Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=2)[N:5]=[C:4]([C:22](OC)=[O:23])[CH:3]=1.[BH4-].[Li+]>O1CCCC1.CO>[OH:23][CH2:22][C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=2)[N:5]=1
Reactant: COC(=O)c1cc(O)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc(Nc2cc(O)cc(CO)n2)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 16 g of methyl 4-hydroxy-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridine-2-carboxylate dissolved in 200 ml of tetrahydrofuran, 2.0 M of lithium borohydride dissolved in 30 ml of tetrahydrofuran solution was added, and the mixture was stirred at 60° C. for 1 hour. The resulting mixture was cooled to 0° C., and then 10% hydrochrolic adid in methanol was added thereto to adjust the pH of the solution to 4. After stirred 30 minutes at room temperature, the mixture was concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])/[CH:22]=[CH:23]/[C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[C:29](=[N:33][O:34][CH3:35])[CH2:28][CH2:27]4)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:37]1[CH:42]=[CH:41][C:40]([CH:43]=[O:44])=[CH:39][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[CH2:22][CH:23]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[C:29](=[N:33][O:34][CH3:35])[CH2:28][CH2:27]4)[C:43](=[O:44])[C:40]3[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccncc1
Reactant: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ccc21
Product: CON=C1CCc2cc(C(CC(=O)c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3)C(=O)c3ccncc3)ccc21
Yield: 88 %

Procedure:
The title compound (0.9 g, 88%) was prepared from the product of Step 2 and pyridine-4-carboxaldehyde using the method of Example 1 Step 4; MS(ES+) m/e 597 [M+H]+.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([OH:19])=[CH:14][N:15]2[CH3:18])=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([O:19][C:13]1[C:12](=[O:20])[C:11]2[C:16](=[CH:17][C:8]([F:7])=[CH:9][CH:10]=2)[N:15]([CH3:18])[CH:14]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Oc1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanesulphonyl chloride (1.5 ml) was added to a stirred mixture of 7-fluoro-3-hydroxy-1-methyl-4quinolone (3.0 g), obtained as described in Example 3a-f, triethylamine (4.35 ml) and dry dichloromethane (100 ml) at ambient temperature and the resultant solution stirred for 5 minutes then kept at ambient temperature overnight. Further ethanesulphonyl chloride (0.2 ml) was added and the solution stirred at ambient temperature for 4 hours and then kept at this temperature for 3 days. The mixture was filtered and the filtrate was washed with water (2×150 ml). The dichloromethane solution was dried over magnesium sulphate and the solvent evaporated to give a residue which was crystallised from industrial methylated spirit (100 ml). The solid was triturated with diethyl ether (100 ml) and then water (500 ml) to give the novel compound 7-fluoro-1-methyl-4-oxo-1,4-dihydro-quinol-3-yl ethanesulphonate, m.p. 154°-156.5°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[N:31][CH:32]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:32]=[N:31][CH:30]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COc1cncc(Br)c1
Product: COc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1)(355 mg, 1.0 mmol) and commercially available 5-bromo-3-methoxypyridine (169 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (210 mg, 45%). MS (ISP) 463.2[(M+H)+]; mp 232-234° C.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][NH:6][CH2:7][CH2:8][NH:9][CH3:10]>>[C:1]([CH2:2][CH2:3][N:6]([CH3:5])[CH2:7][CH2:8][N:9]([CH2:3][CH2:2][C:1]#[N:4])[CH3:10])#[N:4]
Reactant: CNCCNC
Reactant: C=CC#N
Product: CN(CCC#N)CCN(C)CCC#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
5.3 g of acrylonitrile were slowly added to 4.4 g of N,N'-dimethyl-ethylenediamine, while cooling with ice. The mixture was allowed to warm slowly to RT and was stirred at RT for 14 hours. It was heated at 80° C. for 3 hours and the volatile constituents were then removed in vacuo at a bath temperature of 80° C. 9.6 g of N,N'-bis-(2-cyanoethyl)-N,N'-dimethyl-ethylenediamine were obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:32])([CH2:21][CH2:22][C@@H:23]([O:27]S(C)(=O)=O)[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:34])([C@@H:17]([OH:33])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.[CH2:35](O)[CH2:36][OH:37].N1C=CC=CC=1>CCOC(C)=O>[OH:1][C@@H:2]1[CH2:26][C@@H:25]2[C@:20]([CH3:32])([CH2:21][CH2:22][C@H:23]([O:27][CH2:35][CH2:36][OH:37])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:34])([C@@H:17]([OH:33])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: OCCO
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 120 °C
Yield: 37 %

Procedure:
A pressure vessel (250 mL flask) containing the compound of Example 1A (10.0 g, 20 mmol) was charged with ethylene glycol (20 mL) and pyridine (4 mL) at ambient temperature, sealed and then heated at 120° C. for 4 hours. The reaction was cooled to ambient temperature, diluted with EtOAc (50 mL), and quenched with 1N HCI (30 mL). The layers were separated and the organic layer was washed with 1N HCI (2×30 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%->40% acetone/hexanes) provided the title compound (3.5 g, 37%). MS (ESI) m/e 484 (M+NH4)+
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([O:10][CH2:11][CH3:12])=[O:9].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[O:21]=[C:2]1[O:1][CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1C2CCC(=O)C21
Solvent: ClCCl
Product: CCOC(=O)C1C2CCOC(=O)C21
Reaction time: 15 h
Yield: 60 %

Procedure:
To a stirred solution of ethyl (1SR,5RS,6SR)-2-oxo-bicyclo[3.1.0]hexane-6-carboxylate (34.8 g, 207.2 mmol) in dichloromethane (300 mL), 70% m-chloroperbenzoic acid (51.1 g, 207.2 mmol) was added and refluxed overnight. The following day, additional 70% m-chloroperbenzoic acid (51.1 g, 207.2 mmol) was added and reflux continued for 15 hours. After that time, the mixture was diluted with dichloromethane (200 mL), filtered and washed with 10% Na2SO3 (2×200 mL) and with a saturated aqueous solution of sodium bicarbonate (2×200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography using ethyl acetate and hexane 1:2 as eluent to give 22.89 g (60% yield) of ethyl (1SR,6SR,7SR)-2-oxo-3-oxa-bicyclo[4.1.0]heptane-7-carboxylate as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:15]=2[OH:22])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C)C=O.Cl[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:15]=2[O:22][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: COC(=O)C(C)Cl
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
To a one liter round bottom flask equipped with a mechanical stirrer and a thermometer was added 157.13 grams (1.14 moles--1.3 equiv.) of potassium carbonate, followed by 215.27 grams (0.875 mole--1.0 equiv.) of 89.9% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol, and 230 mL (%Wt/Vol. Phenol to Solvent--93.6%) of N,N-dimethylformamide. The mixture was vigorously stirred and heated to 110° C., and then 139.3 grams (1.14 moles--1.3 equiv.) of methyl 2-chloropropanoate was added during a one hour period. Upon completion of addition, the reaction mixture was analyzed by GC, which indicated the reaction was incomplete. The reaction mixture was heated at 110° C. for seven hours. After this time, the reaction mixture was again analyzed by GC, which indicated the reaction was complete. The reaction mixture was filtered, and the orange filtrate was kept under a nitrogen atmosphere for about 48 hours. After this time, the filtrate was concentrated under vacuum at 90° C. and 10 mm of mercury to yield a red, brown liquid. The liquid was taken up in 200 mL of toluene, and the resulting solution was washed with two 500 mL portions of an aqueous saturated sodium chloride solution. The organic layer was separated from the aqueous layer, dried with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum at 90° C. and 10 mm of mercury, yielding 252.7 grams of 83.6% pure methyl 2-[2-(morpholin-4-ylmethyl)-5-ethylphenoxy]propanoate (78.6% yield). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8]([O:12][C:13]([C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:17][CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)=[CH:17][CH:16]=1)=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: Cc1cc(C)on1
Reactant: CC(C)(C)OC(=O)c1ccc(OCCCCCCBr)cc1
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)OC(C)(C)C)cc2)on1
Yield: 23 %

Procedure:
[I; R is CH3, n is 5, X is O, Ar is 4--(CH3)3 --COOCC6H4 ], m.p. 76° C., in 23% yield from 3,5-dimethylisoxazole and 6-(4-tertiary-butyloxycarbonylphenoxy)hexyl bromide; MIC vs. rhinovirus Type 2 in vitro=6.2 μg/ml.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].S([O-])(O[O-])(=O)=[O:12].[K+].[K+].S(=O)(=O)(O)O>C(O)(=O)C.O>[CH3:8][C:7]1[C:6](=[O:12])[CH:5]=[C:4]([CH3:9])[C:3](=[O:10])[C:2]=1[CH3:1]
Reactant: O=S(=O)([O-])O[O-]
Reactant: Cc1ccc(C)c(O)c1C
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 74 %

Procedure:
A solution of 13.6 g (100 mmol) of 2,3,6-trimethylphenol in 40 ml of acetic acid and a solution of 73.7 g (240 mmol) of 50% by weight potassium peroxomonosulfate in 320 ml of water were simultaneously added dropwise to a stirred solution of 0.68 g (2.0 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene and 0.5 ml of concentrated sulfuric acid in 50 ml of acetic acid at room temperature with cooling. The reaction mixture was then subjected to steam distillation. The distillate was extracted by shaking with methylene chloride. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and concentrated to a yellow oil, which slowly solidifed. 11.1 g (74%) of 2,3,5-trimethyl-p-benzoquinone were obtained in the form of yellow oily crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: Clc1ncccn1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Oc2ncccn2)cc1
Temperature: 110 °C
Yield: 91.8 %

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (950 mg, 6.88 mmol) in DMF (15 mL) was added 2-chloropyrimidine (750 mg, 6.55 mmol) and K2CO3 (1086 mg, 7.86 mmol). The mixture was heated at 110° C. overnight. Purification via reverse phase flash chromatography then afforded the title compound (1.3 g, 6.01 mmol, 92% yield). LCMS: rt=1.85 min, [M+H+]=218
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.38 h
Yield: 66.1 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.30 g, 1.6 mmol) in anhydrous N,N-dimethylformamide (5.5 mL) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (82.5 mg, 2.06 mmol) under nitrogen. The reaction was stirred at 0° C. for 20-25 min. At this time, the reaction was then treated with (2-(chloromethoxy)ethyl)trimethylsilane (340 μL, 1.92 mmol) and was purged with nitrogen. The ice/water bath was removed, and the reaction was allowed to warm to room temperature where it stirred over 3 nights. At this time, the reaction was diluted with water (50 mL) and was extracted with ethyl acetate (2×50 mL). The combined organics were washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and rinsed with ethyl acetate, and concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 1-30% ethyl acetate/hexanes) afforded 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a viscous yellow oil (336.5 mg, 66.3%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.26-0.05 (m, 9H) 0.74-0.98 (m, 2H) 3.44-3.65 (m, 2H) 5.60 (s, 2H) 6.78 (d, J=3.77 Hz, 1H) 7.90 (d, J=3.77 Hz, 1H). LC-MS calcd. for C12H18Cl2N3OSi [(M+H)+] 318, obsd. 317.9.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[OH:16][C:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][C:19](=O)[C:18]=1[N+:28]([O-:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[N+:28]([C:18]1[C:19]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[N:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:17]=1[O:16][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6])([O-:30])=[O:29]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1[nH]c2c(c(O)c1[N+](=O)[O-])CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)nc2c(c1OS(=O)(=O)C(F)(F)F)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Trifluoromethanesulfonic anhydride (8.0 mL, 47 mmole) was added via a syringe to a cooled (0° C.) homogeneous mixture containing 5,6,7,8-tetrahydro-4-hydroxy-3-nitro-2(1H)-quinolinone (4.0 g, 19 mmole) and triethylamine (6.6 mL, 47 mmole) in methylene chloride (200 mL). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was filtered through a layer of silica gel and the gel eluted with methylene chloride. The organic phase was evaporated under vacuum to provide 8.4 g of the desired product as a yellow oil.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]C)=O)=[CH:15][N:14]=2)[CH2:9][CH:8]1[CH3:23])[CH3:6].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:41][C:19]([C:16]3[CH:17]=[N:18][C:13]([N:10]4[CH2:11][CH2:12][N:7]([CH2:5][CH3:6])[CH:8]([CH3:23])[CH2:9]4)=[N:14][CH:15]=3)=[O:21])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: CCN1CCN(c2ncc(C(=O)OC)cn2)CC1C
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ncc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
Trimethylaluminium (2M in toluene, 1.65 ml, 3.31 mmol) was added dropwise to a stirred suspension of methyl 2-(4-ethyl-3-methylpiperazin-1-yl)pyrimidine-5-carboxylate (303 mg, 1.15 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (283 mg, 1.15 mmol) in toluene (5.73 ml) at room temperature. The resulting solution was stirred at 60° C. overnight. The reaction mixture was quenched into methanol (100 mL) and treated with HCl (2N aqueous solution, until the pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product as a yellow dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (269 mg, 49%) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(N2CCCCC2)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(N3CCCCC3)n2)ccc1-n1cnc(C)c1
Yield: 78 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 2-chloro-4-methyl-6-piperidin-1-yl-pyrimidine (70 mg, 0.33 mmol) in analogous manner as described in example 90. The crude product was purified by stirring with diethyl ether. It was obtained in 78% yield as a light brown solid. MS ISP (m/e): 379.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.21 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 7.01 (s, 1H), 6.19 (s, 1H), 3.77 (s, 3H), 3.62 (m, 4H), 2.20 (s, 3H), 2.14 (s, 3H), 1.63 (m, 2H), 1.53 (m, 4H).
Reaction SMILES: I[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH:14]=[O:15].O>CN(C=O)C>[CH2:2]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH:14]=[O:15])[CH3:3]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 18 h

Procedure:
At 20° C. iodoethane (3.78 g) was added to a suspension of K2CO3 (1.09 g) and 3-hydroxy-4-nitro-benzaldehyde (1.0 g) in DMF (5 ml). The reaction mixture was stirred at 70° C. for 18 h, poured into water and then extracted with ethyl acetate. The organic phases were combined, dried (MgSO4) and concentrated in vacuo. The title product was obtained as a yellow solid. Yield: 1.17 g. MS-ESI: [M+H]+=196.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:26][C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:26][C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(Br)nc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)n1
Temperature: 140 °C
Yield: 86.2 %

Procedure:
A suspension of 6-bromo-3-nitro-2-(trifluoromethyl)pyridine (400 mg, 1.5 mmoL), (S)-2-methylpyrrolidine tosylate salt (381 mg, 1.5 mmoL) and K2CO3 (620 mg, 4.5 mmoL) in H2O (4 mL) was heated at 140° C. under microwave irradiation for 30 minutes. The solution was extracted with EtOAc (50 mL×3) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4 and purified by silica gel column chromatography to afford (S)-6-(2-methylpyrrolidin-1-yl)-3-nitro-2-(trifluoromethyl)pyridine (350 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=9.2 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 4.55-4.42 (m, 1H), 4.02-3.30 (m, 2H), 2.30-2.00 (m, 3H), 1.81 (brs, 1H), 1.27 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: O=C1CCc2ccc(Cl)cc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2ccc(Cl)cc2C1=O
Yield: 39 %

Procedure:
A solution of 20.2 g of 6-chloro-1-indanone, 25 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 25 ml of 2,2-dimethoxypropane and 200 ml of anhydrous toluene was boiled under reflux for 16 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 10.3 g (39%) of (RS)-2-(2-buten-1-yl)-6-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10])=[O:5])[CH3:2]>O1CCOCC1.[Pd]>[CH2:28]([O:27][C:25]([CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:26])[CH3:29]
Reactant: CCOC(=O)C(C(=O)OCC)C(CC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)O)c1ccccc1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a solution of benzyl 4,4-bis(ethoxycarbonyl)-3-phenylbutyrate (3.98 g) in dioxane (50 ml) was added 10% palladium on carbon (0.5 g). The mixture was hydrogenated at 4 kgf/cm2 for 1 hour. The reaction mixture was filtered and the filtrate was evaporated off to give 4,4-bis(ethoxycarbonyl)-3-phenylbutyric acid (2.7 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][CH:34]([CH2:36]Br)[CH2:33][C:32]=2[CH:38]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:19][C:2]([F:18])([F:1])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][N:12]([CH2:36][CH:34]3[CH2:33][C:32]4[CH:38]=[C:28]([O:27][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:29]=[CH:30][C:31]=4[O:35]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: OC1(Cc2ccc(OC(F)(F)F)cc2)CCNCC1
Product: OC1(Cc2ccc(OC(F)(F)F)cc2)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=514.6 (M+H+) was prepared from 4-(4-trifluoromethoxy-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.