Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].I.C(O)(=O)C>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Agent: I
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A mixture of 432 mg of 1-bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (1 mmol), 63 mg of red phosphorous (2 mmol), 0.4 ml of aqueous 57 wt % HI (3 mmol), and 1 ml of glacial acetic acid was refluxed with stirring for 30 min. Then the reaction mixture was diluted with 25 ml of ethyl acetate, filtered by suction through a pad of celite, washed with a solution of 0.2 g of NaHSO3 in 5 ml of water, and washed twice with 5 ml of concentrated aqueous sodium bicarbonate solution. The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (85:15). 123 mg of the title compound were obtained; 1H NMR (CDCl3): δ=11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38 to 7.63 (m, 7H), 4.49 (t, 2 H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])[C:28]1[C:33]([Cl:34])=[CH:32][C:31]([Cl:35])=[CH:30][C:29]=1[Cl:36])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])[C:28]3[C:29]([Cl:36])=[CH:30][C:31]([Cl:35])=[CH:32][C:33]=3[Cl:34])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)c1c(Cl)cc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3c(Cl)cc(Cl)cc3Cl)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.088 g, 0.318 mmol) was reacted with N-(2-azidoethyl)-2,4,6-trichlorobenzamide (0.093 g, 0.318 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2,4,6-trichlorobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), δ 7.34 (s, 1H), δ 7.26 (s, 2H), δ 6.42 (s, 1H), δ 5.97 (s, 2H), δ 4.51 (s, 2H), δ 3.94 (s, 2H), δ 2.45 (t, 2H), δ 2.20 (s, 2H), δ 1.47 (m 13H), δ 1.21 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 164.7, 148.0, 135.7, 134.6, 132.9, 128.7, 128.1, 127.3, 122.3, 84.9, 53.7, 49.3, 39.9, 31.8, 29.2, 28.9, 28.2, 25.5, 22.8, 14.3 ppm; HRMS (ESI) calcd for C24H30Cl3N7O3 (M+) 569.1476. found 569.1477, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2,4,6-trichlorobenzamide hydrochloride (0.116 g, 72% yield). 1H NMR (300 MHz, CD3OD) δ 8.36 (s, 1H), δ 7.45 (s, 2H), δ 6.46 (s, 1H), δ 4.77 (s, 2H), δ 3.97 (s, 2H), δ 2.80 (s, 2H), δ 2.48 (t, 2H), δ 1.73 (s, 2H), δ 1.62 (s, 2H), δ 1.41 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 165.5, 147.3, 136.9, 134.5, 132.7, 128.2, 128.0, 127.6, 108.6, 51.2, 39.0, 28.1, 27.7, 24.1, 23.8 ppm; HRMS (ESI) calcd for C19H22Cl3N7O (M+) 469.0951. found 469.0941.
Reaction SMILES: Cl.[NH2:2]O.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:20][N:2]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)on1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Hydroxylamine hydrochloride (0.65 g, 9.42 mmol) was added to a suspension of ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (2.0 g, 7.85 mmol) in absolute ethanol (40 mL) and the reaction was heated to reflux for 4 hours. After cooling to room temperature, the resulting white solid was filtered, washed with water and cold ethanol and dried in vacuo to obtain ethyl 5-(4-chlorophenyl)isoxazole-3-carboxylate (1.19 g, 4.73 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.Cl.[CH3:18][C:19](C)=[O:20].C(Cl)(=O)C>C(N(CC)CC)C>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(=[O:20])[CH3:18]
Reactant: CC(C)=O
Reactant: Nc1ccccc1N1CCc2ccccc21
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred slurry, under N2, of 9.96 g of 1-(2-amino-phenyl)indoline.HCl and 300 ml of dry acetone is treated with 10.1 g of triethylamine over a 10 minute period. After cooling to 0°-5° C., 4.70 g of acetyl chloride is added dropwise over 0.5 hour. The mixture is stirred 18 hours at ambient temperature, then filtered. The filtrate is diluted with 100 ml of water and concentrated. When all the acetone is removed, the residue is filtered off, washed well with water, and dried to afford 1-(2-acetamidophenyl)indoline, m.p. 125°-128° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][NH2:10])=O.[CH2:11]([N:18]=[C:19]=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[CH2:11]([N:18]1[C:19]([S:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)=[N:10][N:9]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=NCc1ccccc1
Reactant: Clc1ccc(CBr)cc1
Reactant: NNC(=O)c1ccccn1
Product: Clc1ccc(CSc2nnc(-c3ccccn3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-pyridinecarboxylic acid hydrazide, benzyl isothiocyanate and 4-chlorobenzyl bromide as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:22])[N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[O:25]=[C:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C:32](O)=[O:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:22])[N:16]3[CH2:17][CH2:18][N:19]([C:32](=[O:33])[CH2:31][N:27]4[CH2:28][CH2:29][CH2:30][C:26]4=[O:25])[CH2:20][CH2:21]3)[N:13]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: O=C(Nc1nc(CC(=O)N2CCNCC2)cs1)c1ccc(Cl)cc1
Reactant: O=C(O)CN1CCCC1=O
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CN3CCCC3=O)CC2)cs1)c1ccc(Cl)cc1

Procedure:
54.3 Using general procedure A, 4-chloro-N-[4-(2-oxo-2-piperazin-1-yl-ethyl)-thiazol-2-yl]-benzamide was coupled with (2-oxo-pyrrolidine-1-yl)-acetic acid (CAS 53934-76-2) to give 4-chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-pyrrolidin-1-yl)-acetyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide. White solid. MS 490.4 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(C)c(C)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 67.5 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate (35 mg, 0.13 mmol) and 1-(3-methoxy phenyl) piperazine (50 mg, 0.26 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (40 mg, 0.26 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 37 mg of the titled compound (yield, 68%). NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.39 (s, 3H), 3.22-3.30 (m, 4H), 3.75 (m, 4H), 3.80 (s, 3H), 4.13 (s, 3H), 6.46-6.49 (m, 2H), 6.55-6.58 (m, 1H), 7.20-7.23 (m, 1H), 7.52 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:4]=1[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])#[CH:2].CO>[Pd]>[CH2:1]([C:3]1[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:4]=1[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])[CH3:2]
Reactant: C#Cc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Pd]
Solvent: CO
Product: CCc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a suspension of 2-ethynyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (145 mg, 0.561 mmol) in 5% Pd/C (30 mg) was added CH3OH (4 ml). The mixture was purged three times with hydrogen gas (50 psi) and shaken for 2 hours at room temperature. The reaction mixture was filtered over a pad of Celite and concentrated under reduced pressure. The crude residue was chromatographed to yield the 2-ethyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (112 mg, 76%).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=O)C.[O:15]1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:15][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:14])=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(CCC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OCCCc1ccc(O)cc1
Yield: 65 %

Procedure:
To 3.82 g (17.36 mmoles) of methyl ester of 3-(4-acetylphenyl) propionic acid were added 100 ml of dry tetrahydrofurane. To this solution were slowly added 1.80 g (47.43 mmoles) of lithium aluminium hydride (LiAlH4). The reaction mixture was refluxed in an argon atmosphere for 4 hours. At the end of the reaction, water was carefully added, extraction was performed three times with diethyl ether and the result was vacuum dried over anhydrous sodium sulphate, giving 1.70 g (65% yield) of 3-(4-hydroxyphenyl)-1-propanol. Crystallisation in methanol gave a white crystalline solid m,.p.=52-53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7](=[CH:22][N:23]([CH3:25])[CH3:24])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Product: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O

Procedure:
The mixture of 2.2 g of 8-chloro-1-phenyl-3,4-dihydro-2-benzazepin-5-one and 15 ml of dimethylformamide-dimethylacetal is refluxed for one hour and the excessive reagent removed under reduced pressure at a temperature not exceeding 135°. The residue is crystallized from diethyl ether, to yield the 8-chloro-4-dimethylaminomethylidene-1-phenyl-3,4-dihydro-2-benzazepin-5-one; m.p. 179°-180°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:46]3[O:45][C:44]([NH2:47])=[N:43][C:42]=3[C:41]([O:48][CH3:49])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[C:46]3[O:45][C:44]([NH:47][C:4](=[O:6])[CH2:3][O:2][CH3:1])=[N:43][C:42]=3[C:41]([O:48][CH3:49])=[CH:40][CH:39]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCC(=O)Nc1nc2c(OC)ccc(-c3ccc(F)cc3)c2o1

Procedure:
From methoxyacetic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [Mg:1].C1C2C(=CC3C(C=2)=CC=CC=3)C=CC=1.C=CC(=C)C.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>O>[CH3:22][C:21]([CH3:24])([O-:25])[CH3:23].[Mg+2:1].[CH3:22][C:21]([CH3:24])([O-:25])[CH3:23]
Reactant: CC(C)(C)O
Reactant: [Mg]
Solvent: c1ccc2cc3ccccc3cc2c1
Solvent: O
Solvent: C=CC(=C)C
Product: CC(C)(C)[O-]
Product: [Mg+2]
Temperature: 50 °C

Procedure:
9.0 g (370 mmol) of powdered magnesium (Timminco <150 μm) were suspended in 480 g of water-free THF in a 1 liter double-walled glass reaction vessel with a reflex cooler, internal thermometer and drip funnel and was mixed with 1.9 g (11 mmol, 3 mol %) of anthracene. The mixture was then heated to 50° C. After approximately 20 minutes the solution became orange in colour due to the formation of the Mg-anthracene adduct. 51 g (750 mmol) of isoprene were then dipped in within 10 min, and stirring took place for 1.5 hours at an internal temperature of between 50 and 55° C. A sample was taken and was titrated for total base content: the base content of 0.29 mmol/g was equivalent to reaction of approximately 21% of the total magnesium used. A mixture of 58 g of t-butanol (780 mmol) and 6 g of isoprene (90 mmol) was then added within 130 minutes. In the course of this care was taken to see that the colour deriving from the Mg-anthracene complex did not disappear.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[C:15]([OH:17])=[O:16].[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([O:16][C:15]([C:3]2[C:2]([CH3:18])([CH3:1])[C:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[CH:7]=[CH:6][C:5]=3[N:4]=2)=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: CC1(C)C(C(=O)O)=Nc2ccc3ccccc3c21
Solvent: ClCCl
Product: CC1(C)C(C(=O)Oc2ccccc2)=Nc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 2.8 %

Procedure:
200 mg of 1,1-dimethyl-1H-benzo[e]indole-2-carboxylic acid 3 (0.84 mmol) and 395 mg (4.2 mmol) phenol were dissolved in 50 mL methylene chloride. Then 188 μL (1.12 mmol) trifluorosulfonic acid anhydride were added and the reaction mixture was stirred at room temperature for 5 hours. After evaporation of the solvent under reduced pressure, the residue was taken up in methylene chloride and washed with 0.1 N NaOH and water. The organic phase was separated, dried over sodium sulfate and filtered. The solvent was removed under vacuum and the crude product was purified by preparative HPLC column chromatography (eluent: water-acetonitrile). The appropriate fractions were combined and dried by lyophilization to yield 7.5 mg of product 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([C:12](O)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]1([CH2:21][CH2:22][C:23](=[O:26])[CH2:24][OH:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1.C1C[O:45][CH2:44]C1>>[C:15]1([CH2:21][CH2:22][C:23](=[O:26])[CH2:24][O:25][C:44]([CH2:12][C:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[O:10][CH:9]=2)=[O:45])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2c(C(=O)O)coc12
Reactant: O=C(CO)CCc1ccccc1
Reactant: C1CCOC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1cccc2c(CC(=O)OCC(=O)CCc3ccccc3)coc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
7-methoxybenzofuran-3-carboxylic acid (220 mg) was dissolved in THF (5 ml). To this solution, 4-phenyl-2-oxo-1-butanol (211 mg) and dicyclohexylcarbodiimide (330 mg) were added and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was filtered and the filtrate was poured into water layer (50 ml), followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (178 mg, yield: 47%).
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:32]([N:36]=[C:37]=[O:38])([CH2:34][CH3:35])[CH3:33]>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:37]([NH:36][CH:32]([CH2:34][CH3:35])[CH3:33])=[O:38])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CCC(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and sec-butyl isocyanate (29 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (81 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]([O-])([O-])=O.[Cs+].[Cs+].C[N:27]([CH:29]=O)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:29]#[N:27])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCC#N)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid tert-butyl ester 31 (0.365 g, 1.37 mmol) and Cs2CO3 (0.672 g, 2.06 mmol) in anhydrous DMF (8 mL) was heated at 65° C. for 30 min. lodoacetonitrile (0.276 g, 1.651 mmol) was then added to the mixture in one portion. The mixture was stirred at 65° C. overnight, and then cooled to room temperature. The precipitated solid was filtered, and the filtrate was partitioned between water and dichloroniethane (each 50 mL). The organic layer was separated, washed with brine (3×50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with a mixture of diethyl ether/dichloromethane (6:94, v/v), to afford the desired product 40 (0.109 g, 38% yield) as a colorless-viscous oil. 1H NMR (300 MHz, CDCl3): δ 1.43 (s, 9H), 1.57 (m, 4H), 2.60 (t, 2H), 3.15 (m, 2H), 4.49 (br, 1H), 4.75 (s, 2H), 6.91 (d, 2H), 7.13 (d, 2H).
Reaction SMILES: C(NCC)C.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[C:14]([N:16]3[CH2:21][CH2:20]O[CH2:18][CH2:17]3)[N:15]=2)[CH:12]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[C:14]([N:16]([CH2:21][CH3:20])[CH2:17][CH3:18])[N:15]=2)[CH:12]=1
Reactant: Brc1ccc2nc(N3CCOCC3)nn2c1
Solvent: CCNCC
Product: CCN(CC)c1nc2ccc(Br)cn2n1

Procedure:
Using diethylamine, this compound was prepared following the same method as for the synthesis of 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridine Light brown solid (2.0 g, 82%). MS: m/z=270 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:38]=[CH:39][CH:40]=3)[O:20][C:21]3[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:24]=[N:23][C:22]=3[C:35]([OH:37])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].C([Al+2])C.CCCCCC>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:40]=[CH:39][C:38]4[C:35](=[O:37])[C:22]5[N:23]=[N:24][N:25]([CH2:26][C:27]6[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=6)[C:21]=5[O:20][C:19]=4[CH:18]=3)[CH2:9][CH2:8]2)=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2nnc(C(=O)O)c2Oc2cccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)c2)cc1
Agent: CC[Al+2]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnc3c(=O)c4ccc(OCCCN5CCN(Cc6ccc(Cl)cc6)CC5)cc4oc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-{3-{3-[4-(4-Chlorobenzyl)-1-piperazinyl]-propoxy}phenoxy}-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid, (0.50 g, 0.84 mmole), was dissolved in dry dichloromethane (20 ml) and oxalyl chloride, (1.00 ml, 11.7 mmole), added, followed by 1 drop of dimethylformamide. The reaction was stirred overnight, then excess oxalyl chloride and solvent evaporated in vacuo. The acid chloride was resuspended in dry dichloromethane, (20 ml), under nitrogen and cooled with stirring in an ice bath. A 25% solution of ethyl aluminium dichloride in hexane, (1.61 ml, 3.38 mmole) was added dropwise and the reaction stirred in ice for 2 hours, warmed to room temperature over 1 hour, and stirred for a further 3 hours. The mixture was quenched with dilute hydrochloric acid, (50 ml) and left to stand overnight. The resultant cream solid was filtered, stirred in water, (25 ml), and neutralized to pH7 with dilute sodium hydrogen carbonate solution. The aqueous phase was decanted and the gummy residue purified by column chromatography using silica gel, eluting with chloroform to give the title compound as a colourless oil which crystallized on trituration with methanol. 171 mg (35%) mp (MeOH) 135°-138° C. νmax (mull) 1518, 1535, 1565, 1620, 1680 cm-1 δ(CDCl3) 2.00 (2H, m, CH2), 2.50 (10H, bs, piperazinyl+CH2), 3.43 (2H, s, N--CH2), 3.77 (3H, s, OCH3), 4.13 (2H, t, J 6 Hz, OCH2), 5.56 (2H, s, N--CH2), 6.93 (2H, m, aromatics), 7.12 (4H, ABq, Δν 45 Hz, J 9 Hz, C6H4OCH3), 7.29 (4H, s, C6H4Cl) 8.28 (1H, d, J 9 Hz, aromatic).
Reaction SMILES: C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[N:28]=1.[F:39][C:40]1[C:49]2[O:48][CH2:47][CH2:46][O:45][C:44]=2[C:43]([O:50][CH3:51])=[CH:42][C:41]=1[CH:52]=O.C[Si]([C:58]#[N:59])(C)C>C1COCC1>[F:39][C:40]1[C:49]2[O:48][CH2:47][CH2:46][O:45][C:44]=2[C:43]([O:50][CH3:51])=[CH:42][C:41]=1[CH:52]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[N:28]=[C:27]([CH3:26])[O:31][N:30]=2)=[CH:33][CH:34]=1)[C:58]#[N:59]
Reactant: COc1cc(C=O)c(F)c2c1OCCO2
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)c(F)c2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 71 mg of Yb(OTf)3 in 4 ml of THF there were added 204 mg of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 247 mg of 5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde, 250 mg of MS3A and 0.30 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give (5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile (crude product).