). The solution was stirred at room temperature for 15 min and then refluxed for 5 hours equipped with Dean-Stark water trap. The solution was diluted with ethyl acetate, washed with diluted hydrochloride acid water solution, water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate 1% to 10%) gave 5.5 g of 5,7-dimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate and 3.2 g of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]1[NH:10][C:9]2[CH:11]=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:8]=2[N:7]=1)C.[NH2:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[C:26]#[N:27].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[K]>C1COCC1>[NH2:27][C:26]1[C:25]2[C:24](=[CH:31][CH:30]=[CH:29][C:28]=2[F:32])[NH:23][C:4](=[O:22])[C:5]=1[C:6]1[NH:10][C:9]2[CH:11]=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:13]=[CH:14][C:8]=2[N:7]=1
Reactant: CCOC(=O)Cc1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Reactant: N#Cc1c(N)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3nc(-c4c(N)c5c(F)cccc5[nH]c4=O)[nH]c3c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (250 g, 820 mmol) (dried with ethanol as described above) was dissolved in THF (3800 mL) in a 5000 mL flask fitted with a condenser, mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-fluoro-benzonitrile (95.3 g, 700 mmol) was added to the solution, and the internal temperature was raised to 40° C. When all the solids had dissolved and the solution temperature had reached 40° C., solid KHMDS (376.2 g, 1890 mmol) was added over a period of 5 minutes. When addition of the potassium base was complete, a heterogeneous yellow solution was obtained, and the internal temperature had risen to 62° C. After a period of 60 minutes, the internal temperature decreased back to 40° C., and the reaction was determined to be complete by HPLC (no starting material or uncyclized intermediate was present). The thick reaction mixture was then quenched by pouring it into H2O (6000 mL) and stirring the resulting mixture until it had reached room temperature. The mixture was then filtered, and the filter pad was washed with water (1000 mL 2×). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50° C. overnight providing 155.3 g (47.9%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:18]1([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
The mixture of 2-[(naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (41) (220 mg, 0.61 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (42) as white solid (196 mg, 97%).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[C:20]3[N:21]=[CH:22][CH:23]=[C:24]([OH:25])[C:19]=3[CH:18]=[N:17]2)=[CH:13][CH:12]=1.O>CN(C=O)C>[Cl:8][C:23]1[CH:22]=[N:21][C:20]2[N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=3)[N:17]=[CH:18][C:19]=2[C:24]=1[OH:25]
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(O)c(Cl)cnc32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
NCS (1.57 g, 11.8 mmol) was added in one portion to a solution of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.00 g, 11.8 mmol) in DMF (30 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour and then cooled to room temperature. After 18 hours, an additional lot of NCS (0.5 eq.) was added to the reaction mixture and stirred at room temperature for an additional 48 hours. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed once with water (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 2% MeOH/CH2Cl2 to provide 5-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (466 mg, 1.61 mmol, 13.7% yield). LCMS (APCI+) m/z 290 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:20]=1[NH2:21].Cl>C1(O)CCCCC1.CCOCC>[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:20]=1[NH:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Agent: Cl
Solvent: CCOCC
Solvent: OC1CCCCC1
Product: COC(=O)c1cc2c(Nc3cc(O)c(C)cc3F)ccnc2cc1OC
Temperature: 100 °C

Procedure:
A suspension of 4-chloro-7-methoxy-6-methoxycarbonylquinoline (0.252 g, 1 mmol), (prepared as described for the starting material in Example 55), and 2-fluoro-5-hydroxy-4-methylaniline (0.15 g, 1.2 mmol), (prepared as described for the starting material in Example 1), in cyclohexanol (5 ml) containing 1M ethereal hydrogen chloride (1.2 ml) was heated at 100° C. for 2 hours. The mixture was cooled to ambient temperature and diluted with ether. The solid was collected by filtration then absorbed onto silica using methylene chloride/methanol (1/1) containing ammonium hydroxide (1 ml). The product was eluted with methylene chloride/methanol (100/0 increasing to 94:6). Removal of the solvent by evaporation and trituration of the solid with ether followed by collection of the solid by filtration gave 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxy-6-methoxycarbonylquinoline as a cream solid. (195 mg, 54%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Cc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F
Yield: 2.8 %

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-fluoro-4-methylbenzyl bromide (0.9 g) in place of benzyl chloride. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14; found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.42 (m, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.84-6.81 (m, 1H), 6.78-6.75 (m, 1H), 5.33 (s, 2H), 2.95-2.92 (m, 4H), 2.87-2.84 (m, 2H), 2.81-2.78 (m, 2H), 2.22 (s, 3H).
Reaction SMILES: Cl.[NH2:2][OH:3].Cl[C:5](Cl)(Cl)[CH:6]([OH:8])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.Cl>O>[N:2](=[CH:5][C:6]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:8])[OH:3]
Reactant: COc1ccc(N)cc1
Reactant: NO
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(NC(=O)C=NO)cc1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 11.4 g of hydroxylamine hydrochloride in water (50 ml) was added to a solution of chloral hydrate (9.6 g) and sodium sulfate (83 g) in water (200 ml) at 60° C. The mixture was held at 60° C. while, in a separate flask, a solution of 4-anisidine (6.4 g) and concentrated hydrochloric acid (4.3 ml) in water (80 ml) was warmed to 80° C. The first solution was then added to the second and the reaction was refluxed for 2 minutes, cooled slowly to room temperature and then cooled in an ice bath. The tan precipitate which formed was collected by vacuum filtration, washed with water and dried under vacuum to give 8.6 g (85% yield) of N-(2-hydroximinoacetyl)-anisidine.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[N:15]3[N:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:14]3[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:23][CH2:24][CH2:25][OH:26]>C(OCC)(=O)C>[Cl-:23].[OH:26][CH2:25][CH2:24][N+:3]1[CH:4]=[CH:5][N:1]([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[N:15]3[N:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:14]3[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH:2]=1
Reactant: Cc1cc(NCCCn2ccnc2)n2ncc([N+](=O)[O-])c2n1
Reactant: OCCCl
Solvent: CCOC(C)=O
Product: Cc1cc(NCCCn2cc[n+](CCO)c2)n2ncc([N+](=O)[O-])c2n1
Product: [Cl-]

Procedure:
3 g of (3-imidazol-1-ylpropyl)(5-methyl-3-nitropyrazolo[1,5-a]pyrimidin-7-yl)amine and 10 g of 2-chloroethanol were introduced into a 25 cc three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer and a condenser. The medium was refluxed for 6 hours. The reaction medium was poured into 160 cc of ethyl acetate and refluxed. The precipitate was filtered off at room temperature. This gave 3.8 g of 1-(2-hydroxyethyl)-3-[3-(5-methyl-3-nitropyrazolo[1,5-a]pyrimidin-7-ylamino)propyl]-3H-imidazol-1-ium chloride (beige powder) after drying under vacuum over phosphoric anhydride.