Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>C(O)C.[Pt]=O>[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: c1ccc(CCc2ccnc3ccccc23)nc1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2c(CCC3CCCCN3)ccnc2c1
Reaction time: 8 h

Procedure:
30 ml of a 10 N aqueous solution of acetic acid are added to a solution containing 7 g of 4-[2-(2-pyridyl)-ethyl]-quinoline in 700 ml of ethanol, then 1.4 g of 82% platinum oxide is added as catalyst. Hydrogenation is effected at 45° C. under a hydrogen pressure equal to the normal pressure (1 bar) for 24 hours, being careful to replace the catalyst used every eight hours by fresh catalyst. At the end of the 24 hours (the quantity of hydrogen absorbed is then 2.9 liters), the catalyst is removed by filtration, the ethanol is evaporated under reduced pressure and the residue is taken up with 200 ml of water. The aqueous phase is extracted with chloroform, then made alkaline with concentrated ammonia and extracted with methylene chloride. The methylene chloride phase is dried over magnesium sulfate and evaporated under reduced pressure. The oily residue (6.3 g) is fixed on a column containing 630 g of silica, then eluted with a 9/1 toluene-diethylamine mixture. 1.9 g are thus isolated of 4-[2-(2-piperidyl)-ethyl]-quinoline.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[S:4][C:5]([N:8]=[C:9]=[O:10])=[N:6][N:7]=1.[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C1C=CC=CC=1>[OH:17][CH2:16][CH2:15][N:14]([CH3:13])[C:9]([NH:8][C:5]1[S:4][C:3]([C:2]([F:11])([F:1])[F:12])=[N:7][N:6]=1)=[O:10]
Reactant: CNCCO
Reactant: O=C=Nc1nnc(C(F)(F)F)s1
Solvent: c1ccccc1
Product: CN(CCO)C(=O)Nc1nnc(C(F)(F)F)s1
Reaction time: 0.17 h

Procedure:
2-Trifluoromethyl-1,3,4-thiadiazol-5-yl isocyanate dimer (8 grams), N-methyl-N-β-hydroxyethylamine (3.1 grams) and benzene (40 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, reflux condenser and thermometer. The reaction mixture was heated at reflux, with stirring for a period of about 10 minutes. After this time the reaction mixture was stripped of solvent under reduced pressure to yield the desired product N-(β-hydroxyethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)urea as an oily residue.
Reaction SMILES: [NH2:1][CH:2]1[N:11]2[C:7](=[N:8][N:9]=[CH:10]2)[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]([CH2:16][C:17]([N:19]([CH:26]([CH3:28])[CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[C:3]1=[O:29].[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH:26]([N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:17](=[O:18])[CH2:16][N:4]1[C:3](=[O:29])[CH:2]([NH:1][C:37]([NH:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[N:11]2[C:7](=[N:8][N:9]=[CH:10]2)[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]1=2)([CH3:27])[CH3:28]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)N(C(=O)CN1C(=O)C(N)n2cnnc2-c2ccccc21)c1ccccc1
Solvent: ClCCl
Product: CC(C)N(C(=O)CN1C(=O)C(NC(=O)Nc2ccccc2)n2cnnc2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A mixture of 2-(4-Amino-5-oxo-4,5-dihydro-1,2,3a,6-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-phenyl-acetamide (140 mg, 0.361 mmol), prepared as in Intermediate 36, and phenyl isocyanate (39.2 uL, 0.361 mmol) in 5 mL dry DCM is stirred at ambient temperature under nitrogen overnight. After concentrating in vacuo, the residue is chromatographed on flash grade silica gel using 95% ethyl acetate in n-hexane. The fractions containing the product are combined, concentrated in vacuo, and triturated with hexane. After removing the solvent in vacuo, the product is dried overnight at ambient temperature under high vacuum to provide the title compound (84 mg, 0.165 mmol) as a white solid. The product is lyophilized from acetonitrile/water. 1H NMR (300 MHz, d6-DMSO): 0.89-0.96 (m, 6H); 4.02 (d, J=16.3 Hz, 1H); 4.16 (d, J=16.3 Hz, 1H); 4.62-6.73 (m, 1H); 5.99-6.05 (m, 1 H); 6.93 (t, J=7.2 Hz; 1H); 7.10-7.89 (m, 14H); 8.10 (s, 1H); 9.30 (s, 1H). MS (FAB): [M+H]+ 510.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)O1.[H-].[Na+].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>>[N:10]1([C:6]2[CH:5]=[C:4]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:6]3[C:5]4[C:24](=[CH:23][CH:27]=[CH:16][CH:4]=4)[CH2:25][C:2]=3[C:7]=2[C:8]#[N:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccs2)oc1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-6-(thiophen-2-yl)-2H-pyran-3-carbonitrile (286 mg), indanone-2 (132 mg) and NaH (41 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 148-150° C.; FAB MS 357 (M++1); IR (KBr) 2215 cm−1 (CN), 1H NMR (200 MHz, CDCl3) δ 1.60-1.64 (m, 2H, CH2), 1.79-1.82 (m, 4H, 2CH2), 3.20-3.25 (m, 4H, 2CH2), 4.10 (s, 2H, CH2), 6.92 (s, 1H, ArH), 7.10-7.24 (m, 5H, ArH & CH), 7.49-7.54 (m, 2H, ArH & CH); HRMS calcd. for C23H20N2S 356.13472. Found 356,13580.
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[I:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1I
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(C(F)(F)F)c1I
Temperature: 25 °C
Yield: 99.4 %

Procedure:
2-Iodo-3-(trifluoromethyl)benzoic acid (10.0 g, 31.6 mmol) was stirred in thionyl chloride (100 mL, 31.6 mmol) at reflux for 2 hours. The mixture was then cooled to room temperature. The thionyl chloride was removed under vacuum, and the residue was azeotroped with dry toluene to give the product as a yellow-orange semi-solid (10.51 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.I[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH:14]([CH3:16])[CH3:15])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: O=C1NCc2ccc(O)c(Cl)c21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1Cl)C(=O)NC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A mixture of 7-chloro-6-hydroxy-2,3-dihydro-isoindol-1-one (500 mg, 2.72 mmol), 2-iodopropane (556 mg, 3.27 mmol), and cesium carbonate (1.33 mg, 4.08 mmol) in DMF (20 mL) was stirred at 80° C. overnight. The solution was cooled to room temperature and the reaction mixture partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptanes/EtOAc) to give 7-chloro-6-isopropoxy-2,3-dihydro-isoindol-1-one (133a, 300 mg, 65% yield) as a solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:24])=[C:6]([C:20]([F:23])([F:22])[F:21])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:9]=1)([O-])=O.Cl>[Fe].CCO>[F:21][C:20]([F:22])([F:23])[C:6]1[C:5]([NH2:24])=[C:4]([NH2:1])[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: Nc1c([N+](=O)[O-])cc(-c2ccccc2C(F)(F)F)cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(-c2ccccc2C(F)(F)F)cc(C(F)(F)F)c1N
Temperature: 80 °C
Reaction time: 6 h

Procedure:
5-Nitro-3,2′-bis-trifluoromethyl-biphenyl-4-ylamine (11.3 g, 32.5 mmol, as prepared in the previous step) was placed in a 500 mL round-bottom flask equipped with a magnetic stir bar. Anhydrous EtOH (150 mL) and 3M aq HCl (30 mL) were added via syringe. Iron powder (9.07 g, 162 mmol) was added, and the mixture was stirred at 80° C. for 6 h. The reaction was cooled to RT and filtered through a pad of Celite. The filter cake was washed with MeOH (300 mL). The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with water (150 mL). The aqueous layer was diluted with brine (100 mL) and extracted twice with EtOAc (50 mL). The combined organic extracts were washed with satd aq NaHCO3, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The material was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH3:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C

Procedure:
500 mg tert-butyl 4-(1H-indol-3-yl)-piperidine-1-carboxylate are placed in 8 ml dimethylformamide and 73.3 mg sodium hydride (60% in mineral oil) are added. After 15 min 175 μl methyl iodide are added. The reaction mixture is stirred at ambient temperature. After the reaction is complete the product is purified directly by preparative HPLC (method C). 302 mg of the product are obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])CO)[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:21]([CH2:19][CH3:20])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:14]
Reactant: CCCCC(CC)CO
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCC(CC)COC(=O)CCCC(C)(C)c1ccc(O)cc1O

Procedure:
5.0 parts of methyl 5-(2,4-dihydroxyphenyl)-5-methylhexanoate, 50 parts of 2-ethyl-hexanol and 0.5 parts of p-toluene sulphonic acid are heated on a steam-bath for 18 hours. The reaction mixture is then diluted with ether, washed with sodium bicarbonate solution, water, and evaporated. The residue, after stripping off excess 2-ethylhexanol on a rotary evaporator at 100° C. and 0.13 mb pressure gives 2-ethylhexyl 5-(2,4-dihydroxyphenyl)-5-methylhexanoate as a viscous amber liquid with the following percentage composition by weight.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:39])[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:39][CH2:33][C:34]2[O:38][CH:37]=[CH:36][CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NCc1ccco1
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccco4)ncnc32)[C@]1(C)F
Yield: 44.2 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added furfurylamine (about 0.96 ml, 10.38 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.20 g) as a colorless gummy mass. Yield: 44.2%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[N:8]([N:12]=[C:13]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=4)[N:14]=3)[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[CH:26]1(Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH:26]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[N:8]([N:12]=[C:13]([NH:15][C:16]5[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=5)[N:14]=4)[CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(Nc2nc3c(-c4cn[nH]c4)cccn3n2)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2nc3c(-c4cnn(C5CCCC5)c4)cccn3n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A suspension of methyl 4-(8-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate (43 mg, 0.13 mmol, 1 equiv), cyclopentyl bromide (41 μL, 0.38 mmol, 3.0 equiv) and cesium carbonate (126 mg, 0.383 mmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was heated at 100° C. After 2 h, the reaction mixture was diluted with ethyl acetate, and the resulting solution was washed with saturated aqueous sodium chloride solution. The collected organic was concentrated. Purification of the resulting residue by flash column chromatography (20% ethyl acetate in dichloromethane) afforded a white solid (23.5 mg, 45% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1 H), 8.74-8.55 (m, 2 H), 8.32 (s, 1 H), 7.91 (dd, J=13.9, 8.1 Hz, 3 H), 7.85 (d, J=8.9 Hz, 2 H), 7.10 (t, J=7.0 Hz, 1 H), 4.81 (s, 1 H), 3.82 (s, 3 H), 2.25-2.11 (m, 2), 2.11-1.93 (m, 2 H), 1.85 (d, J=3.5 Hz, 2 H), 1.77-1.63 (m, 2 H).
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]1[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(Cl)Cl>O>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH3:19]
Reactant: CCCCCCCCC(O)(CC(CC)CCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCC1(CC(CC)CCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (0.37 mL) was added dropwise to 7-([2,2′-bithiophen]-3-yl)-5-ethylpentadecan-7-ol (IId) (0.25 g, 0.60 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Id) (0.040 g, 17%). 1H-NMR (CDCl3): δ=7.12 (d, J=4.8 Hz, 2H), 6.93 (d, J=4.8 Hz, 2H), 1.90 (t, 2H), 1.82 (m, 2H), 1.28-1.12 (m, 5H), 1.00-0.74 (m, 16H), 0.62 (t, 9H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[C:20]1([C:26]2[C:35]([C:36](O)=[O:37])=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[N:31][CH:32]=3)[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[C:35]([C:36]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:37])=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[N:31][CH:32]=3)[N:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: O=C(O)c1cc2cnccc2nc1-c1ccccc1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1cc2cnccc2nc1-c1ccccc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Phenyl-[1,6]naphthyridine-3-carboxylic acid. LC-MS (basic): tR=1.20 min; [M+H]+=509.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]1[N:47]=[C:48]([CH:62]([CH3:64])[CH3:63])[N:49](COCC[Si](C)(C)C)[C:50]=1[C:51](O)=[O:52].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:51]([C:50]2[NH:49][C:48]([CH:62]([CH3:63])[CH3:64])=[N:47][C:46]=2[CH3:45])=[O:52])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(C(C)C)n(COCC[Si](C)(C)C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(C)C)[nH]c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
HATU (103 mg, 0.27 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (56.2 mg, 0.18 mmol), 4-methyl-2-(1-methylethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (54 mg, 0.18 mmol) and diisopropylethylamine (47 uL, 0.27 mmol) in DMF (1 mL). The reaction mixture was stirred at RT overnight and the solvent was removed under vacuum. The residue was dried in vacuo and the residue was treated with TFA (0.5 mL) in DCM (1.0 mL) at RT and stirred overnight. Neutralized with saturated NaHCO3 and extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (0-5% 2M NH3 solution of MeOH in DCM) and HPLC to afford the title compound (50 mg, 60%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.68 (1H, br. s.) 7.56 (1H, br. s.) 7.31-7.40 (2H, m) 7.23 (1H, s) 7.14 (1H, d, J=1.3 Hz) 7.02 (1H, s) 4.62 (2H, d, J=6.4 Hz) 2.96 (1H, dt, J=13.7, 6.8 Hz) 2.56 (3H, s) 1.30 (6H, d, J=7.0 Hz). LCMS: m/z 461 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C-]#[N:13].[Na+].O>C(O)C>[C:6]1([CH2:5][CH2:4][CH2:3][C:2]#[N:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCCCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 1-bromo-4-phenylbutane (58.8 g, 0.24 mole) and sodium cyanide (25 g, 0.5 mole) in ethanol (300 ml)-water (100 ml) is heated at reflux with stirring for 5 hours. The resulting reaction mixture is concentrated in vacuo and extracted with ether. The ethereal extract is filtered and evaporated at reduced pressure to afford the title compound which is purified by distillation.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:21][C:19]1[O:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[C:16](=[O:15])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1cc(O)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(=O)n(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])o1

Procedure:
226 g of 4-chloro-3-nitrobenzotrifluoride, 129 g of 3-hydroxy-5-methylisoxazole, 336 g of sodium hydrogen carbonate, and 600 ml of dimethylsulfoxide were mixed with each other and reacted at 75° C. for 6 hours. After completion of the reaction, the reaction solution was poured into water, and the crystals which precipitated were purified using a silica gel short column chromatography and recrystallized from water-methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:11]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:9]#[N:10].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:9]([CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=1)[CH:11]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:10]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: N#CC(c1ccccc1Br)C(c1cccnc1)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccccc2C(C#N)C(c2cccnc2)c2cccnc2)c1
Temperature: 160 °C

Procedure:
A mixture of 2-(2-bromophenyl)-3,3-dipyridin-3-ylpropanenitrile (0.050 g, 0.137 mmol), 3-cyanophenylboronic acid (0.030 g, 0.206 mmol), cesium carbonate (0.045 g, 0.137 mmol) and Pd(dppf)2 (0.100 g, 0.137 mmol) in THF (0.75 mL) and water (0.75 mL) at −78° C. was heated to 160° C. in microwave for 15 min. The reaction was diluted with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give (±)-2′-(1-cyano-2,2-dipyridin-3-ylethyl)-1,1′-biphenyl-3-carbonitrile. 1H-NMR (500 MHz, CDCl3) δ 8.57 (d, 1H, J=3.9), 8.45 (d, 1H, J=4.2), 8.42 (s, 1H), 7.88 (s, 1H), 7.71 (m, 1H), 7.66-7.56 (m, 3H), 7.51 (td, 1H, J=7.5, 1.2), 7.41 (td, 1H, J=7.6, 1.3), 7.34-7.32 (m, 2H), 7.18-7.07 (m, 3H), 7.00 (d, 1H, J=7.8), 4.57 (d, 1H, J=10.0), 4.33 (d, 1H, J=9.8). LRMS m/z (M+H) Calcd: 387.1604, found: 387.1592.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][CH2:7][C:8]([NH:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:12]=1[Cl:20])=[O:9]>>[Cl:20][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:8](=[O:9])[CH2:7][Cl:6])[C:18]([NH2:19])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Product: NC(=O)c1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
16.8 Parts of concentrated sulfuric acid were stirred and cooled to 0° C. and there were added portionwise 4.2 parts of 2-chloro-N-(2,6-dichloro-4-cyanophenyl)acetamide. Upon completion, stirring was continued for 3 hours in an ice-bath. The reaction mixture was allowed to stand overnight at room temperature and poured onto ice-water. The precipitated product was filtered off, washed with water, dried and boiled in acetonitrile. The product was filtered off and dried, yielding 2.7 parts of 3,5-dichloro-4-[(2-chloroacetyl)amino]benzamide; mp. +260° C. (intermediate 71).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[S:9][CH:8]=[C:7]([C:10](OC)=[O:11])[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:14][N:2]([CH2:3][C:5]1[S:9][CH:8]=[C:7]([CH2:10][OH:11])[CH:6]=1)[CH3:1]
Reactant: COC(=O)c1csc(C(=O)N(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)Cc1cc(CO)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A solution of methyl 5-[(dimethylamino)carbonyl]-3-thiophenecarboxylate (0.5 g) in dry diethylether (50 ml) was added to a slurry of lithium aluminium hydride (0.3 g) in dry diethylether (100 ml). The mixture was stirred for 3 hours at room temperature. Water was cautiously added, the mixture was filtered and the filtrate was evaporated to give the title compound (0.4 g) as a colourless oil b.p. 120°/0.1 mm. The oxalate was formed in and recrystallised from ethanol m.p. 107°-8°.