Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[K].[C:21]([O:24][CH2:25][C:26]([OH:28])=[S:27])(=[O:23])[NH2:22]>O1CCOCC1.C(OCC)(=O)C.O.[Br-].[Zn+2].[Br-]>[C:21]([O:24][CH2:25][C:26]([S:27][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])=[O:28])(=[O:23])[NH2:22]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: NC(=O)OCC(O)=S
Agent: [Br-]
Agent: [K]
Agent: [Zn+2]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1SC(=O)COC(N)=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of 4-(R)acetoxy-3(R)-[1(R)t-butyldimethylsilyloxyethyl]azetidin-2-one (2.87 g) in dioxane (40 ml) the potassium salt of carbamoyloxythioacetic acid (2.1 g) was added. Zinc bromide (2.7 g) was added to the resulting suspension and the reaction mixture was stirred for 4 hours at 40° C. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The solid residue was taken-up with CH2Cl2. Upon addition of hexanes and cooling a white solid was precipitated, and collected by filtration to give 3.26 g of the title product (90% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1.C(N(CC)CC)C>CC(O)C>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([N:22]5[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]5)=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: OC1CCNC1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 70 °C
Yield: 99.5 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (5.00 g, 14.7 mmol), pyrrolidin-3-ol (2.55 g, 29.3 mmol), and triethylamine (4.09 mL, 29.3 mmol) in 2-propanol (32 mL) was heated in the microwave for 30 minutes at 70° C. in two vials. The reaction mixtures were combined and concentrated. The crude product was purified by flash chromatography using a Horizon purification system in three batches (2×40M and 1×40S columns) eluting with chloroform/methanol (0.1-8%). The resulting solid was dissolved in chloroform containing 0.1% methanol (810 mL) and washed with water and 1:1 water:brine, dried (MgSO4), filtered and concentrated to afford 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-ol (5.08 g, 99%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])(=[O:22])=[O:21])=[CH:16][CH:15]=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])(=[O:22])=[O:21])=[CH:18][CH:19]=1)=[O:9]
Reactant: CSc1ccc(S(=O)(=O)N2CCCC2=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(S(=O)(=O)N2CCCC2=O)cc1
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
A solution containing 2.41 g of m-chloroperbenzoic acid in 48 cm3 of methylene chloride is added to 3.4 g of 1-(4-methylthiobenzene-sulphonyl)pyrrolidin-2-one prepared as in Example 4 in solution in 34 cm3 of methylene chloride, at a temperature not exceeding 25° C. After agitation at ambient temperature for 30 minutes, the reaction medium is then treated with a 10% aqueous solution of sodium sulphite. The organic phase is separated off, washed with a 5% aqueous solution of sodium bicarbonate, then with water. After drying, the solvent is evaporated off under reduced pressure, and the residue is crystallized from 95% ethanol. 1.70 g of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]([CH3:27])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[CH3:27]
Reactant: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49 e) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (D): 371.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1O[N:23]=[CH:22][CH:21]=1.[Na].Cl.[C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=[NH:29])[NH2:28].C(O)(=O)C>C(O)C>[NH2:29][C:27]1[NH:28][C:20]([CH3:19])=[C:21]([C:22]#[N:23])[CH:17]([C:14]2[CH:13]=[N:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]3)[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: Cc1ccno1
Reactant: O=Cc1cncc2ncc(-c3ccccc3)cc12
Reactant: CCOC(=O)CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(N)NC(C)=C(C#N)C1c1cncc2ncc(-c3ccccc3)cc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
2 g (8.5 mmol) of 3-phenyl-1,7-naphthyridine-5-carboxaldehyde are suspended in 20 ml of ethanol and stirred with 0.7 ml (8.5 mmol) of 5-methylisoxazole. A solution of 196 mg of sodium in 14 ml of ethanol is added and the mixture is stirred for 2 hours at 50° C. 1.42 g of ethyl amidinoacetate hydrochloride and 0.51 ml (8.5 mmol) of acetic acid are added and the mixture is boiled for 16 hours. After cooling, 10 g of silica gel are added and the mixture is concentrated in vacuo. The residue is chromatographed on a silica gel column using toluene/ethyl acetate mixtures. After concentration of the pure fractions, the product is crystallized by trituration with ether. 2 g of crystals are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]#[N:13])[C:6]=2[CH:14]=1.CN(C)[C:17]1[O:18][C:19](=[O:27])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1>C(O)(=O)C>[O:18]=[C:17]1[NH:22][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:20][C:19](=[O:27])[N:1]1[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]#[N:13])[C:6]=2[CH:14]=1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: N#CCOc1nsc2ccc(N)cc12
Solvent: CC(=O)O
Product: N#CCOc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of [(5-amino-1,2-benzisothiazol-3-yl)oxy]acetonitrile (4.30 g, 21.0 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (4.37 g, 21.0 mmol) in acetic acid is refluxed for three hours, stirred overnight at room temperature, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried overnight in a vacuum oven at 55° C. to give the title product as a brown solid (2.63 g, mp 254-258° C.).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[NH2:8][CH2:9][C:10]#[N:11].CCOCC.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](Cl)=[O:22]>O.C(OCC)(=O)C>[C:10]([CH2:9][NH:8][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][N:26]=[C:18]([F:17])[CH:19]=1)#[N:11]
Reactant: N#CCN
Reactant: O=C(Cl)c1ccnc(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N#CCNC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
2.4 g (0.056 mol) of sodium hydroxide was dissolved in 24 ml of water. 3.6 g (0.017 mol) of aminoacetonitrile sulfate was added to the solution. 30 ml of ether containing 3.0 g (0.017 mol) of 2-fluoroisonicotinoyl chloride was added dropwise to the solution while the temperature was kept below 5° C. The mixture was stirred at room temperature for 2 h to conduct a reaction. Water and ethyl acetate were added to the mixture to conduct extraction. The organic layer was washed with a saturated aqueous common salt solution and dried over anhydrous sodium sulfate. The solvent was distilled. The resulting crude crystalls were recrystallized from a solvent mixture of n-hexane and ethyl acetate to obtain 2.3 g (yield: 75.3%) of white crystal having a melting point of 124° to 125° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14](=[O:21])[NH:13][N:12]=2)=[CH:6][C:3]=1[C:4]#N.[OH-:22].[Na+].S(=O)(=O)(O)[OH:25]>O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14](=[O:21])[NH:13][N:12]=2)=[CH:6][C:3]=1[C:4]([OH:25])=[O:22]
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Crude 2-fluoro-5-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-ylmethyl)benzonitrile (10) (9.9 g, 34.9 mmol) was suspended in water (245 ml) and treated with sodium hydroxide (6.98 g, 174 mmol). The mixture was heated to 60° C. for 18 hours. The reaction was then cooled to 5° C. and concentrated sulfuric acid added dropwise until a precipitate formed (ca 10 ml, pH2). The suspension was stirred for 10 minutes at 5° C. and filtered. The solid isolated was washed with water (2×8 ml) and triturated with DCM (20 ml) before being dried. Single peak in LC-MS, (4.48 g, 98% purity) and was taken through to the next without any further purification; m/z (LC-MS, ESN), RT=1.96 mins (M−H 301.3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[S:21])[C@H:12]([CH2:13]O)[C@@H:11]([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9]1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:9][O:10][C@H:11]([C:15]([F:16])([F:17])[F:18])[C@H:12]1[CH2:13][S:21][C:20]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:19]2
Reactant: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
A solution of N-((3S,4R,5S)-3-(2-fluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)-tetrahydrofuran-3-ylcarbamothioyl)benzamide (258.3 g, 583.8 mmol) in CH2Cl2 (1.55 L) was cooled to −19.4° C. Pyridine (118 mL, 1.46 mol) was added while maintaining temperature at −20° C., and then the reaction mixture was cooled to −24° C. In another nitrogen purged vessel, CH2Cl2 (258 mL) was added followed by trifluoromethanesulfonic anhydride (108.0 mL, 642.2 mmol). The resulting solution was added to the reaction mixture over 30 min, while maintaining temperature <−19.7° C. Upon completed addition, the reaction mixture was stirred for 30 min at −20° C. to −15° C., and then warmed to −11° C. over 20 min. Saturated aq. NH4Cl (646 mL) and water (390 mL) was added. The mixture was warmed to ambient temperature and the aq. layer was removed. The organics were washed with premixed saturated aq. NH4Cl (646 mL) and water (390 mL). The aq. layers were combined, and extracted once with CH2Cl2 (520 mL). The organics were combined, and concentrated under vacuum to afford a light orange foam (250 g, 100%). The residue was used in the next stage without purification. 1H NMR (500 MHz, CDCl3) δ ppm 8.03 (d, J=6.7 Hz, 2H), 7.52 (t, J=7.0 Hz, 1H), 7.48-7.31 (m, 4H), 7.20 (t, J=7.4 Hz, 1H), 7.12 (dd, J=12.0, 8.4 Hz, 1H), 4.82-4.73 (m, 1H), 4.60 (d, J=8.9 Hz, 1H), 4.03 (d, J=8.3 Hz, 1H), 3.57 (d, J=2.7 Hz, 1H), 3.20 (d, J=13.6 Hz, 1H), 2.81 (dd, J=13.8, 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 171.50, 159.57 (d, JCF=247.2 Hz), 134.62, 132.49, 130.65 (d, JCF J=8.8 Hz), 129.77, 128.51, 128.45, 125.14 (q, JCF=281.8 Hz), 124.97 (d, JCF=3.0 Hz), 124.66 (d, JCF=10.3 Hz), 117.05 (d, JCF=23.5 Hz), 66.81 (d, JCF=5.2 Hz), 38.90, 23.20.
Reaction SMILES: [C:1]1(=O)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3][CH2:2]1.Cl.[NH2:16]O.CO.C([O-])(=O)C.[Na+]>O>[CH:1]1([NH2:16])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCc2cccc3cccc1c23
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC1CCc2cccc3cccc1c23
Yield: 71.6 %

Procedure:
To a stirred mixture of 2,3-dihydro-phenalen-1-one (1.32 g, 7.24 mmol), hydroxylamine hydrochloride (0.85 g, 12.2 mmol) and water (6 ml) was added dropwise at 75° C. MeOH (7.5 ml) and afterwards a solution of sodium acetate (2.58 g, 19.0 mmol) in water (4 ml). Stirring was continued over a period of 1.5, h, water (20 ml) was added and after cooling (ice bath) the solid was collected by filtration. After drying in vacuo the crude product was dissolved in 3.5 N NH3 /MeOH (100 ml) and hydrogenated over Raney-Nickel (0.5 g, washed with MeOH) at RT for 17h. The catalyst was filtered off, the solution evaporated in vacuo and the residue purified by column chromatography on silica gel (dichloromethane/MeOH 9:1) to yield (RS)-2,3-dihydro-1H-phenalen-1-yl-amine (0.95 g) as a brown oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]([C:29]1[CH:37]=[CH:36][C:32](C(Cl)=O)=[CH:31][CH:30]=1)#[N:28].[N:38]1[C:47]2[C:42](=[CH:43][C:44]([NH2:48])=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1>>[C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:10][C@H:9]2[C:24]([NH:48][C:44]2[CH:43]=[C:42]3[C:47](=[CH:46][CH:45]=2)[N:38]=[CH:39][CH:40]=[CH:41]3)=[O:26])=[O:7])=[CH:36][CH:37]=1)#[N:28]
Reactant: Nc1ccc2ncccc2c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: N#Cc1ccc(C(=O)N2CC(=NOCc3ccc(Cl)c(Cl)c3)C[C@H]2C(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 6-quinolinamine the title compound was obtained in 52% purity by LC/MS. MS(ESI+): m/z=558.6.
Reaction SMILES: [OH:1][C:2]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:20][CH:21]=[CH2:22])[CH2:3][O:4][C:5](=[O:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cr](Cl)([O-])(=O)=[O:43].[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl.CCOCC>[Si:25]([O:24][CH2:23][C:2]1([CH2:3][O:4][C:5](=[O:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:1][C:22](=[O:43])[CH2:21][CH2:20]1)([C:38]([CH3:40])([CH3:39])[CH3:41])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=CCC(O)(COC(=O)CCCCCCCCCCCCC)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)OCC1(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC(=O)O1
Reaction time: 12 h
Yield: 70.8 %

Procedure:
A stirred solution of 2d (1.04 g, 1.8 mmol) in dry THF (35 mL) at -78° C. was treated dropwise with a THF solution of BH3 ·SMe2 (2M, 1.8 mL) while maintained under a blanket of argon. The reaction mixture was allowed to reach room temperature during the course of 3 h and was stirred further for 12 h. Evaporation of the solvent under reduced pressure gave a residue that was dissolved in dry CH2Cl2 (100 mL) and treated with pyridinium chlorochromate (PCC, 15 g, 69.5 mmol). The dark reaction mixture was stirred at room temperature for 3 days and was diluted with dry ether (500 mL) before being filtered through a short silica gel column. The solution obtained was dried (Na2SO4) and reduced to dryness. The residue was purified by flash column chromatography over silica gel using 10% EtOAc in hexane as eluant to give 3d (0.758 g, 71%) as a pale yellow oil; IR (neat) 1785.6, 1743.5 cm-1 ; 1H NMR (CDCl3) δ 0.87 (distorted t, 3 H, CH3), 1.05 (s, 9 H, C(CH3)3), 1.25 (m, 20 H, CH3 (CH2)10CH2CH2CO); 1.55 (m, 2 H, CH3 (CH2)10CH2CH2CO), 2.00-2.40 (m, 4 H, H-4, CH3 (CH2)10CH2CH2CO), 2.60 (m, 2 H, H-3), 3.70 (AB q, J=10.8 Hz, 2 H, CH2OSi), 4.20 (AB q, J=12.0 Hz, 2 H, CH2OCO), 7.30-7.70 (m, 10 H, Ph); 13C NMR δ 14.10, 19.17, 22.67, 24.78. 25.91, 26.72, 28.87, 29.08, 29.20, 29.33, 29.41, 29.57, 29.62, 31.90, 34.03, 65.64, 66.15, 85.77, 127.88, 130.01, 132.25, 132.50, 135.52, 135.59, 173.15, 176.28. Anal. Calcd for C36H54O5Si: C,72.68; H, 9.16. Found: C,72.76; H, 9.22.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].B(O)(O)[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[N:8]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)[nH]n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1

Procedure:
The title compound was prepared as described in the final step of Example 1 from 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea (0.022 g, 0.050 mmol), and p-tolylboronic acid (0.014 g, 0.1 mmol), using copper (II) acetate (0.014 g, 0.075 mmol), pyridine (0.01 mL, 0.1 mmol), molecular sieves (4 Å activated, 0.030 g) and methylene chloride (2 mL). The title compound was obtained as a yellow-white solid (0.013 g, 50%), mp 144-146° C.; 1H NMR (DMSO) δ 1.26(s, 9H), 2.36(s, 3H), 2.53(t, 4H) 2.82(t, 2H), 3.52(t, 4H), 4.23(t, 2H), 6.32(s, 1H), 6.94(d, 1H), 7.33(d, 1H), 7.42(d, 1H), 7.54(m, 3H), 7.90(d, 1H), 8.15(d, 1H), 8.18(d, 1H), 8.82(s, 1H), 8.96(s, 1H); MS (CI) 528(M++H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:14]4[O:22][CH:21]=[CH:20][C:15]=4[CH:16]=[N:17][C:18]=3[NH2:19])=[N:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:32](=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@H:11]([O:12][C:13]4[C:14]5[O:22][CH:21]=[CH:20][C:15]=5[CH:16]=[N:17][C:18]=4[NH2:19])[CH3:32])=[N:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ncc2ccoc2c1OCc1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.047 mmol), phenylboronic acid (11.5 mg, 0.095 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (19.6 mg, 0.142 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=5.94 (s, 2H), 6.78 (d, J=2.3 Hz, 1H), 7.52-7.60 (m, 4H), 7.94-8.00 (m, 4H), 8.32 (d, J=9.6 Hz, 1H). MS (ES+): m/z 359.04 (100) [MH+]. HPLC: tR=2.21 min (ZQ3, polar—5 min).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14].C(=O)([O-])[O-].[K+].[K+].[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CC(C)=O>[Cl:3][C:2]1[N:1]=[C:8]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:11]([Cl:10])[CH:12]=2)[N:7]=[C:5]([NH:33][CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:4]=1
Reactant: NC1CCCCCC1
Reactant: COc1ccc(N)cc1Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl

Procedure:
A convenient, one-pot synthesis of 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cyclopheptyl-[1,3,5]triazine-2,4-diamine was carried out as follows. To cyanuric chloride (50 g) dissolved in acetone was added a solution of 3-chloro-4-methoxyaniline (42.5 g) in acetone at 0–5° C. followed by the addition of potassium carbonate (112 g). The reaction mass was maintained at the same temperature for about 1 hour. The progress of the reaction was monitored by TLC. When the reaction was complete, cycloheptylamine (29 g dissolved in acetone) was added at 0–10° C. The reaction mass was maintained under reflux for about 2–3 hours. Completion of the reaction was checked by TLC. The reaction mass was cooled to 20–30° C. and poured over crushed ice under stirring. The solid compound thrown out was filtered and dried. The crude compound was then recrystallised from ethylacetate (Wt. 50 g Y: 48%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O.C(N(CC)CC)C.Cl.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([NH:40][C@@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@@H:42]1[NH2:47])=[O:39])=[CH:32]2>ClCCl>[ClH:18].[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([NH:40][C@@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@@H:42]1[NH:47][C:13]([CH:10]1[CH2:9][CH2:8][N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:12][CH2:11]1)=[O:15])=[O:39])=[CH:32]2
Reactant: O=S(Cl)Cl
Reactant: N[C@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCC[C@@H]1NC(=O)C1CCN(c2ccncc2)CC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
1-(4-Pyridyl)piperidine-4-carboxylic acid (Tetrahedron, 1998, Vol. 44, p. 7095) (206 mg) was suspended in dichloromethane (50 ml), thionyl chloride (144 μl) was added under ice cooling, and the mixture was stirred for 30 minutes. After triethylamine (969 μl) was added to the reaction mixture, (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (328 mg) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, and water was added to the residue, the solution was concentrated under reduced pressure, and precipitate deposited was collected by filtration to obtain the title compound (310 mg) as a pale brown solid.