Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:19]=2)=[CH:11][CH:10]=1.[F:27][C:28]([F:44])([F:43])[C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])[N:30]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([C:37]([C:36]4[CH:40]=[CH:41][CH:42]=[C:34]([C:31]5[N:30]=[C:29]([C:28]([F:43])([F:27])[F:44])[O:33][N:32]=5)[CH:35]=4)=[O:38])[CH2:25][CH2:26]3)[N:19]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2nc(CN3CCNCC3)cs2)cc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(Cc2csc(-c3ccc(F)cc3)n2)CC1
Yield: 34 %

Procedure:
This compound was synthesized from 2-(4-fluorophenyl)-4-(piperazin-1-ylmethyl)thiazole TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (26 mg, yield 34%). 1H NMR (400 MHz, CDCl3) δ 8.20-8.17 (m, 2H), 7.95-7.92 (dd, J=8.8 Hz, 5.1 Hz, 2H), 7.64-7.59 (m, 2H), 7.16-7.11 (m, 3H), 3.89 (m, 2H), 3.80 (s, 2H), 3.51 (m, 2H), 2.72 (m, 2H), 2.57 (m, 2H). MS (ESI) m/z: Calculated for C24H19F4N5O2S: 517.12. found: 518.2 (M+H)+
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:9]([OH:11])[CH:10]=1.C([O:28][C:29]1[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=1)C1C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:9]([CH:10]=1)[O:11][C:32]1[CH:33]=[CH:34][C:29]([OH:28])=[CH:30][CH:31]=1
Reactant: COc1cccc(Cc2ccc(OC)cc2O)c1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(Cc2ccc(OC)cc2Oc2ccc(O)cc2)c1
Temperature: 90 °C
Yield: 20.9 %

Procedure:
The title compound was synthesized by referring to J. Am. Chem. Soc., 1999, 121 (18), 4369. To a suspension of 60% sodium hydride (600 mg) in toluene (50 ml) was added 5-methoxy-2-(3-methoxybenzyl)phenol (2.4 g), and the solution was stirred at 90° C. until generation of gas was stopped. The reaction solution was cooled to room temperature, then 1-benzyloxy-4-bromobenzene (2.6 g), palladium(II) acetate (112 mg), 2-(di-tert-butylphosphino)biphenyl (149 mg) were sequentially added thereto, and the solution was stirred for 18 hours and 50 minutes at 95° C. To the reaction solution was added water, the solution was extracted with ethyl acetate, then the insoluble material was filtered through celite pad, the filtrate was dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), 2-(4-benzyloxy phenoxy)-4-methoxy-1-(3-methoxybenzyl)benzene (1.4 g) was used according to an analogous synthetic method to Example 22 to provide the title compound (690 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[N:6]2[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].[NH3:35].C(O)C>>[NH2:35][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[N:6]2[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]
Reactant: N
Reactant: N#Cc1cccc(-n2c(-c3cccc(F)c3)nc3c(Cl)nc(C#CC4(O)CCCCC4)nc32)c1
Solvent: CCO
Product: CCCCCC(O)C#Cc1nc(N)c2nc(-c3cccc(F)c3)n(-c3cccc(C#N)c3)c2n1
Temperature: 25 °C
Yield: 73 %

Procedure:
3-{6-Chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]benzonitrile (2.0 g) was suspended in 200 ml of a 20% ammonia/ethanol and reacted at 100° C. in an autoclave for 8 hours. The resulting mixture was cooled to room temperature, concentrated to dryness and purified by a silica gel column (40 g of silica gel). It was eluted with dichloromethane containing 5% of methanol. The fractions containing the aimed product were collected, concentrated to dryness, suspended in 100 ml of a mixed solvent of ethyl acetate and hexane (1:1) and the resulting product was collected by filtration and washed with hexane to give 1.4 g of the title compound. The yield was 73%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CS(C)=O.[OH:14][C@@H:15]([C@@H:26]([NH:31][C:32]([C:34]1([NH:40][C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:33])[CH2:27][CH2:28][CH2:29][CH3:30])[C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[OH:25])=[O:17]>ClCCl>[O:17]=[C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[C:15](=[O:14])[C@@H:26]([NH:31][C:32]([C:34]1([NH:40][C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)=[O:33])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)C(=O)C(=O)N[C@H]1CCCCC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
Under nitrogen stream, at 0° C., 1.45 g (11.2 mmol) of N,N-diisopropylethylamine was added dropwise to a mixed solution of anhydrous dimethylsulfoxide (5 ml) and anhydrous dichloromethane (5 ml) containing 1.78 g (11.2 mmol) of sulfur trioxide pyridine complex salt. Moreover, to the mixture was added an anhydrous dichloromethane (5 ml) solution containing 465 mg (0.94 mmol) of N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide, and the resulting mixture was stirred at 0° C. for 3 hours. After completion of the reaction, ice-water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography to obtain 402 mg (Yield: 87%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[Cl-].[Na+]>C1COCC1.O>[CH:27]1([C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10]4[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][CH:3]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
2-(N-Cyclohexanecarbonyl-4-aminophenyl)-5-trifluoromethyl benzimidazole was prepared from the amino, 2-(4-aminophenyl)-5-trifluoromethyl benzimidazole (1.2; see above). The amine (0.239 g, 0.86 mmol) was dissolved in THF:H2O (5 ml, 1:1) followed by K2CO3 (0.1213 g, 0.88 mmol) and cyclohexyl carbonyl chloride (130 μL, 0.95 mmol). The reaction mixture was shaken for 23 h at room temperature. Sodium chloride was added to the reaction and the mixture extracted with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4 and concentrated under vacuum. The resulting solid was purified by preparative TLC (10% MeOH in CH2Cl2).
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[CH:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:8]([C:10]1[CH:11]=[C:12]([NH:17]C(=O)C)[CH:13]=[CH:14][C:15]=1[OH:16])=O.[BH4-].[Na+].[ClH:27]>CO>[ClH:27].[CH2:21]([C:7]1[O:16][C:15]2[CH:14]=[CH:13][C:12]([NH2:17])=[CH:11][C:10]=2[CH:8]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(Br)C(=O)c1cc(NC(C)=O)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CCCCc1cc2cc(N)ccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Sodium bicarbonate (3.36 g, 40.0 mmol) was added in several portions to a stirred boiling mixture of N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a] (13.13 g, 40.0 mmol) and methanol (30 mL). The mixture was stirred under reflux conditions for 2 hour. Sodium borohydride (1.51 g, 40.0 mmol) was added in several portions to the mixture at 0-5° C. (ice/water bath). The mixture was stirred for 30 min at the same temperature and 15% hydrochloric acid (100 mL) was added. The solution was stirred for 4 hours under reflux conditions and for 1 hour at 0-5° C. (ice/water bath). The precipitated crystals were filtered off, washed on the filter with water (20 mL) and ethyl acetate (20 mL) and dried to give 7.62 g (84.5% yield from 3 steps) of 2-butyl-5-benzofuranamine hydrochloride [12a] as off-white crystals with mp 190-193° C. (dec.).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]=[O:9]>[Ag]=O.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:8]([OH:1])=[O:9])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydroxide (12g.; 0.3m) was dissolved in 200 ml. of water, silver oxide (11.6g.; 0.05m) added and the resulting mixture warmed to 50° C, 3-methoxy-4-benzyloxybenzaldehyde (12.1g; 0.05m) added in one portion and the mixture heated to 60° C with stirring for 1 hour, stirred 18 hours at room temperature, filtered and acidified to give the acid which was recrystallised from glacial acetic acid, m.p. 172°-3° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc2c(Sc3cccc(Br)c3)c[nH]c2c1
Reactant: Brc1cccnc1
Product: Clc1ccc2c(Sc3cccc(Br)c3)cn(-c3cccnc3)c2c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(3-bromo-phenylsulfanyl)-6-chloro-1H-indole and 3-bromopyridine.
Reaction SMILES: Br[C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH2:17][CH3:18])[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:8]1[CH:7]2[CH:2]1[C:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:6]=12
Reactant: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(CC)Oc2ccc(C#N)cc2C2OC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A mixture of trans-3-bromo-2,2-diethyl-3,4-dihydro-4-hydroxy-2H-1-benzopyran-6-carbonitrile (1.95 g) and potassium carbonate (1.74 g) in N,N-dimethylformamide (8 ml) was stirred overnight at ambient temperature. The reaction mixture was poured into water, extracted with ethyl acetate, and then washed with water and brine successively. The extract was dried over anhydrous magnesium sulfate, treated with active charcoal, and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of methylene chloride and n-hexane (1:2) as an eluent to give 3,4-epoxy-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-6-carbonitrile (1.17 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][O:15][C:16]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:17]=1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:19]([CH2:18][C:17]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:16]=2[O:15][CH3:14])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Yield: 50.4 %

Procedure:
5-Chloro-2,4-difluorobenzenesulfonyl chloride (200 mg, 0.81 mmol), N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 106, 255 mg, 0.97 mmol) and pyridine (196 μL, 2.43 mmol) in dichloromethane (3 mL) were stirred at room temperature for 36 hours. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (5 g Varian bond-elut cartridge, heptane/ethyl acetate 100/0 to 70/30) to afford the title compound (193 mg) as a gum.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([O:17][CH3:18])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[C:6]([C:5]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:11][C:4]=1[NH2:1])#[N:7]
Reactant: CCCCOc1cc([N+](=O)[O-])c(C#N)cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCCOc1cc(N)c(C#N)cc1OC
Temperature: 40 °C
Yield: 71.3 %

Procedure:
2-nitro-4-butoxy-5-methoxybenzonitrile (0.563 g, 2.24 mmol), Pd/C (0.035 g) and anhydrous ethanol (25.0 mL) were added into a round bottom flask. The solution was stirred and heated under reflux. Cyclohexene (1.15 mL) was added and refluxed until the disappearance of the starting materials as monitored by TLC. After cooling, the resulting mixture was filtered and washed with ethanol. The filtrate was concentrated to yield a solid product. The crude product was suspended in anhydrous ethanol (4 ml), stirred and heated to 40° C. to react for 30 min, then cooled to room temperature, filtered and air-dried to yield 0.352 g of light yellow solid product with a recovery rate of 71%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]=[CH:10][CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:3]=1>[Pd].CO>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:5]=1
Reactant: Cc1cc(C)nc(C=CC=Cc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)nc(CCCCc2ccc(N)cc2)c1
Reaction time: 4 h
Yield: 70.7 %

Procedure:
Palladium on carbon (10%, 50 mg) was added to a solution of 2,4-dimethyl-6-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-pyridine (0.5 g, 1.78 mmol) in methanol (20 mL) under a nitrogen atmosphere. The reaction mixture was hydrogenated under balloon pressure for 4 h at room temperature, then filtered through celite and washed with methanol. The filtrate was evaporated under reduced pressure and the residue was washed with pentane (20 mL) to afford 4-[4-(4,6-dimethyl-pyridin-2-yl)-butyl]-phenylamine (320 mg, 71%) as a brownish pink semi-solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12>ClCCl.FC(F)(F)C(O)=O>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCCNC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
A mixture of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:5]2=O.O.[NH2:28][NH2:29]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=3)[O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[CH:7][NH:29][N:28]=2)[CH:3]=1
Reactant: NN
Reactant: N#CCCCCOc1cccc(-c2coc3cc(O)c(Cl)cc3c2=O)c1
Solvent: O
Product: N#CCCCCOc1cccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)c1
Yield: 87 %

Procedure:
This compound was synthesised in the same manner as described above. 5-[3-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-pentanenitrile (0.1 g, 0.27 mmol), Hydrazine hydrate (5 ml). The precipitate formed on quenching was filtered to give 5-{3-[3-(5-Chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-phenoxy}-pentanenitrile as a white solid (0.09 g, 87.0%); Rf 0.6 ethyl acetate/hexane (70/30)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:41])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([NH:33]C(OC(C)(C)C)=O)[NH:31][CH:32]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl>ClCCl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:41])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:29]=[C:30]([NH2:33])[NH:31][CH:32]=4)=[CH:26][CH:27]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)c[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)c[nH]1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A solution of 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-t-butyloxycarbonylaminoimidazol-4-yl)benzoyl]piperazine (174 mg, 0.27 mmol) in dichloromethane (1 ml) and dioxan (4 ml) was treated with a solution of hydrogen chloride in dioxan (4 ml of 4M) and stirred overnight. The resulting solid was isolated by filtration to give crude product (163 mg); this was crystallised from ethanol to give 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-aminoimidazol4-yl)benzoyl]piperazine (120 mg, 77% yield), m.p. 274-275° C., 1H NMR (d6DMSO) 3.0-3.1 ppm (broad s,4H), 3.3-3.7 ppm (broad s,4H), 7.35 ppm (d,2H), 7.45 ppm (s,3H), 7.65 ppm (d,2H), 7.8 ppm (t,2H), 8.2 ppm (t,2H), 8.4 ppm (s,1H), 8.45 ppm (s,1H); microanalysis, found: C, 48.8; H, 4.1; N, 11.8; S, 5.5%; C24H22N5O3BrS. 1.0 HCl. 0.5 H2O requires: C, 49.2; H, 4.1; N, 12.0; S, 5.5%; MS (M+H)+ 540/542.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH3:7][C:8]1[N:9]=[CH:10][O:11][C:12]=1[C:13](=[O:16])[CH2:14][CH3:15]>>[O:4]1[CH:5]=[CH:6][C:2]([C:13]([C:12]2[O:11][CH:10]=[N:9][C:8]=2[CH3:7])([OH:16])[CH2:14][CH3:15])=[CH:3]1
Reactant: Brc1ccoc1
Reactant: CCC(=O)c1ocnc1C
Product: CCC(O)(c1ccoc1)c1ocnc1C

Procedure:
Starting with 3-bromofuran and 4-methyl-5-propionyloxazole and following the general method of Example 4 the title compound was prepared.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[O:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].Br[CH2:21][C:22]#[N:23]>O1CCCC1>[C:22]([CH2:21][CH2:19][C:12](=[O:11])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])#[N:23]
Reactant: N#CCBr
Reactant: CC(=O)CCCC(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCCC(=O)CCCC(=O)O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of potassium hexamethyldisilazide (66 mL, 60 mmol) in dry tetrahydrofuran (140 mL) at -70° C. is added slowly 5-oxohexanoic acid (36 mL, 30 mmol). The resulting yellow suspension is stirred at -70° C. for 1 hour and bromoacetonitrile (2.2 mL, 32 mmol) is added slowly. The reaction mixture is stirred at -70° C. for 1 hour and then at room temperature for 0.5 hour. The reaction is quenched by addition of 1N aqueous hydrochloric acid (100 mL). The aqueous layer is extracted twice with ether. Combined organic layer is dried, filtered and evaporated to obtain a dark oil which is purified by silica gel chromatography using 9:1 ether:hexane with 1% acetic acid as eluent to give 7-cyano-5-oxoheptanoic acid as an oil.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.Cl.[O:11]1CCOCC1.O>>[I:9][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:11])[C:7]=1[CH3:8]
Reactant: C1COCCO1
Reactant: Cc1c(I)ccnc1F
Agent: Cl
Solvent: O
Product: Cc1c(I)cc[nH]c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoro-4-iodo-3-methylpyridine (1.68 g, 7.09 mmol) in 1,4-dioxane/water (1:1, 5.2 mL) was added concentrated HCl (5.5 mL). The resulting clear solution was heated to 100° C. After 1 h, the reaction mixture was allowed to cool to ambient temperature and was stirred overnight, during which time a precipate formed. The mixture was filtered and dried to a constant weight to afford 4-iodo-3-methylpyridin-2(1H)-one as a yellow solid 1.47 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14](=O)[CH2:15][C:16]([O:18]CC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1[CH2:34][CH2:33][CH:32]([C:35]2[N:36](C3CC3)[N:37]=[CH:38][C:39]=2[CH:40]=O)CC1)(OC(C)(C)C)=O>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14]1[N:36]([C:35]2[CH:32]=[CH:33][CH:34]=[CH:40][CH:39]=2)[N:37]=[CH:38][C:15]=1[CH:16]=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C=O)cnn2C2CC2)CC1
Reactant: CCOC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Product: O=Cc1cnn(-c2ccccc2)c1CCNC(=O)OCc1ccccc1

Procedure:
[2-(4-Formyl-2-phenyl-2H-pyrazol-3-yl)-ethyl]-carbamic acid benzyl ester was prepared from ethyl 5-benzyloxycarbonylamino-3-oxo-pentanoate in the same manner as N-Boc-4-(2-cyclopropyl-4-formyl-2H-pyrazol-3-yl)-piperidine (Example 108).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12](F)[CH:11]=2)[CH:9]=1)([OH:3])=[O:2].C(N1C(=O)C(C(OC)=O)=CC(C2C=CC(C)=CC=2)=N1)C(C)C>>[C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]([CH3:20])[CH3:21])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:9]=1)([OH:3])=[O:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1F
Agent: COC(=O)c1cc(-c2ccc(C)cc2)nn(CC(C)C)c1=O
Product: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1

Procedure:
Following the procedure of Example 1 (7), 2-isobutyl-4-methoxycarbonyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 86.7%).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH:15](O)([CH3:17])[CH3:16]>>[CH:15]([O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[I:1])([CH3:17])[CH3:16]
Reactant: CC(C)O
Reactant: O=C(O)CCCOc1ccccc1I
Product: CC(C)OC(=O)CCCOc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(2-iodophenoxy)-butyric acid in 10 ml of isopropanol is mixed with 0.5 g of Amberlyst 15, stirred overnight at room temperature and then refluxed for 2 hours. Then, it is filtered from the Amberlyst 15, the filtrate is concentrated by evaporation, the residue is taken up in diethyl ether, washed with diluted sodium carbonate solution, dried and concentrated by evaporation. 920 mg of 4-(2-iodophenoxy)butyric acid isopropylester is obtained as a colorless oil.