Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[N:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](OCC)=[O:17])[C:11]=12.O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH:7]1[N:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[C:11]=12
Reactant: CCOC(=O)c1cccn2cncc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cccn2cncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold solution of lithium aluminum hydride (1.62 g, 42.4 mmol, 4.0 eq) in THF (50 mL) was added the crude ethyl imidazo[1,5-a]pyridine-8-carboxylate (2.7 g, 14.2 mmol, 1.0 eq) and the reaction mixture was heated at reflux for 2 h. The reaction was cooled and water (1.7 mL), 15% NaOH (1.7 mL) and water (5.1 mL) were slowly added. Solution was diluted with excess EtOAc and stirred at rt for 30 min. The solution was filtered and the solid was washed with ethyl acetate. Organic layers were combined, dried and solvent was removed to give crude imidazo[1,5-a]pyridine-8-methanol, which was purified by column chromatography (EtOAc/Hexane). MS: exact mass calculated for C8H8N2O, 148.06; m/z found, 149 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1O[C:10](=O)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)([O-:3])=[O:2].C(=O)(O)O.[NH2:26][NH:27][C:28]([NH2:30])=[NH:29]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1[N:26]2[N:27]=[C:28]([NH2:30])[N:29]=[C:10]2[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)([O-:3])=[O:2]
Reactant: O=c1oc(Cc2cccc([N+](=O)[O-])c2)nc2ccccc12
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Nc1nc2c3ccccc3nc(Cc3cccc([N+](=O)[O-])c3)n2n1
Temperature: 180 °C
Yield: 30 %

Procedure:
To a solution of commercially available (3-nitro-phenyl)-acetyl chloride (2.20 g, 11.05 mmol) in anhydrous DCM (9 mL) was added 2-aminobenzoic acid (0.76 g, 5.50 mmol). Pyridine (3 mL) was then added to the mixture and the reaction mixture was heated under microwave condition at 120° C. for 30 minutes, then diluted with dichloromethane and washed with NaHCO3 satured solution, then with water followed by brine. The organic phase was dried over Na2SO4, filtered and evaporated to give the 2-(3-nitro-benzyl)-benzo[d][1,3]oxazin-4-one intermediate as red oil. To a solution of 2-(3-nitro-benzyl)-benzo[d][1,3]oxazin-4-one in dry pyridine (10 mL) was added aminoguanidine hydrogencarbonate (0.90 g, 6.60 mmol) and the mixture was heated under microwave condition at 180° C. for 20 minutes. The solvent was then evaporated and the crude was purified by flash column chromatography on silica gel eluting with DCM/CH3OH 95/5 to afford the title compound as orange solid (0.35 g, 30% yield).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH2:28][CH3:29])=[CH:19][C:4]=2[N:3]=1
Reactant: O=C1c2cnccc2-c2c1c(Cl)nc1cc(O)ccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cnccc1-3
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
To a suspension of 6-chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34a) (30 mg) and potassium carbonate (60 mg) in N,N-dimethylformamide (0.5 ml) was added iodoethane (25 mg) and the mixture was stirred at 90° C. for 1.5 hrs. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol (100:1) to give 6-chloro-3-ethoxy-5,9-diaza-benzo[c]-fluoren-7-one (18 mg) as a yellow powder. ESI−MS: m/z 311 (MH+); 1H-NMR (CDCl3): δ1.54 (3H, t, J=7 Hz), 4.25 (2H, q, J=7 Hz), 7.39 (1H, dd, J=9 Hz, 2.5 Hz), 7.43 (1H, d, J=2.5 Hz), 8.10 (1H, d, J=5.5 Hz), 8.35 (1H, d, J=9 Hz), 8.95 (1H, d, J,=5.5 Hz), 9.04 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].N1CCCC1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([N:14]2[CH2:15][CH2:16][CH2:13][CH2:12]2)=[O:9])=[CH:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: CC#N
Solvent: C1CCNC1
Product: O=C(NCc1ccc(Br)cc1)N1CCCC1
Yield: 99.7 %

Procedure:
A solution of 4-bromobenzylisocyanate (408 mg, 1.92 mmol) in acetonitrile (15 ml) was treated with triethylamine (390 mg, 3.86 mmol) followed by pyrrolidine (137 mg, 1.93 mmol) at room temperature with stirring under argon. The reaction was stirred at 20° C. for 30 minutes and then partitioned between ethyl acetate (10 ml) and water (20 ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless solid (542 mg, 99%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F-:13].[K+]>CN(C)C=O>[F:13][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: [F-]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1F
Yield: 98.8 %

Procedure:
18.6 g (0.1 mol) of 2-chloro-5-nitrobenzaldehyde and 11.6 g (0.2 mol) of dry potassium fluoride in 50 ml of dimethylformamide are stirred for 12 hours at 100° C. The solvent is then distilled off in vacuo and the residue is stirred in 100 ml of water. The crude 2-fluoro-5-nitrobenzaldehyde is filtered off under suction, washed with water and dried. 16.7 g of 2-fluoro-5-nitrobenzaldehyde with a content of 96% are obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]([C:20](=[O:22])[CH3:21])[NH2:19]>ClCCl>[C:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]([C:20](=[O:22])[CH3:21])[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)N(N)c1ccc(C(=O)O)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(=O)O)ccc1N(N)C(C)=O
Yield: 86.5 %

Procedure:
235 ml of acetic anhydride were added to a suspension of 97.5 g of 2-amino-4-carboxy-N-acetylphenylhydrazine in 450 ml of dichloromethane while stirring. The mixture was stirred at room temperature for 3 hours, then the crystals were filtered by suction, washed with dichloromethane and dried at 60° C. Thus, 101.2 g (86.5%) of 2-acetylamino-4-carboxy-N-acetylphenylhydrazine were obtained, m.p.: 238° C. (with decomposition).
Reaction SMILES: [Na].C([C:4](CC)(C([O-])=O)[C:5]([O-])=[O:6])C.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]=[C:16]([C:20](=[O:22])[CH3:21])[CH2:15]1.[OH-].[K+]>C(O)C.O>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]2[CH:16]([C:20](=[O:22])[CH2:21][C:5](=[O:6])[CH2:4]2)[CH2:15]1
Reactant: CC(=O)C1=CCCN(C)C1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCC2CC(=O)CC(=O)C2C1

Procedure:
A 250 ml three necked flask, equipped with magnetic stirrer, reflux condenser and nitrogen inlet was charged with 80 ml ethanol. Thereafter, 2.28 g of sodium metal, freshly cut, was added and the mixture stirred till all the sodium had dissolved. Then, 12.33 g of diethylmalonate in 6 ml of ethanol, and 9.74 g of 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)ethanone (arecolone) in 6 ml of ethanol, were added to the warm solution and the resulting solution was stirred and heated to reflux for 5 hours. Then, 10.2 g of 85% potassium hydroxide pellets were added and the mixture heated to reflux for four hours. During this period a heavy precipitate formed. With the aid of 50 ml water, the mixture was transferred into a 500 ml flask and concentrated at 30° and 20 mm of pressure. The residue was again concentrated from 50 ml water. It was then taken up in 100 ml water. 45 ml 12N hydrochloric acid were added and the solution was heated to reflux for 2 hours. It was then cooled and concentrated on a rotovap at 40° and 20 mm of pressure.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1[CH:21]([C:22]2[C:23](C)=[N+:24]([O-:28])C=CC=2)C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[CH3:5][C:3]1[C:2]([CH:1]=[O:7])=[CH:21][CH:22]=[CH:23][N+:24]=1[O-:28]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc[n+]([O-])c1C
Reactant: CCOC(=O)CC(C)=O
Agent: N
Solvent: CCO
Product: Cc1c(C=O)ccc[n+]1[O-]

Procedure:
Analogously to the process described in Example 1 there is obtained from 8.4 g of 2-methylpyridine-3-carboxaldehyde-1-oxide, 16.5 ml of ethyl acetoacetate and 6.1 ml of 30% aqueous ammonia in 34 ml of absolute ethanol, 2,6-dimethyl-4-(2-methyl-1-oxido-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which, after recrystallisation from 600 ml of acetonitrile, melts at 228°-230°.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][C:13]([CH3:42])([CH3:41])[CH2:14][CH:15]1[C:19]2([C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH:17]([C:38]([OH:40])=O)[NH:16]1)(=[O:10])[CH3:9].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:67][C:68]1[CH:75]=[CH:74][C:71]([C:72]#[N:73])=[CH:70][CH:69]=1>>[Cl:28][C:24]1[CH:23]=[C:22]2[NH:21][C:20](=[O:29])[C@:19]3([C@@H:18]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=4[F:37])[C@H:17]([C:38](=[O:40])[NH:67][C:68]4[CH:75]=[CH:74][C:71]([C:72]#[N:73])=[CH:70][CH:69]=4)[NH:16][C@H:15]3[CH2:14][C:13]([CH3:42])([CH3:41])[CH2:12][O:11][C:8](=[O:10])[CH3:9])[C:27]2=[CH:26][CH:25]=1
Reactant: CC(=O)OCC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 40.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 103 (0.25 g, 0.4 mmol), was reacted with diisopropylethylamine (0.47 g, 3.6 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.19 g, 1.6 mmol) to give acetic acid rac-3-[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-5′-(4-cyano-phenylcarbamoyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidin]-2′-yl]-2,2-dimethyl-propyl ester as a light yellow foam (Yield 0.1 g, 40%).
Reaction SMILES: Br[C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12][N:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38].C(=O)([O-])[O-].[K+].[K+].CNCCNC.[ClH:51]>[Cu](I)I.C(O)C.C1(C)C=CC=CC=1>[ClH:51].[ClH:51].[O:38]=[C:34]1[CH2:35][CH2:36][CH2:37][N:33]1[C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12][N:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2ccn1CCN(CCCOc1ccc(Br)cc1)Cc1ccncc1
Reactant: O=C1CCCN1
Agent: I[Cu]I
Agent: CNCCNC
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCCN1c1ccc(OCCCN(CCn2ccc3ccccc3c2=O)Cc2ccncc2)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
2-(2-{[3-(4-Bromophenoxy)propyl]pyridin-4-ylmethylamino}ethyl)-2H-isoquinolin-1-one (500 mg), 2-pyrrolidone (0.228 ml), potassium carbonate (415 mg), copper iodide (I)(190 mg), and N,N′-dimethyl ethylenediamine (0.39 ml) were added to toluene (5 ml). The mixture was stirred at 100° C. for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. After adding aqueous ammonia, extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, and dried with sodium sulfate. After the organic layer was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0,70:30). The purified product was condensed under reduced pressure. A condensed hydrochloric acid (0.3 ml) was added to an ethanol solution of the residue, followed by condensation under reduced pressure. The residue was recrystallized from isopropyl alcohol/water to give the title compound (350 mg) as a white powder. mp: 210 to 214° C. (dec.)
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:28](Br)#[N:29]>C(Cl)Cl.O>[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:28]#[N:29])[CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#CBr
Reactant: Cc1cc(Cc2ccccc2)nc(NC2CCNCC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(C#N)CC2)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of (4-benzyl-6-methyl-pyrimidin-2-yl)-piperidin-4-yl-amine hydrochloride (255 mg, 0.8 mmol) in CH2Cl2 (1.5 mL) was added at 0° C. a suspension of sodium hydrogencarbonate (202 mg, 2.49 mmol) in water (0.5 mL) and then within 1 minute a solution of bromocyan (106 mg, 0.97 mmol) in CH2Cl2 (1 mL). The reaction was stirred at 0° C. for 45 minutes and then at room temperature over night. The reaction was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 solution and with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a colorless oil (135 mg, 55%).
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[NH:14][NH:15][NH:16][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(C#Cc2ccccc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: Clc1ccc(C2=C(c3ccccc3)NNN2)cc1
Temperature: 150 °C
Yield: 53.4 %

Procedure:
A mixture of tri-n-butyltin azide (0.86 mL, 3.15 mmol) with the 4-chlorophenylethynylbenzene (3 mmol) was heated at 150° C. for 70 h in a sealed glass bottle. The resulting solution was purified by column chromatography (cyclohexane/AcOEt, 5:1) and recrystallized from (cyclohexane/AcOEt) to give 4-(p-chlorophenyl)-5-phenyl-1H(2H)-[1,2,3]triazole as a white solid (413 mg, 54% yield); m.p. 124-126° C. 1H NMR (200 MHz, CDCl3, 25° C.) δ=7.51-7.46 (m, 4H), 7.38-7.35 (m, 3H), 7.31 (dt, 3J=8.6 Hz, 4J=5J=2.2 Hz, 2H) ppm. ES-MS: m/z=278 [M++Na], 256 [M+]. C14H10ClN3 (255.70): caldc. C, 65.76; H, 3.94; N, 16.43. found C, 65.93; H, 3.84; N, 16.37.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[C:20]=3[NH2:26])=[CH:12][CH:11]=2)[CH:4]=1.[CH:29]([CH:31]=O)=O>CCO>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]3[C:20]4[C:21](=[N:25][CH:29]=[CH:31][N:26]=4)[N:22]=[CH:23][N:24]=3)=[CH:14][CH:15]=2)[CH:4]=1
Reactant: Nc1ncnc(OCCc2ccc(Oc3cc(C(F)(F)F)ccn3)cc2)c1N
Reactant: O=CC=O
Solvent: CCO
Product: FC(F)(F)c1ccnc(Oc2ccc(CCOc3ncnc4nccnc34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
6-{2-[4-(4-Trifluoromethylpyridin-2-yloxy)-phenyl]-ethoxy}-pyrimidine-4,5-diamine (75 mg, 0.19 mmol) was combined with 50% aqueous glyoxal solution (1 mL) in EtOH (5 mL) and stirred overnight at 25° C. The solution was evaporated and the residue extracted with CH2Cl2. The CH2Cl2 layer was washed with H2O and concentrated in vacuo. The residue was recrystallized from hot MeCN to give 4-{2-[4-(4-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethoxy}-pteridine (16 mg, 20%): mp 172-173° C.; EIMS m/z 413; 1H NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 9.07 (s, 1H), 9.02 (s, 1H), 8.30 (s, 1H), 7.43 (d, J=9.5 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 4.63 (t, 6.8 Hz, 2H), 3.17 (t, J=7.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([Br:12])([F:11])[F:10])[CH:5]=[C:4]([O:18][CH:19]([F:21])[F:20])[C:3]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N+:31]([O-])=[CH:30][CH:29]=[CH:28]2)=[O:24].[N:36]12CCCN=C1CCCC[CH2:37]2.O.C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([Br:12])([F:11])[F:10])[CH:5]=[C:4]([O:18][CH:19]([F:21])[F:20])[C:3]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([C:37]#[N:36])[CH:29]=[CH:28]2)=[O:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F)c1ccc2c(ccc[n+]2[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2cc(C(=O)Nc3c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc3OC(F)F)ccc2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 36.1 %

Procedure:
N-[2-Bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]-quinoline-6-carboxamide-1-oxide (0.41 g) was dissolved in tetrahydrofuran (50 ml), added with trimethylsilylnitrile (0.23 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 g), and stirred at 60° C. for 5 hours. Water was added to the reaction solution and extraction was carried out twice using ethyl acetate. The organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The resulting residues were purified by column chromatography to obtain N-[2-bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]-2-cyanoquinoline-6-carboxamide (0.15 g, 36%).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)C(O)=O)[N:16]=2)[CH:12]=[N:11]1)[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].C1C=CC(OP(OC2C=CC=CC=2)([N:40]=[N+]=[N-])=O)=CC=1.C(N(CC)CC)C.O>O1CCOCC1>[NH2:40][C:24]1[CH:23]=[C:22]([NH:21][C:17]2[N:16]=[C:15]([C:13]3[CH:12]=[N:11][N:10]([CH:4]([CH:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)[CH2:3][C:1]#[N:2])[CH:14]=3)[CH:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3cccc(C(=O)O)c3)n2)cn1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3cccc(N)c3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)benzoic acid (228 mg, 0.566 mmol), and diphenylphosphonic azide (0.18 mL, 0.85 mmol), triethylamine (0.16 mL, 1.1 mmol) in 1,4-dioxane (4.2 mL) was stirred at room temperature overnight. To the resulting mixture was added water (0.36 mL). The reaction was refluxed overnight. The crude racemic mixture was used directly in next step. An analytically pure sample was obtained by RP-HPLC (pH 2). LCMS (M+H) 374.1.
Reaction SMILES: C([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=2)[CH2:6]1)(=O)C.Cl.[CH3:29]O>>[NH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:29])=[O:20])[CH:11]=2)[CH2:6]1
Reactant: CO
Reactant: CC(=O)NC1Cc2ccc(C(=CCCCC(=O)O)c3cccnc3)cc2C1
Agent: Cl
Product: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(N)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.1 g of 6-(2-acetylaminoindan-5-yl)-6-(3-pyridyl)hex-5-enoic acid are refluxed for 15 hours with 20 ml of half concentrated hydrochloric acid and then rotary evaporated. The residue is then added to 50 ml of methanol saturated with dry hydrogen chloride. After 30 minutes stirring at ambient temperature the reaction mixture is rotary evaporated to dryness. The residue is taken up in 1N sodium hydroxide solution and adjusted to pH 10. It is then extracted 3 times with 50 ml of methylene chloride, the organic phase is dried and rotary evaporated.
Reaction SMILES: [CH:1](/B(O)O)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[C:20]2[CH:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[S:29][C:21]=2[N:22]([CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[N:23]=1>C(O)C.O.C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:27]([O:26][CH:24]([N:22]1[C:21]2[S:29][C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:31][C:20]=2[C:19](/[CH:1]=[CH:2]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:23]1)[CH3:25])[CH3:28]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CCOC(=O)c1cc2c(Br)nn(C(C)OCC)c2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(/C=C/c3ccccc3)nn(C(C)OCC)c2s1
Temperature: 82 °C
Yield: 87.2 %

Procedure:
1.7 g (1.4 mmol) of tetrakis(triphenylphosphine)-palladium [0], a solution of 6.6 g (43.2 mmol) of trans-β-styreneboronic acid in 40 cm3 of ethanol, and then a solution of 9.2 g (86.4 mmol) of sodium carbonate in 40 cm3 of water are successively added to a solution of 10.0 g (28.8 mmol) of ethyl 3-bromo-1-(1-ethoxyethyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate in 300 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 82° C. for 2.5 hours and is then cooled to a temperature in the region of 25° C. and diluted with 500 cm3 of water and 300 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is washed successively with twice 300 cm3 of water and then 300 cm3 of saturated brine. The organic phase is then dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under a pressure of argon (80 kPa), on a cartridge containing 330 g of silica gel (particle size 32-63 μm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 9.3 g of ethyl 1-(1-ethoxyethyl)-3-((E)-styryl)-1H-thieno[2,3-c]pyrazole-5-carboxylate are thus obtained in the form of a yellow solid. (Rf=0.70, thin-layer chromatography on silica gel, eluent: dichloromethane/methanol (98/2 by volume)).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1>CC(O)=O>[NH2:3][C:4]1[C:11]([Br:1])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: BrBr
Solvent: CC(=O)O
Product: N#Cc1cnc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
Br2 (0.52 mL, 0.01 mol) was added to a solution of 6-aminonicotinonitrile (1.1901 g, 0.01 mol) in AcOH (10 mL) at room temperature. The mixture was stirred at room temperature for 2 h. Then the mixture was concentrated and the residue was purified by flash column chromatography to give the title product (980.0 mg, 49%).