Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:21]=[O:22]>CN(C=O)C.[Cu]>[O:7]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:21]=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1cnccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cnccc1Oc1ccccc1
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of phenol (1.34 g, 14.3 mmol) in DMF (25 ml) was stirred with anhydrous potassium carbonate (0.99 g, 7.2 mmol) at 70°-80° C. for 40 minutes. 4-Chloro-3-pyridinecarboxaldehyde (2.02 g, 14.3 mmol) and copper bronze powder (0.10 g) were added and the resulting suspension stirred at 100°-110° C. for 2 hours. The reaction mixture was cooled, filtered and the residues washed with ether. The combined ether washings were diluted to 400 ml with more ether, washed with saturated brine (4×) and the solvent removed to give 4-phenoxy-3-pyridinecarboxaldehyde as a pale yellow crystalline solid (2.62 g); melting point 74°-75° C.; infrared max (nujol) 1590, 1695, 2760 cm-1 ; 1H NMR delta (CDCl3) 6.75 (1H broad), 7.15 (2H, d), 7.35 (1H, t), 7.50 (2H, t), 8.5-9.7 (2H, broad), 10.7 (1H, s).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16]CC)=O)[N:2]=1.[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.[NH2:30][OH:31]>CN(C=O)C.CO.O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:12]2[C:13]3[CH:1]=[N:2][C:3]([C:14]([NH:30][OH:31])=[O:16])=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: NO
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(NO)c1cc2c3ccccc3n(Cc3ccc(F)cc3)c2cn1
Reaction time: 24 h
Yield: 39 %

Procedure:
To a stirred solution of ethyl 9H-β-carboline-3-carboxylate (368 mg, 1.53 mmol) in DMF (4 mL) under a nitrogen atmosphere was added NaH (61.2 mg, 60% in mineral oil, 1.53 mmol) portionwise, followed by 4-fluorobenzyl bromide (0.19 mL, 1.53 mmol). Stirring was continued for 24 hours at ambient temperature, water (10 mL) was then added to the mixture. The precipitate was filtered, washed with water and dried to give a solid that was dissolved in methanol (20 mL). To the resulting solution, H2NOH (20 mL, 50 wt. % solution in H2O, 0.30 mol) was added. The suspension was stirred for 5 days at ambient temperature. The mixture was then filtered, and the solid was boiled in methanol (40 mL). After filtration, the title product (0.20 g, 39%) was obtained. 1H NMR (300 MHz, DMSO-d6): δ 11.28 (1H, s), 9.02–9.08 (2H, m), 8.85 (1H, s), 8.48 (1H, d, J=9.0 Hz), 7.10–7.84 (7H, m), 5.85 (2H, s). HRMS (M+H)+ found: 336.1157. Calcd for C19H15N3O2F: 336.1148.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C(Cl)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[CH2:41][NH2:42]>>[C:30]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]2[C:17]([NH:42][CH2:41][C:37]2[S:36][CH:40]=[CH:39][CH:38]=2)=[O:19])=[O:7])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NCc1cccs1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCON=C1C[C@@H](C(=O)NCc2cccs2)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 2-thienylmethylamine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=462.4.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:14]O>>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:14])=[O:6]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(OC)ccc1N
Temperature: 60 °C

Procedure:
Hydrogen chloride gas was bubbled through a solution of 2-amino-5-methoxybenzoic acid (5.0 g, 30 mmol) in MeOH (200 mL) for 30 minutes. The solution was heated at 60° C. overnight. The reaction was cooled and the solvent removed in vacuo. The residue was dissolved in water, basified with 5M NaOH and extracted twice with ether. The ether extracts were washed with 5M NaOH and water, dried (MgSO4), filtered and concentrated in vacuo to give i-e (4.25 g, 78%): MS m/z═182 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(#N)C.P(Cl)(Cl)([Cl:17])=O>O>[Cl:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 3-chloro-2-hydroxy-5-nitropyridine (36.0 g), acetonitrile (72 mL), and phosphorus oxychloride (37.5 g) was heated to 80° C. The reaction was then stirred at this temperature for about 15 hours. After cooling the reaction to 40° C., water (27 g) was added, while maintaining the temperature below 70° C. The temperature was adjusted to 45° C., and then more water (189 g) was added slowly. The reaction was then cooled to 23° C., stirred for at least 12 hours, and then filtered. After washing the wet cake with water, the product was dried in a vacuum oven. 1H NMR (400 MHz/CDCl3) δ 9.10 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:6]2=[CH:5][N:4]=1.[Br:21]N1C(=O)CCC1=O.O>O1CCCC1>[Br:21][C:5]1[N:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:11][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCn2c(cnc2C(F)(F)F)C1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
Tert-butyl 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11a (370 mg, 1.27 mmol) was dissolved in 30 mL of tetrahydrofuran, followed by addition of N-bromosuccinimide (453 mg, 2.54 mmol) under −78° C. After stirring for 1 hour, the reaction mixture was heated to room temperature and reacted for 12 hours. The reaction mixture was added with 50 mL of H2O, extracted with ethyl acetate (60 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11b (510 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
Reaction SMILES: C=O.CN1N=NC(C[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][CH2:20]N)=N1.[BH3-][C:23]#[N:24].[Na+].[C:26]([O-])([O-])=O.[K+].[K+]>CO.C(O)(=O)C>[CH3:26][N:24]([CH3:23])[CH2:20][CH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:10][CH:11]=2)[NH:15][CH:14]=1
Reactant: Cn1nnc(Cc2ccc3[nH]cc(CCN)c3c2)n1
Reactant: [BH3-]C#N
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCc1c[nH]c2ccccc12
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of formaldehyde (80 mg of a 30% solution) in methanol (15 ml) was added to a stirred solution of 2-[5-(2-methyltetrazol-5-ylmethyl)-1H-indol-3-yl]etylamine (0.1 g, 0.4 mmol), NaCNBH3 (60 mg) and glacial acetic acid (0.12g) in methanol (15 ml). The solution was stirred for 2 h, basified with K2CO3 solution and the MeOH removed under vacuum. The crude product obtained after extraction into ethylacetate and removal of solvent was chromatographed through silica-gel eluting with CH2Cl2 /EtOH/NH3 (40:8:1) to give the desired N,N-dimethyltryptamine (96 mg, 87%). The oxalate salt was prepared: mp 185°-187° C. (MeOH/Et2O); (Found: C, 54.42; H, 5.74; N, 22.53. C15H20N6. C2H2O4 requires C, 54.54; H, 5.92; N, 22.45%); δ (360 MHz, D2O) 2.91 (6H, s, 2 of CH3); 3.21 (2H, t, J=7.4 Hz, CH2); 3.47 (2H, t, J=7.4 Hz, CH2); 4.30 (3H, s, CH3); 4.34 (2H, s, CH2); 7.17 (1H, dd, J=1.5 and 8.4 Hz, Ar--H); 7.33 (1H, s, Ar--H); 7.48 (1H, d, J=8.4 Hz, Ar--H); 7.59 (1H, s, Ar--H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:34]1[CH:38]=[CH:37][C:36](NC)=[CH:35]1.[CH3:41][N:42](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:20]1([CH2:19][CH2:18][NH:17][C:13]2[N:12]=[C:11]3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:42][CH2:41][C:36]5[CH:37]=[CH:38][S:34][CH:35]=5)[CH:3]=4)[C:16]3=[CH:15][N:14]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2cnc(NCCN3CCOCC3)nc21
Reactant: CNc1ccsc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccsc3)c2)c2cnc(NCCN3CCOCC3)nc21

Procedure:
To a stirred solution of [3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 40 supra) (250 mg, 0.47 mmol), thiophen-3-yl-methylamine (54 mg, 0.564 mmol), DavePhos (37 mg, 20% mol) and t-BuONa (54 mg, 0.564 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (27 mg, 10% mol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100° C. for 6 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 100:1, v/v) to give (2-morpholin-4-yl-ethyl)-[3-{3-[(thiophen-3-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine. (Yield 150 mg, 56%).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].C1(C)C=CC=CC=1.[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C>O>[N:2]1[NH:23][N:24]=[N:25][C:1]=1[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C#N
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1c1nn[nH]n1
Temperature: 130 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
A mixture of tert-butyl [(1S,2R)-2-cyanocyclopentyl]carbamate (2.8 g), toluene (50 ml), sodium azide (2.1 g), and triethylamine hydrochloride (4.5 g) was stirred at 130° C. for 24 hours. To the reaction mixture was added water (40 ml) at room temperature. The aqueous layer was separated, citric acid was added thereto under ice-cooling, and the solid precipitated was collected by filtration and washed with water to obtain tert-butyl [(1S,2R)-2-(2H-tetrazole-5-yl)cyclopentyl]carbamate (3.0 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[Br:32][C:33]1[CH:34]=[N:35][C:36](Cl)=[N:37][CH:38]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[N:35][C:36]([O:3][CH2:4][CH2:5][O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:15])=[O:16])[C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[N:37][CH:38]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To sodium hydride (220 mg, 55-65% in mineral oil) was added THF (35 ml) followed by addition of 2-phenyl-ethenesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (250 mg). The mixture was stirred for 1 h at rt. Then 5-bromo-2-chloro-pyrimidine (188 mg) was added and stirring continued for 21 h at 80° C. The solvent was evaporated and diethylether (20 ml) was added to the residue. The precipitate was filtered off and washed with diethylether, dissolved in water and acidified by citric acid. The precipitate was filtered off and the crude material was purified by chromatography over silicagel with hexane/EtOAc=1/1 to give 2-phenyl-ethenesulfonic acid {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (91 mg); tR=5.39 (LC); [M+H]+=570.34 (ES+); [M−H]−=568.45 (ES−).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=3[S:11][C:10]=2[CH2:25]C2C3C(=CC=CC=3)N=CC=2)=[O:8])[CH2:3]1.[CH2:36]([N:38](CC)[CH2:39]C)C.O[N:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[OH:1][CH:2]1[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:12]=3[S:11][C:10]=2[CH2:25][N:44]2[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[N:46]=[C:36]2[NH:38][CH3:39])=[O:8])[CH2:3]1
Reactant: CCN(CC)CC
Reactant: On1nnc2ccccc21
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O)CO3)c(Cc3ccnc4ccccc34)sc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CNc1nc2ccccc2n1Cc1sc2c(c1C(=O)N1CC(O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(S)-4-Hydroxyisoxalidine hydrochloride (Example 1, part b)) (0.08 g) and triethylamine (0.09 ml) were added to a solution of the product of part b) (0.13 g) in dichloromethane (5 ml). 1-Hydroxybenzotriazole (0.09 g) was added as well as 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride (0.12 g). The reaction mixture was stirred for 12 h at room temperature. The solution was concentrated under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-3% methanol in ethyl acetate. The product obtained was recrystallised from ethyl acetate/isohexane/methanol to give the title compound as a white solid (0.07 g). MS(APCI) 513.2 [M+H]+. δ 1HDMSO 0.82-0.86 (6H,m), 2-2.1 (1H, m), 2.9 (3H, m), 3.2 (3H, s), 3.6-3.68 (3H,m), 3.78-3.84 (1H, m), 3.9-3.94 (1H, m), 4-4.12 (1H, m), 4.6-4.8 (1H, 2m), 5.2-5.61 (3H, m), 6.86-6.99 (3H, m), 7.19-7.27 (2H, m)
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20]C=1.CC[N:26](C(C)C)C(C)C>CC(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:1][N:2]([CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:26]=2)[CH2:13][CH2:12]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: Clc1ccncc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(CC1CCNCC1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CN(CC1CCN(c2ccncn2)CC1)C(=O)OC(C)(C)C
Yield: 51 %

Procedure:
tert-Butyl methyl(piperidin-4-ylmethyl)carbamate (1.4 mmol, 1.0 eq) and 4-chloropyridine (4.2 mmol, 3.0 eq) were dissolved in 2-propanol (5 ml) and DIPEA (7.0 mmol. 5.0 eq) and refluxed for 16 hours. After monitoring by TLC, the reaction solution was diluted with ethyl acetate and sat. sodium hydrogen carbonate solution and the phases were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were dried over magnesium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution). Yield: 51%
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[O:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[O:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2oc(-c3ccc(C(F)(F)F)cc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methanol (271 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (146 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.4 mL) and 1,1′-(azodicarbonyl)dipiperidine (404 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methoxy)benzoate as an oil. The obtained methyl 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methoxy)benzoate was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (138 mg, 39%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH2:10][O:11][C:12](/[C:14](/[C:22]#[N:23])=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C(O)C>[NH2:23][C:22]1[O:7][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]=1[C:12]([O:11][CH2:10][CH3:9])=[O:13]
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)OC2=C(C(=O)CCC2)C1c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 1,3-cyclohexane dione (0.56 g, 5.0 mmole) in hot ethanol (10 ml) was added ethyl trans-α-cyanocinnamate (1.0 g, 5.0 mmole) and the mixture heated at reflux for 18 h. The mixture was cooled to room temperature, filtered and washed with ethanol to provide the desired product (1.30 g, 83%) as a white powder. 1H NMR (400 MHz; CDCl3) δ 7.29-7.0 (m, 5H); 6.2 (bs, 2H); 4.72 (s, 1H); 4.09-3.96 (m, 2H); 2.64-2.48 (m, 2H); 2.40-2.26 (m, 2H); 2.06-1.88 (m, 2H); 1.14 (t, 3H, J=7.4 Hz). LC MS shows MH+ at 314.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.5 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxazol-2-yl-ethyl)-amide (75 mg, 0.14 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.45 ml, 5.6 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.6 ml, 8.4 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 23 mg (39%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxazol-2-yl-ethyl)-amide as a light yellow powder. MS: (M+H)+=406; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.95 (br. s., 1H), 9.13 (s, 1H), 8.66 (d, J=8.7 Hz, 1H), 8.51 (s, 1H), 8.47 (dd, J=9.1, 5.3 Hz, 1H), 8.11 (s, 1H), 7.69 (dd, J=9.6, 2.1 Hz, 1H), 7.24 (s, 1H), 7.02-7.11 (m, 1H), 5.48-5.60 (m, 1H), 4.15 (s, 3H), 1.66 (d, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][O:6][CH:7]=1.C(OCC)(=O)[CH2:19][C:20]([O:22]CC)=[O:21].[H-].[Na+].Cl>O1CCCC1>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:4]2[C:3]([CH2:2][CH2:19][C:20]([OH:22])=[O:21])=[CH:7][O:6][N:5]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: FC(F)(F)c1ccc(-c2nocc2CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1conc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A solution of 4-chloromethyl-3-(4-trifluoromethylphenyl)isoxazole (2.90 g) in tetrahydrofuran (100 ml) was added to a mixture of diethyl malonate (5.35 g), sodium hydride (60%, oil, 1.30 g) and tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at room temperature overnight. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give 3-[3-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (2.49 g, yield 79%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 173–174° C.