Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:3]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:4]=[N:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nc[nH]c1-c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.6 %

Procedure:
To a solution of 4-methyl-5-phenylimidazole (250 mg, 1.58 mmol) in 5 mL DMF at rt, were added TEA (242 μL, 1.74 mmol) and TrCl (485 mg, 1.74 mmol). The mixture was stirred at rt for 20 h, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford 504 mg of Intermediate 20.1 as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[CH2:25][CH3:26])C1C=CC=CC=1.[H][H].C>CN(C)C=O.[Pd].C(OCC)(=O)C>[CH2:25]([C:10]1[N:11]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14](=[O:15])[C:9]=1[OH:8])[CH3:26]
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(O)c(=O)ccn1CCOC(=O)C(C)(C)C
Yield: 534.9 %

Procedure:
To a solution of 3-benzyloxy-2-ethyl-1-(2-pivaloyloxyethyl)pyridin-4-one (0.5 g) in dimethylformamide (25 ml) was added 5% palladium on charcoal catalyst (0.1 g) and the reaction mixture was stirred at room temperature under a constant stream of hydrogen for 24 hours. The dimethylformamide was then removed under high vacuum by rotary evaporation to give an oil. The solid obtained on cooling the oil was dissolved in hot ethyl acetate and the solution treated with activated charcoal, refluxed for 5 minutes, filtered and rotary evaporated. The resultant residue was recrystalized from petroleum ether (boiling point 40°-60° C.) to give the title compound (2 g, 53%) as colourless crystals, m.p. 113°-115° C., νmax (nujol) 1580, 1630, 1725, 3130 cm-1 ; δ(90 MHz, CDCl3), 7.25 (1H, d), 6.43 (1H, d), 5.25 (1H, s, br), 4.29 (2H, t), 4.21 (2H, t), 2.85 (2H, q), 1.27 (3H, t), 1.28 (9H, s).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Br)(Br)[Br:39].C(Cl)(Cl)Cl.CO.[NH4+].[OH-]>C(OCC)C.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:39])=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCc1cc(CO)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: BrP(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCc1cc(CBr)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2

Procedure:
To a solution of 0.200 g (0.381 mmol) of the product of Example 65 dissolved in 1.5 mL of diethyl ether was added 0.837 mL (0.837 mmole) of 1.0M phosphorus tribromide in methylene chloride solution under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 2 hours when TLC analysis (80:15:1 CHCl3 -MeOH-NH4OH) indicated that the reaction was nearly complete. The reaction was quenched at 0° C. with water and then partitioned with EtOAc. The aqueous portion was separated and the EtOAc portion was washed with brine (2×10 mL). The EtOAc portion was then dried over MgSO4, filtered, evaporated to a residue, and then used in the next step of the reaction scheme.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH2:9][NH2:10].[BH3-]C#N.[Na+].CC(O)=O>CO>[CH:1]1([CH2:4][NH:10][CH2:9][CH:8]([O:11][CH3:12])[O:7][CH3:6])[CH2:3][CH2:2]1
Reactant: COC(CN)OC
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(CNCC1CC1)OC
Reaction time: 24 h
Yield: 61 %

Procedure:
A solution of cyclopropanecarboxaldehyde in MeOH (0.2 M) was treated with 2,2-dimethoxyethylamine (1.2 eq). The solution was cooled with an ice/water bath and treated portionwise with NaCNBH3 (1.0 eq). The pH of the resulting solution was adjusted to 6 with AcOH, and the reaction left at RT for 24 h. The mixture was concentrated, diluted with EtOAc, washed with sat. aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product (61%). 1H NMR (300 MHz, DMSO-d6, 300 K) δ 0.05-0.07 (m, 2H), 0.15-0.17 (m, 2H), 0.87-0.93 (m, 1H), 2.39-2.41 (m, 2H), 2.64-2.66 (m, 2H), 3.3 (s, 6H), 4.46 (t, J 3.0, 1H), 5.38 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>ClCCl>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([N:1]([C:2]3[C:7]4[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=4[CH:5]=[CH:4][CH:3]=3)[C:27](=[O:26])[C:22]=12)=[O:25]
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: Cc1oc2c(N)cccc2c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc2c(N3C(=O)c4c(Cl)ccc(Cl)c4C3=O)cccc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A mixture of 7-amino-2,3-dimethylbenzo[b]furan (161 mg), triethylamine (202 mg) and 3,6-dichlorophthalic anhydride (261 mg) in dichloromethane (5 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was washed with 1N-hydrochloric acid and brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol and treated with diazomethane. The separated solid was collected and washed with methanol to give 7-(3,6-dichlorophthalimido)-2,3-dimethylbenzo[b]furan (250 mg).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>C1COCC1.CN(C=O)C>[CH2:13]([O:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCBr
Reactant: O=C1OCCN1CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOCCN1CCOC1=O
Yield: 79.6 %

Procedure:
To 5.12 g of 60% NaH in 130 ml of THF and 30 ml of DMF was added 12.9 of 3-(2-hydroxyethyl)oxazolidin-2-one and the contents were refluxed for 2 hours. 17 g of 1-bromooctane was added and the reaction mixture was refluxed overnight. It was cooled, poured into water and extracted with ether. The combined organic extracts were dried, concentrated and the residue Was kugelrohr distilled (150°-155° C./0.5 mm) to give 16.87 g (79.6%) of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: BrCCc1ccccc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnn(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (226 mg, 2.0 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (0.33 g, 2.4 mmol) and 1-bromo-2-phenylethane (0.44 g, 2.4 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The mixture was diluted with EtOAc (40 mL), then washed with water (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The crude material was purified by chromatography on silica gel, eluting with Hex:EtOAc=80:20→70:30 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=3.20 (t, J=7.0 Hz, 2H), 4.37 (t, J=7.0 Hz, 2H), 7.04-7.07 (m, 2H), 7.25-7.32 (m, 3H), 7.81 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:4][CH2:5][O:6][CH3:7].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([NH:24][C:25](=[O:26])[NH:1][C:2]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=2[O:4][CH2:5][O:6][CH3:7])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCOc1c(N)cc(OC)cc1C(C)(C)C
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: COCOc1c(NC(=O)Nc2ccccc2)cc(OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A tetrahydrofuran (THF) (20 ml) containing 2.4 g of (2-amino-4-methoxy-6-tert-butylphenoxy)methoxymethane and 1.09 ml of phenyl isocyanate was stirred at room temperature for 3 hours, and then the solvent was removed under reduced pressure. The obtained residue was crystallized from hexane, and recrystallized from an ethyl acetate-hexane mixed solution to give 2.3 g of [2-(3-phenylureido)-4-methoxy-6-tert-butylphenoxy]methoxymethane (yield: 64%, melting point: 121°-123° C., IR: 3300, 1650 cm31 1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=[O:3].[CH3:11][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1.C(OCCCC)CCC>[Br:10][C:6]1[CH:5]=[C:4]([C:2]([OH:3])([CH3:11])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCOCCCC
Product: CC(C)(O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a stream of argon, 6.5 g of 3-bromoacetophenone are placed in a round-bottomed flask and dissolved in 544 ml of diethyl ether and 272 ml of tetrahydrofuran. The mixture is cooled at 0° C. using an ice bath, and 100 ml of a 1M solution of methylmagnesium bromide in dibutyl ether are added thereto, dropwise. The mixture is stirred at 0° C. for 1 h and 400 ml of a saturated aqueous solution of ammonium chloride are added. The organic phase is separated, dried over magnesium sulphate and concentrated under reduced pressure. 10.0 g of compound are obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20].[C:22](C#N)(=[O:26])[O:23][CH2:24][CH3:25]>CCOCC.O.CN(C)P(N(C)C)(N(C)C)=O>[OH:20][C:15]1[C:14]([CH3:21])([CH3:13])[CH2:19][CH2:18][CH2:17][C:16]=1[C:22]([O:23][CH2:24][CH3:25])=[O:26]
Reactant: CCOC(=O)C#N
Reactant: CC1(C)CCCCC1=O
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)C(C)(C)CCC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Into a 500 mL round-bottomed flask was added diisopropylamine (3.5 mL) in ether (200 mL). After cooling to −30° C., butyllithium (16 mL) (1.6M in hexane) was added slowly. After stirring 30 minutes, the temperature was cooled to −5° C. 2,2-Dimethylcyclohexanone (3 g) was added slowly. The mixture was warmed up to 0° C. and stirred for 1 hour. After cooling to −5° C., hexamethylphosphoramide (8 mL) and ethyl carbonocyanidate (2.5 mL) were added. After stirring at −5° C. for 20 minutes, and warming to room temperature, the reaction was stirred for 1 hour. The mixture was poured into cold water, and the layers were separated. The aqueous layer was extracted with ether (3×20 mL). The combined the organic layers were washed with saturated aqueous NH4Cl (3×20 mL). After drying over Na2SO4, the mixture was filtered and the filtrate was concentrated. The crude product was purified by flash chromatography on silica with 0-10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[CH:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:7]=2[CH:35]=1.O.NN>C(O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH2:17])=[CH:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:7]=2[CH:35]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 28, 8-trifluoromethyl-1-(phthalimidomethyl)-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol, to give 8-trifluoromethyl-1-(aminomethyl)-6-(o-chlorophenyl)-4H-imidazo-[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:20])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>[OH-].[Na+]>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:20])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCC(=O)O
Reactant: CCCCCCCCC/C=C/C=C/C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCC/C=C/C=C/C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
In the second method, trans,trans-2,4-tetradecadienoic acid (99.6 g) was dissolved in thionyl chloride (87 ml), and the mixture was stirred at room temperature. The excessive thionyl chloride was removed by distillation to give trans,trans-2,4-tetradecadienoic acid chloride (102.0 g). To glycine (66.8 g) dissolved in an aqueous 2N sodium hydroxide solution (540 ml) were added at the same time trans,trans-2,4-tetradecadienoic acid chloride (102.0 g) and 2N sodium hydroxide (270 ml) with 1/10 portions at a 3 minute interval. After the addition was completed, the mixture was warmed to room temperature, stirred for 15 minutes and acidified with concentrated hydrochloric acid (140 ml) under ice-cooling. Precipitates thus produced were collected by filtration and desiccated to give trans,trans-2,4-tetradecadienoyl glycine (75.0 g). To the solution of trans,trans-2,4-tetradecadienoyl glycine (4.7 g) and 6-6-(spicaminyl-amino)purine (5.1 g) in N,N-dimethylformamide (DMF, 60 ml) was added N-hydroxysuccinimide (2.1 g), and the mixture was ice-cooled. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.4 g) dissolved in DMF (100 ml) was added dropwise to the mixture. After the addition was completed, the mixture was heated to room temperature and stirred for 12 hours. Water (500 ml) was added to the reaction mixture, and precipitates produced were collected by filtration and desiccated. Sodium methoxide (3.1 g) was added to a suspension of the precipitates in methanol (100 ml), and the mixture was stirred at room temperature, then ice-cooled and acidified by adding dropwise thereto a 10% methanolic hydrochloric acid solution. Precipitates produced were filtered, dried and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK241 in the yield of 5.00 g.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:6][CH:7]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>O1CCCC1>[CH2:24]([N:27]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:6][CH:7]=1)[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2ccccc2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1coc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)n1
Yield: 67 %

Procedure:
0.30 g (0.00091 mol) of 3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 40 ml of tetrahydrofuran, treated with 2.5 ml (0.0183 mol) of dipropylamine and boiled at reflux for 20 hrs. The solution was completely freed from the solvents and the residue was chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent. There was obtained 0.24 g (67%) of 3-(4-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a white solid. An analytical sample was recrystallized from diisopropyl ether and gave white crystals; m.p. 109-110°.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.[OH-].[Li+].ON1C2C=CC=CC=2N=N1.[CH:62]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63]1.Cl.C(N=C=NCCCN(C)C)C.Cl>O1CCCC1.O.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:67][CH:62]3[CH2:66][CH2:65][CH2:64][CH2:63]3)=[O:44])[CH:47]=[CH:48][CH:49]=2)=[N:17]1
Reactant: NC1CCCC1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCCC1)c1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Yield: 5 %

Procedure:
The title compound was prepared as described in Example 381, using methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.402 g, 0.62 mmol) and lithium hydroxide (0.045 g, 1.88 mmol) in tetrahydrofuran (3 mL) and water (2 mL); 1-hydroxybenzotriazole (0.253 g, 1.87 mmol), cyclopentylamine (0.184 mL, 1.87 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.360 g, 1.88 mmol), and additional tetrahydrofuran (2 mL); 4 N hydrochloride solution in dioxane (10 mL). The final crude product was purified by preparative HPLC (10-90% acetonitrile to H2O, 20 min.) (0.012 g, 5% yield over 3 steps): 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.44 (s, 1H), 8.20 (d, 1H), 8.13 (d, 1H), 7.89 (dd, 1H), 7.70 (d, 1H), 7.66 (t, 1H), 3.60 (m, 1H), 2.07 (m, 2H), 1.82 (m, 2H), 1.68 (m, 4H); ES-MS (m/z) 373 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13]COC[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.BrC1C=CC(C(Cl)=O)=CC=1.CNC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH3:13])[CH3:9])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Agent: CNC
Agent: O=C(Cl)c1ccc(Br)cc1
Product: CN(C)C(=O)c1ccc(Br)cc1
Yield: 93 %

Procedure:
Following the general method as outlined in Intermediate 174, starting from 4-bromobenzoyl chloride and dimethylamine, the title compound was obtained as a pink solid in 93% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][Si](C(C)(C)C)(C)C)=[CH:9][C:8]=1[OH:21])=O)[CH3:2].Cl[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:26].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:5]1[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[O:21][C:24]=1[C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(O)ccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
To a solution of [4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-phenyl]-oxo-acetic acid ethyl ester from step 2 (2.0 g, 6.16 mmol) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (1.65 g, 7.4 mmol, 1.2 eq) in anhydrous N,N-dimethylformamide (100 mL) was added potassium carbonate (1.7 g, 12.3 mmol, 2 eq). The reaction mixture was stirred at 90° C. for 16 h. The mixture was cooled to room temperature then poured into ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). Combined the organic layer was washed by water (2×100 mL), dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by column chromatography eluted with 20% EtOAc/hexane then 50% EtOAc/hexane solution to afford an yellow solid (843 mg, 36%) as product. 1H-NMR (CD3CN): δ 7.79 (d, J=8.0 Hz, 1H), 7.64 (d, 1.9 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.47(dd, J=2.3, 8.3 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 7.0 (dd, J=2.3, 8.0 Hz, 1H), 4.11(q, 2H), 1.21(t, 3H).; LC-MS (MH+=379/381).
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:31]([CH3:33])[CH3:32])=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>>[CH:31]([C:7]1[N:6]=[C:5]2[NH:4][N:3]=[CH:2][C:10]2=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[CH:8]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2c(N)n[nH]c2n1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2cn[nH]c2n1
Yield: 74.5 %

Procedure:
In analogy to GP 6, reaction of 100 mg of 1-[4-(3-Amino-6-isopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (0.22 mmol, 1 eq.) with 35 μL concentrated sulphuric acid and 37 mg sodium nitrite (2.5 eq.) yielded 72 mg of the desired product (74% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[C:13]([NH:18]C(=O)OC(C)(C)C)[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[C:13]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[NH2:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(Cc2cc(C)cc(NC(=O)OC(C)(C)C)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2cc(C)cc(N)c2)CC1

Procedure:
To a solution of tert-butyl 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylphenylcarbamate (306 mg, 0.88 mmol) in CH2Cl2 (4 mL) was added TFA (4 mL) at room temperature. After 2 hours the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylaniline as a white solid. 1H-NMR (300 MHz, CDCl3) δ 6.52 (s, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 3.62 (m, 4H), 3.45 (m, 2H), 3.39 (s, 2H), 2.40 (m, 4H), 2.25 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:24][C@@:7]12[CH2:8][CH2:9][C@@H:10]3[C@:15]([CH3:21])([CH2:14][CH2:13][CH2:12][C:11]3([CH3:23])[CH3:22])[C@H:16]1[CH2:17][S:18][C:19]1[C:6]2=[CH:5][CH:4]=[C:3]([OH:2])[CH:20]=1
Reactant: COc1ccc2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC[C@]2(C)[C@H]3CSc4cc(O)ccc4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
To a solution of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (51) (0.25 g, 0.73 mmol) in CH2Cl2 (10 mL), cooled to 0° C., a solution of BBr3 (1.0 M in CH2Cl2, 2.90 mL, 2.90 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction was quenched with MeOH (3×10 mL) and concentrated to dryness. Purification by column chromatography on silica gel (Hexanes/EtOAc, 10:1) gave (1R,10R,11S,16S)-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-ol (Compound No. 53) (0.22 g, 92%) as a white solid. 1H NMR (CDCl3): δ 7.14 (d, 1H), 6.49 (m, 2H), 4.45 (br s, 1H), 2.95 (q, 2H), 2.40 (m, 1H), 1.84-1.35 (m, 9H), 1.20 (s, 3H), 1.18-0.98 (m, 2H), 0.95 (s, 3H), 0.88 (m, 3H), 0.85 (s, 3H).