Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]=2[NH2:25])=[CH:5][CH:4]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].O>N1C=CC=CC=1>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[C:10]=2[NH:25][C:28](=[O:32])[C:29]([NH:25][C:10]2[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=2)=[O:30])=[CH:7][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1)C(=O)Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 4,4″-Bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-ylamine (700 mg, 1.84 mmol) in pyridine (5 mL) was treated with oxalyl chloride (73 μL, 0.837 mmol). The resulting suspension was stirred at rt overnight under Ar, then poured into H2O. The precipitate was filtered, washed with H2O and dried in vacuo. The resulting solid was crystallized from toluene/heptane, then recrystallized from toluene to afford N,N′-Bis-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-yl)-oxalamide (430 mg).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(Br)n1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-bromothiazole-4-carboxylate (600 mg, 2.54 mmol) was suspended in ethanol (15 mL). Sodium hydroxide (7.5 mL, 1 M) was added and the reaction mixture was stirred at 35° C. for 0.5 hours. The reaction mixture was acidified to pH ˜3 with 1 M HCl, then diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with brine (100 mL), dried (sodium sulfate), filtered and concentrated to provide the title compound. MS (APCI) m/z=208/210 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14]([CH3:25])[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1.B(Br)(Br)Br.CCN(CC)CC>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14]([CH3:25])[C:15]([C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1ccc(-c2nc3cnc(C4CCNC(C)C4)[nH]c-3c2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(O)cc2)nc2cnc(C3CCNC(C)C3)[nH]c1-2
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
To a −78° C. solution of 1-[2,7-dimethyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]-4-methoxybenzene (Example 136) (0.45 g, 1.34 mmol) in CH2Cl2 (20 mL) under a N2 atmosphere was added 1 M BBr3 (2.6 mL, 2.60 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for an additional 20 h. The reaction mixture was then poured onto ice-water (200 mL) and the pH of the aqueous solution was adjusted to pH 9 with the addition of NEt3 (2 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was transferred to a separatory funnel. The organic solution was separated, washed with H2O (100 mL), saturated NaCl (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford 272 mg (64%) of 4-[2,7-dimethyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]phenol as a beige colored solid. This compound (272 mg, 0.80 mmol) was dissolved in 4:2:1 EtOAc/MeOH/CH2Cl2 (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (0.80 mL, 0.80 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×5 mL) and dried under vacuum at 60° C. to give 107 mg (23%) of the title compound as brown colored crystals. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.61 (br s, 6), 2.24 (s, 3), 2.54 (s, 3), 3.93 (br s, 4), 6.91 (d, 2, J=8.1), 7.43 (d, 2, J=8.4), 9.96 (s, 1), 11.70 (s, 1), 13.94 (s, 1). MS m/z: 323 (M+1 for free base). Anal. Calcd for C19H22N4O.HCl.0.75H2O: C, 61.28; H, 6.63; N, 15.05; Cl, 9.52. Found: C, 61.32; H, 6.62; N, 14.96; Cl, 9.45.
Reaction SMILES: Cl.C([O:4][C:5](=[O:25])[CH:6]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[CH:9]=1)C.C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1>O>[CH2:22]([O:21][C:19]([NH:18][CH:6]([CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:40]([C:35]2[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=2)(=[O:42])=[O:41])[CH:9]=1)[C:5]([OH:4])=[O:25])=[O:20])[CH:23]=[CH2:24]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)O
Reaction time: 8 h
Yield: 38.7 %

Procedure:
2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride (110 mg, 0.294 mmol) and sodium carbonate (93.5 mg, 0.882 mmol) were dissolved in water (1.5 mL) and 3,5-dichlorobenzenesulfonylchloride (86.7 mg, 0.353 mmol) was added. This mixture was stirred overnight. The reaction was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (59 mg, 37%). MS (Cl) m/z 545.7 (M+1) C. 2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])([O-:3])=[O:2].[Cl:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:20][CH2:21][C:22]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](=[O:12])[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:23]
Reactant: O=C(Nc1ccccc1)Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)CCl
Product: O=C(CCl)N(C(=O)Nc1ccccc1[N+](=O)[O-])c1ccccc1

Procedure:
A solution containing N-(2-Nitrophenyl)-N′-phenyl-urea (5.76 g) and chloroacetyl chloride (40 mL) was refluxed under nitrogen for 30 min. After the excess chloroacetyl chloride was removed in vacuo, diethyl ether (50 mL) was added and the resulting solid was filtered and dried to yield N′-(2-chloroacetyl)-N-(2-nitrophenyl)-N′-phenyl-urea as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][O:5][CH:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH2:3]1
Reactant: [H][H]
Reactant: O=C1C=COC(CN2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Yield: 87 %

Procedure:
2-(4-Oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione (13 g, 0.051 mol) was dissolved in ethyl acetate (250 ml) and placed in a Parr bottle. 10% Pd/C (1.5 g) was carefully added and the mixture was shaken under a pressure of 30 psi of hydrogen for 6.5 hours (Parr apparatus). Filtration followed by evaporation of the ethyl acetate in vacuo afforded a crude 11.5 g of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione pure enough for the next step. Analytical pure compound could be obtained by purification of a small sample (250 mg) by column chromatography on silica gel, utilising a mixture of hexane/ethyl acetate as a gradient (from 100/0 to 50/50). Pure fractions were collected and the solvent evaporated in vacuo affording 142 mg (55%) of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[I-].[NH2:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]3[N:23]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: N[n+]1ccccc1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccccn2)c(OC)c1
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(-c3ccccn3)c(OC)c2)nn2ccccc12

Procedure:
A solution of ethyl(2E)-3-(3-methoxy-4-pyridin-2-ylphenyl)prop-2-enoate (55 mg, 0.2 mmol) and 1-aminopyridinium iodide (86 mg, 0.4 mmol) in DMF (1 mL) was stirred at rt for 2 days open to the atmosphere. The deep purple reaction mixture was diluted with CH2Cl2 (25 mL) and washed with a saturated solution of sodium thiosulfate (25 mL) and brine (25 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 3:2) to afford the desired ethyl 2-(3-methoxy-4-pyridin-2-ylphenyl)pyrazolo[1,5-a]pyridin-3-carboxylate as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1)=[O:2].[BH4-].[Na+]>CO.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3CO)c2)cc1
Reaction time: 2 h
Yield: 83 %

Procedure:
tert-Butyl 3-(4-(2′-formylbiphenyl-3-ylmethoxy)phenyl)propanoate (0.30 g, 0.72 mmol) was dissolved in a mixed solution of methanol (6 mL) and tetrahydrofuran (6 mL), and sodium borohydride (14 mg, 0.36 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (0.25 g, yield 83%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OC(CCl)CCCl
Product: O=[N+]([O-])c1ccc(OCC(O)CCCl)cc1

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-nitrophenol to give white title compound, m.p. 60°-63° C.
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C@@H:21]([CH2:22][CH:23]=[O:24])[NH:20][C:19]1=[O:25])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:3][C:2]([C@@H:18]1[C:19](=[O:25])[NH:20][C@@H:21]1[CH2:22][C:23]([OH:28])=[O:24])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6])[CH3:1]
Reactant: CC(C)=O
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one (9 mg) in acetone (1 ml) was added 2 N Jones reagent (60 μl) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. After addition of isopropyl alcohol (100 μl), the mixture was evaporated in vacuo. The residue was taken up in chloroform (20 ml) and washed with brine. The aqueous layer was extracted with chloroform (5 ml). The combined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, and evaporated to give {(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxo-azetidin-2-yl}acetic acid (7 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[N:13]([CH3:24])[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]2[N:13]([CH3:24])[C:12]3[CH:25]=[CH:26][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41](=[O:48])[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(N)c3)ccc21
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(NC(=O)c4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To [5-(2-amino(4-pyridyloxy))-1-methylbenzimidazol-2-yl] (4-chlorophenyl)amine (1 eq) in tetrahydrofuran added EDC (2 eq) and HOAT (1 eq) and N,N-disopropylethylamine (4 eq) and benzoic acid (1 eq) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was then dried with sodium sulfate and concentrated and purified by preparative chromatography to give N-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]benzamide. MS: MH+=470.9.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>O1CCOCC1>[CH2:23]([NH:25][C:26](=[O:27])[O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)[CH3:24]
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 74.8 %

Procedure:
A solution of 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol) and ethyl isocyanate (0.080 mL, 1.0 mmol) in 10 mL of dioxane was heated at 80° C. for 48 hours. The reaction mixture was concentrated in vacuo. The residue was crystallized from EtOAc/hexane to give 0.275 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of ethyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepentanoate(10.0 g), 2-methylimidazole(7.20 g), potassium carbonate(12.1 g) and N,N-dimethylformamide(80 ml) was stirred for 2 hours at 120-130° C. Water was added to the reaction mixture to give 30 ethyl 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanoate(9.97 g, 88%). This was recrystallized from ethyl acetate-isopropyl ether to give colorless prisms. mp 93-94° C.
Reaction SMILES: O.[N+:2]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)=[CH:14][CH:15]=2)=[CH:38][CH:39]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CCCCCCc3ccc(Cc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cc2ccc(CCCCCCc3ccc(Cc4ccc(N)cc4)cc3)cc2)cc1
Yield: 84.5 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 3.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 35.0 g of 1,6-bis(4-(4-nitrobenzyl)phenyl)hexane in 200 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Crystals were dissolved in chloroform, subjected to a column chromatography treatment with active alumina and silica gel, and thereafter the solution was reconcentrated to give a concentrate, which was then recrystallized from a mixed solvent of toluene and denatured ethanol, to obtain 26.1 g of 1,6-bis(4-(4-aminobenzyl)phenyl)hexane. Melting point was from 111.4° to 112.2° C.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[CH2:7]([SH:9])[CH3:8]>>[CH2:7]([S:9][CH2:3][CH2:2][CH2:1][N:4]=[C:5]=[O:6])[CH3:8]
Reactant: C=CCN=C=O
Reactant: CCS
Product: CCSCCCN=C=O

Procedure:
A mixture of 16.6 grams (0.2 mole) of allyl isocyanate and 12.4 grams (0.2 mole) of ethanethiol is irradiated at -30° C for 24 hours in the manner described in Example 1 to yield the olefinic adduct, i.e. 3-ethylthiopropyl isocyanate as the major product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].[C:14]([NH:16][C:17]([NH2:19])=[NH:18])#[N:15].[ClH:20]>O>[ClH:20].[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:14]([NH:16][C:17]([NH2:19])=[NH:18])=[NH:15])[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: N#CNC(=N)N
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(NC(=N)NC(=N)N)cc(C(C)=O)c1

Procedure:
Compound No. 12. A suspension of 3,5-diacetylaniline (0.531 g) in water (8 mL) was treated with cyanoguanidine (0.285 g) and conc. HCl (0.25 mL) and heated at reflux. After 6 hr the mixture was cooled and concentrated and 0.248 g of off-white solid was filtered out and dried to give N-(3,5-diacetylphenyl)biguanide hydrochloride, mp 260°-70° C. (dec).
Reaction SMILES: [CH2:1]=O.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:30])=[N:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Na].N>CO.ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:30])=[N:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:1])[CH2:27][CH2:28]3)[CH:22]=2)[CH:17]=1
Reactant: Cc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Reactant: C=O
Agent: N
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: Cc1nn(C2CCN(C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
37% Aqueous formaldehyde (0.042 ml) at 0° C. was added to a stirred solution of 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (178 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) over a period of 5 minutes under argon. The resulting solution was stirred at 0° C. for 5 minutes. Then sodium triacetoxyhydroborate (121 mg) was added and the mixture was stirred for 5 minutes at 25° C. A solution of ammonia in methanol 7N (2 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness, then the resulting solid was stirred in acetonitrile overnight, filtered and dried to afford 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (125 mg) as a solid; NMR Spectrum: (DMSOd6) 1.88-2.11 (m, 6H), 2.21 (s, 3H), 2.33 (s, 3H), 2.81-2.93 (m, 2H), 3.97-4.11 (m, 1H), 7.38-7.50 (m, 2H), 7.65 (bs, 2H), 7.79 (d, 1H), 7.84 (d, 1H), 8.07 (s, 1H), 8.28 (s, 1H), 8.35 (s, 1H); Mass spectrum: M+H+: 389
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Br[C:24]1[C:25]2[N:26]([CH:31]=[CH:32][N:33]=2)[N:27]=[C:28]([Cl:30])[CH:29]=1>C1COCC1>[Cl:30][C:28]1[CH:29]=[C:24]([N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:25]2[N:26]([CH:31]=[CH:32][N:33]=2)[N:27]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: COc1ccc(CNc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of N-(4-methoxybenzyl)aniline (6.42 g, 30.10 mmol) in THF (10 mL) was stirred at 25° C., and potassium tert-butoxide (1M in THF, 90.30 mL, 90.30 mmol) was added. After 30 minutes, 8-bromo-6-chloroimidazo[1,2-b]pyridazine (7.00 g, 30.10 mmol, Example 1 from WO 2007/038314) was added, and the reaction solution stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2×200 mL). The organic layer was washed with saturated aqueous NaHCO3 (100 mL) and saturated aqueous at NaCl (100 mL). The organic phase was dried Na2SO4, filtered and concentrated in vacuo. The residue was purified via ISCO (5% EtOAC/DCM; 120 g column) to give 6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (9.09 g, 83% yield) as a tan solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=3.918 minutes [M+H]=365.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([OH:12])=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1>[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=2)=[CH:15][CH:14]=1)([OH:12])=[O:11]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(C=Nc2cc(Cl)cc(Cl)c2)cc1

Procedure:
To a reaction flask, equipped with a Dean-Stark trap, is added 3,5-dichloroaniline (16.2 g., 0.10 mole), p-carboxybenzaldehyde (0.10 moles), p-toluenesulfonic acid monohydrate (0.2 g), and toluene (100 ml.). The reaction mixture is then warmed to reflux and the water (1.65 ml.) collected by azeotroping. The cooled reaction mixture is treated with charcoal and the filtrate reduced to vacuo to give an amber oil that crystallizes on standing to give N-(p-carboxybenzylidene)-3,5-dichloroaniline which is recrystallized from pentane.