Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A 12 L 3-necked round-bottomed flask was charged with DMF (2L), 5-nitroindazole (200 g, 1.22 mol.) and potassium carbonate (186 g, 1.35 mol). Benzyl bromide (230 g, 1.35 mol) was then added to the stirred suspension at a rate as to maintain the temperature below 40° C. Once the addition was complete the mixture was heated to 75° C. for a further 8 hours, the reaction being monitored by TLC (SiO2, 1:1 ethyl acetate:hexanes). The reaction was then cooled to room temperature, water (2L) added and the resulting slurry stirred at room temperature for 0.5 h. The resulting yellow solids were filtered off and dried at 45° C. and 5 mm Hg vacuum for 48 h. This afforded 424 g of a 1.25:1 mixture of 1- and 2-benzyl-5-nitroindazoles as determined by HPLC analysis (Rt 1-benzyl=14.9 min, Rt 2-benzyl=14.1 min). This material was then split into four approximately 100 g batches and each batch dissolved in acetone (470 mL). Water (156 mL) was then added slowly as a steady stream. After stirring for an additional 1 hour at room temperature the resulting solids were filtered off and vacuum dried. This process afforded a combined total of 126 g (41%) of 1-benzyl-5-nitroindazole, which was 92.1% pure by HPLC analysis, the major contaminant being the 2-benzyl derivative.
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH2:31]Br)=[O:27])=[CH:24][CH:23]=1>C(O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH2:31][S:1][C:2]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reactant: Cn1c(S)nc2ccccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2cccc(C(=O)c3ccc(Cl)cc3)c2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) and sodium hydroxide (250 mg) in 50% ethanol (15 ml)-DMF (15 ml) was added 3-(4-chloro-benzoyl)benzyl bromide (1.88 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixtrue was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (2.22 g). 1H-NMR (CDCl3) 8: 3.59(3H,s), 4.59(2H,s), 7.34-7.52(5H,m), 7.61-7.80(5H,m), 7.96(1H,d,J=2.0Hz), 8.22(1H,dd,J=8.0,1.4Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>C1COCC1>[CH3:15][N:16]([CH3:20])[C:17]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:18]
Reactant: CN(C)C(=O)Cl
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-hydroxypiperidine (5.0 g, 49 mmol) in THF (70 mL) was added triethylamine (14.4 mL, 103 mmol) and dimethylcarbamyl chloride (9.0 mL, 98 mmol) slowly. The mixture was stirred at room temperature for 1.5 hours. The white precipitate was filtered off, washed with THF. The THF solution was concentrated to dryness then purified with column chromatography (SiO2, MeOH/CH2Cl2=1:19) to afford 4-hydroxypiperidine-1-carboxylic acid dimethylamide as colorless oil. Yield: 7.8 g (94%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH:15](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[O:16]C.[Cl:32][C:33]1[C:38]([CH:39]=O)=[CH:37][C:36]([Cl:41])=[CH:35][N:34]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[CH3:13][O:14][C:15](=[O:16])[CH2:39][C:38]1[C:33]([Cl:32])=[N:34][CH:35]=[C:36]([Cl:41])[CH:37]=1
Reactant: O=Cc1cc(Cl)cnc1Cl
Reactant: COC(OC)P(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(Cl)cnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a −78° C. solution of diisopropyl amine (1.21 mL, 9.0 mmol) in tetrahydrofuran (100 mL) was added n-butyl lithium (3.45 mL, 2.5 M in hexanes, 9.0 mmol). The reaction mixture was stirred at −78° C. for 20 minute and 0° C. for 15 minutes, and then cooled to −110° C. To the cooled reaction mixture was added dimethoxymethyl diphenyl phosphine oxide (2.18 g, 8.0 mmol) in tetrahydrofuran (120 mL) and then 2,5-dichloro-pyridine-3-carbaldehyde (1.37 g, 8.0 mmol) in tetrahydrofuran (15 mL) while keeping the reaction temperature less than −100° C. The reaction mixture was stirred at −110° C. for 45 minutes and then quenched with water (50 mL), extracted with diethyl ether and washed with brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was azeotroped with toluene and then dissolved in tetrahydrofuran (80 mL) and treated with potassium tert-butoxide (0.97 g, 9.0 mmol) at ambient temperature. After stirring for 2 hours the dark solution was treated with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.61 g).
Reaction SMILES: P(=O)(O)(O)O.O.[CH2:7]([N:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:15]1[CH2:19][C@H:18]([C:20]([O-:22])=[O:21])[C@H:17]([CH3:23])[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1([C@H](N)C)C=CC=CC=1>CC(OC)(C)C>[CH2:24]([N:14]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C@@H:15]1[CH2:19][C@H:18]([C:20]([OH:22])=[O:21])[C@H:17]([CH3:23])[CH2:16]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)C[C@@H]1C(=O)[O-]
Agent: C[C@@H](N)c1ccccc1
Agent: O=P(O)(O)O
Solvent: COC(C)(C)C
Solvent: O
Product: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)C[C@@H]1C(=O)O
Yield: 99.2 %

Procedure:
Phosphoric acid (11.40 mL, 196 mmol) was added to a flask containing water (500 mL). The solution was stirred for about 5 min. (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate•(R)-1-phenylethanamine (83 g, 187 mmol) was added to the solution in small portions. MTBE (500 mL) was added and the contents were mixed well, dissolving the solid. The phases were settled and separated. The aqueous layer was back extracted with MTBE (150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (60 g, 99%) as an oil: HPLC (Table 1, Method x) Rt=4.57 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH:15]([CH2:16][CH3:17])[CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>ClCCl>[CH:12]([CH:13]1[CH:15]([CH2:16][CH3:17])[CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:11]
Reactant: CCOC(=O)C1C(CC)C1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(C=O)C1CC
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of oxalyl chloride (0.21 mL, 2.4 mmol) in anhydrous dichloromethane (30 mL) at −78° C. under nitrogen atmosphere, dimethylsulfoxide (0.36 mL, 5.0 mmol) was added and stirred for 30 minutes. To this mixture, a solution of ethyl (1SR,2SR,3RS)-2-hydroxymethyl-3-ethylcyclopropane carboxylate (350 mg, 2.0 mmol) in anhydrous dichloromethane (20 mL) was added and reaction stirred at the same temperature for 45 minutes. Then, triethylamine (1.4 mL, 10.0 mmol) was added and the mixture was allowed to react at room temperature. After 30 minutes, the reaction was quenched with water (30 mL), the layers were separated and the aqueous one was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium anhydride, filtered and evaporated to dryness. The resulting residue was purified by column chromatography using ethyl acetate and hexane 1:4 as eluent to afford 310 mg (90% yield) of ethyl (1SR,2SR,3RS)-2-formyl-3-ethylcyclopropane carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:29]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:29]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1cccc(C(C)Cl)n1
Agent: Cl
Product: Cc1cccc(C(C)Sc2c(Cl)ccc3c2CCNCC3)n1

Procedure:
Use a method similar to the Example 315, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and (±)-2-(1-chloroethyl)-6-methylpyridine hydrochloride to give, after deprotection by a method similar to the General Procedure 1-4, the title compound as a tan solid. MS (ES+) m/z: 333 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11]C(O)=O)=[C:6]([F:15])[CH:5]=1.[Xe](F)[F:18].CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][F:18])=[C:6]([F:15])[CH:5]=1
Reactant: COC(=O)c1ccc(OCC(=O)O)c(F)c1
Reactant: F[Xe]F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCF)c(F)c1
Yield: 51.5 %

Procedure:
A solution of 4-carboxymethoxy-3-fluoro-benzoic acid methyl ester (2.73 g, 11.9 mmol) in CH2Cl2 was treated with xenon difluoride (2.23 g 13.1 mmol, 1.1 eq.) at r.t. for 16 hrs. in a teflon reactor vessel. After addition of satd. NaHCO3 solution the organic phase was dried over Na2SO4 and evaporated. The residue was chromatographed over 100 g SiO2 (Merck 230-400 mesh) with EtOAc/nHexane 1:4 affording the title compound (1.24 g, 51% yield) as a white solid. MS: m/e=202 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:12][CH2:11][CH2:10][Br:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1cccc(OCCCBr)c1
Reaction time: 24 h
Yield: 13.1 %

Procedure:
To a solution of 3-fluorophenol (0.040 mL, 0.448 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.450 mL, 4.43 mmol) followed by Cs2CO3 (0.246 g, 0.756 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0137 g, 13.2%). EI-MS Rt (2.28 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]Br.[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1>C1COCC1>[F:30][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C@H:18]2[CH2:17][CH2:16][C@H:15]([C@H:12]3[CH2:13][CH2:14][Si@H:9]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:11]3)[CH2:20][CH2:19]2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: Fc1ccc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Reactant: COCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
3.1 g (20 mmol) of 3-methoxypropyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.1 g (20 mmol) of 1-chloro-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the reacted mixture thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.5 g (yield 81%) of trans-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-(3-methoxypropyl)-1-silacyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]([CH3:12])[C:8]([O:10]C)=[O:9])=[CH:4][C:3]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=2)[C:18]([C:30]2[C:34]3[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:33]=3[O:32][N:31]=2)=[C:17]1[CH3:41].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]([CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][C:26]([F:28])([F:27])[F:29])[CH:23]=2)[C:18]([C:30]2[C:34]3[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:33]=3[O:32][N:31]=2)=[C:17]1[CH3:41]
Reactant: COC(=O)[C@@H](C)Oc1ccc(Cl)c(Cn2c(C)c(-c3noc4cc(OC)ccc34)c3ccc(OC(F)(F)F)cc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(-c3c(C)n(Cc4cc(O[C@H](C)C(=O)O)ccc4Cl)c4cc(OC(F)(F)F)ccc34)noc2c1
Reaction time: 2 h

Procedure:
To a solution of 15 (312 mg, 0.46 mmol) in aqueous methanol was added a solution of 1.0M NaOH (1.5 eq). After 2 hours, reaction was complete by TLC. The solution was concentrated and purified by preparatory LC (C18, 100×20 mm I.D., 5 um). Product was isolated as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12]C(O)=O)[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)c([N+](=O)[O-])c(F)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A mixture of (3,5-difluoro-4-nitrophenyl)acetic acid (41 g), potassium carbonate (24.6 g) and DMF (205 ml) was slowly heated to about 50° C. for 30 minutes. The reaction was then cooled to about 25° C. and quenched into 2M HCl (1025 ml) and hexane (400 ml) and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (400 ml). The combined hexane layers were washed with saturated brine (2×200 ml), then dried with anhydrous sodium sulphate and the solution was concentrated to give the title compound as a low melting solid (26 g).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][C:29]([S:33]([NH:36][CH2:37][CH2:38][CH2:39][N+:40]([CH3:43])([CH3:42])[CH3:41])(=[O:35])=[O:34])=[CH:28][C:27]=3[F:44])=[N:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][C:4]=1[O:45][CH3:46].[C:47]([O-:50])([O-])=[O:48].[K+].[K+]>CN(C=O)C>[Cl-:2].[C:47]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:36]([CH2:37][CH2:38][CH2:39][N+:40]([CH3:41])([CH3:43])[CH3:42])[S:33]([C:29]2[CH:28]=[C:27]([F:44])[C:26]([CH2:25][S:24][C:15]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:12]([C:9]([C:6]4[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:45][CH3:46])[CH:5]=4)([CH3:10])[CH3:11])=[CH:13][N:14]=3)=[C:31]([F:32])[CH:30]=2)(=[O:35])=[O:34])=[CH:5][CH:4]=1)([OH:50])=[O:48]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCC[N+](C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)N(CCC[N+](C)(C)C)Cc4ccc(C(=O)O)cc4)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 24 h
Yield: 187.8 %

Procedure:
To a solution of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorphenylsulfonamido)-N,N,N-trimethylpropan-1-aminium chloride (96 mg, 0.13 mmol) in DMF (2 mL) was added K2CO3 (80 mg, 0.58 mmol) and methyl-(4-bromomethyl)-benzoate (40 mg, 0.18 mmol) at 25° C. and the resulting suspension was stirred for 24 h. The reaction mixture was quenched into water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated to a colorless oil. The oil was reconstituted in THF (6 mL) and added to a solution of LiOH.H2O (420 mg) in water (10 mL) at 25° C. After 30 min the reaction was concentrated and adjusted to pH 1 with conc HCl. The aqueous layer was extracted with DCM, and combined extracts were dried (MgSO4) and concentrated to furnish the title product (104 mg, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=8.2 Hz, 2H), 7.62 (d, J=6.4 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 7.01 (t, J=8.7 Hz, 2H), 6.61 (dd, J=8.8, 4.9 Hz, 2H), 6.55 (d, J=1.8 Hz, 1H), 6.50 (dd, J=8.3, 1.9 Hz, 1H), 4.51 (s, 2H), 4.02 (s, 2H), 3.68 (s, 3H), 3.28-3.14 (m, 2H), 3.14-3.04 (m, 2H), 2.92 (s, 9H), 1.67 (d, J=8.3 Hz, 2H), 1.47 (s, 6H); MS (EI) m/z 815 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.O>COC(C)(C)C>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:9]
Reactant: C1COCCN1
Reactant: Cc1ccccc1OCc1ccccc1C(=O)Cl
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccccc1OCc1ccccc1C(=O)N1CCOCC1
Yield: 51.4 %

Procedure:
At 20 to 30° C., 2.6 g (0.01 mol) of 2-(2-methylphenoxymethyl)benzoyl chloride (EP-A 493 711, page 22) are added dropwise to a solution of 1.8 g (0.02 mol) of morpholine in 40 ml of tert-butyl methyl ether. The mixture is admixed with water and the organic phase is separated off, dried over sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from 5 ml of methanol. 1.6 g (51.4% of theory) of N-[2-(2-methylphenoxymethyl)-benzoyl]-morpholine are obtained.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C(C)C)=N2)C=CC=1C#N.[O:75]1CCN(C2C=CC(N)=CC=2)CC1>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:75])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccc(N4CCOCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccc(N4CCOCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 11 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(4-morpholinophenylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 4-morpholinoaniline instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (33) (the second stage yield: 11%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(4-morpholinophenylamino)benzonitrile instead of compound (1f).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([N+:23]([O-:25])=[O:24])[C:7]=1[OH:8]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2[N+](=O)[O-])c1=O
Reaction time: 0.5 h

Procedure:
3-(4-Chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.06 g) was added to ice-cold con. nitric acid (10 ml). After stirring for 30 min, crushed ice was added. The yellow crystals were collected by filtration to afford the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:21])[CH:14]([CH2:17][CH2:18][CH2:19][Cl:20])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]([OH:21])[CH:14]([CH2:17][CH2:18][CH2:19][Cl:20])[CH2:15][CH2:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2c(-c3ccc(Cl)cc3)noc2C=CC1CCCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1c2c(-c3ccc(Cl)cc3)noc2CCC1CCCCl
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 98.8 %

Procedure:
In 100 ml of anhydrous THF was dissolved 6.0 g 3-(4-chlorophenyl)-5-(3-chloropropyl)-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere. The solution was cooled to -5° C. and 840 mg sodium borohydride was added. The reaction mixture was stirred at 0° C. for 45 minutes and then warmed to 10° C. for 20 minutes. After cooling to 0° C., the reaction mixture was quenched with aqueous NH4Cl (saturated) then extracted with ether. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 6.0 g of 3-(4-chlorophenyl)-5-(3-chloropropyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole as an oil.