Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[K].C([O-])(C)(C)C.[CH3:35][N:36]([CH3:51])[C:37]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]1>C1COCC1>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:43][CH:40]2[CH2:39][CH2:38][C:37]([N:36]([CH3:35])[CH3:51])([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:42][CH2:41]2)=[CH:27][CH:28]=1
Reactant: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Reactant: [Cl-]
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(C=Cc2ccc(F)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-fluorobenzyltriphenyl phosphonium chloride (1.22 g, 3 mmole) was suspended under argon in abs. THF (15 ml) and cooled to −5° C. Potassium-tert-butanolate (337 mg, 3 mmole) dissolved in THF (14 ml) was added dropwise and the mixture post-stirred for 30 min at <0°. 4-dimethylamino-4-phenylcyclohexane carbaldehyde (467 mg, 2 mmole) dissolved in THF (8 ml) was subsequently added dropwise and the mixture stirred for 20 h with gradual heating to RT. For working up, the mixture was evaporated and 15 ml 1M HCl, 5 ml water and 30 ml ether were added to the residue. After stirring for 60 min, between the aqueous phase and the organic phase, there was a white solid which was suction filtered and washed with ether (3×2 ml). Following analysis and DC, this solid was the hydrochloride of the least polar of four possible diastereoisomers of {4-[2-(4-fluorophenyl)vinyl]-1-phenylcyclohexyl}dimethylamine (145 mg, mp. 255 to 258° C.).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:24])[N:4]=[C:5]2[C:10](=[O:11])[NH:9][C:8]([C:12]3[C:13]([O:21][CH2:22][CH3:23])=[N:14][CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=3)=[N:7][C:6]=12.C(OCC)(=O)C>Cl.C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:1][C:2]1[N:3]([CH3:24])[N:4]=[C:5]2[C:10](=[O:11])[NH:9][C:8]([C:12]3[C:13]([O:21][CH2:22][CH3:23])=[N:14][CH:15]=[C:16]([NH2:18])[CH:17]=3)=[N:7][C:6]=12
Reactant: CCOc1ncc([N+](=O)[O-])cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1ncc(N)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Yield: 42.3 %

Procedure:
Titanium trichloride (20.93 g, 140 mL of a 15% solution in hydrochloric acid) was added to a solution of 3-bromo-5-(2-ethoxy-5-nitropyridin-3-yl)-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 53) (7.66 g, 19.4 mmol) in acetic acid (100 mL). After 2 h the acetic acid was evaporated and azeotroped with toluene. The residue was partitioned between sodium bicarbonate solution and dichloromethane and the titanium salts filtered to aid separation of the aqueous and organic phases. The aqueous layer was saturated with sodium chloride and re-extracted with dichloromethane. The organics were dried (MgSO4) and concentrated to give a solid. Trituration with ethyl acetate gave 3 g of pure product.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:19])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]1[O:59][NH2:60]>CN(C=O)C>[CH:1]1([NH:6][C:7](=[O:19])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([NH:60][O:59][CH:54]3[CH2:55][CH2:56][CH2:57][CH2:58][O:53]3)=[O:18])=[CH:13][CH:12]=2)[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)O)s1
Reactant: NOC1CCCCO1
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: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)NOC2CCCCO2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(1-(3-cyclopentylureido)ethyl)thiophene-2-carboxylic acid obtained in step 2 in DMF (1 mL) was added HATU (62 mg, 0.165 mmol) and N,N-diisopropylethylamine (130 μL, 0.75 mmol) was added a solution of O-(tetrahydropyran-2-yl)hydroxylamine (19.3 mg, 0.165 mmol) in N,N-dimethylformamide (1.0 mL). The reaction was stirred at room temperature for 12 hours. The solution was evaporated to dryness and to the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give crude 5-(1-(3-cyclopentylureido)ethyl)-N-(tetrahydro-2H-pyran-2-yloxy)thiophene-2-carboxamide. LC-MS: (FA) ES+382.
Reaction SMILES: CS[C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12.[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])#[CH:17].[ClH:25].N1C=CC=CC=1>C(O)(C)(C)C>[ClH:25].[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][CH:6]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[CH:3]=[C:4]2[N:15]=[CH:14][N:13]=[C:5]12)#[CH:17]
Reactant: C#Cc1cccc(N)c1
Reactant: CSc1c2c(cc3c1=NCN=C3)=NC=N2
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: C#Cc1cccc(NC2C3=NC=NC3=Cc3cncnc32)c1
Temperature: 25 °C

Procedure:
A mixture of 4-methylthio-6H-imidazo[4,5-g]quinazoline (0.0455 g, 0.210 mmol), prepared as described in Leonard, N. J.; Morrice, A. G.; Sprecker, M. A., J. Org. Chem., 1975, 40 (3), 356-363, 3-ethynylaniline (0.0672 g, 0.574 mmol) and pyridine hydrochloride (0.0274 g, 0.237 mmol) in t-butanol (5 mL) was heated to reflux for 6 hours then cooled to room temperature. Precipitate was collected and washed with t-butanol to give 4-(3-ethynylanilino)-imidazo[4,5-g]-quinazoline hydrochloride as a yellow solid: 0.0349 g (58%); 1H NMR (DMSO-d6) δ4.34 (1H, s), 7.48 (1H, m), 7.53 (1H, m), 7.82 (1H, m), 7.98 (1H, s), 8.13 (1H, s), 8.81 (1H, s), 8.99 (1H, s), 9.24 (1H, s), 11.49 (1H, br s ); m/e 286 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[C:20]([CH3:27])[C:21]([C:24](O)=[O:25])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[CH3:36][NH:37][CH3:38]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[C:20]([CH3:27])[C:21]([C:24]([N:37]([CH3:38])[CH3:36])=[O:25])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CNC
Reactant: Cc1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cnc1C(=O)O
Agent: Cl
Product: Cc1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cnc1C(=O)N(C)C

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-methylpyridine-2-carboxylic acid and dimethylamine hydrochloride. LCMS (M+H)+: m/z=487.3.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2F)=O)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.Cl.[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1(C)C(C)=CC=CC=1>[CH2:21]([N:28]1[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([OH:12])[CH:8]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNCc1ccccc1
Reactant: O=C(c1ccc(O)cc1F)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Oc1ccc2c(C3CC3)nn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropyl(2-fluoro-4-hydroxyphenyl)methanone (6.51 g) which can be prepared according to the method described in Reference example 2, etc., sodium acetate (14.3163 g; manufactured by Wako Pure Chemical Industries, Ltd.), and benzylhydrazine-dihydrochloride (10.72 g; manufactured by Sigma-Aldrich Co.) were suspended in xylene (180 mL). By using a dean-stark apparatus, the mixture was stirred overnight at reflux. After cooling to room temperature, the mixture was added with water and extracted twice with ethyl acetate. The organic layer was washed twice with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, insoluble matters were dissolved by adding n-hexane to the residue and the title compound was obtained as a crude product (10.97 g).
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14](=[O:26])[CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[Cl:25])[CH3:16])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:27])[CH:2]=[CH2:3].[F:28][C:29]([Si](C)(C)C)([F:31])[F:30]>>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14]([OH:26])([C:29]([F:31])([F:30])[F:28])[CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[Cl:25])[CH3:16])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:27])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)COc2ccc(C(=O)C(C)c3ccc(OC)cc3Cl)cc21
Reactant: C[Si](C)(C)C(F)(F)F
Product: C=CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 56, step 3, 4-allyl-6-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-4H-benzo[1,4]oxazin-3-one (7.2 g) was reacted with (trifluoromethyl)-trimethylsilane. The product was purified by crystallization with heptane/AcOEt (4:1) to give the title compound (4.45 g) as an off-white solid. MS (m/e)=456.3 [M+H+].
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([C@H:18]([O:20][C@@H:21]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:25]([C:33](OC)=[O:34])[CH2:24][CH2:23][O:22]2)[CH3:19])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.[Cl-].[NH4+].O1C[CH2:44][CH2:43][CH2:42]1>>[CH2:1]([C:33]([CH2:44][CH:43]=[CH2:42])([C@@H:25]1[CH2:24][CH2:23][O:22][C@H:21]([O:20][C@@H:18]([C:10]2[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:8]([C:7]([F:6])([F:38])[F:37])[CH:9]=2)[CH3:19])[C@H:26]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:34])[CH:2]=[CH2:3]
Reactant: C=CC[Mg]Br
Reactant: COC(=O)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCC(O)(CC=C)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Allylmagnesium bromide (1.0M in hexanes, 8.8 mL, 8.8 mmol) was added slowly to a stirred, cooled (0° C.) solution of methyl(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxylate (Description 37; 1.4 g, 2.9 mmol) in tetrahydrofuran (10 mL). The mixture was warmed to room temperature and stirred for 30 minutes. Saturated aqueous ammonium chloride (50 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced-pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (80:20), to give the title compound as a colorless oil (1.48 g, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:11].O=P(Cl)(Cl)Cl.Cl.[OH-].[Na+]>O>[Cl:11][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc[n+]([O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccncc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound was prepared by a modified procedure based on the method of J. Rokach and Y. Girard, J. Heterocycl. Chem. 1978, 15, 683–684. 4-Cyanopyridine-N-oxide (250 g, 2.08 mol) was added portionwise to a stirred suspension of PCl5 (599.94 g, 2.88 mol) and POCl3 (800 mL, 8.71 mol) at 20° C. under nitrogen, in a reactor fitted with a reflux condensor. During the addition the temperature rose to 41° C. The mixture was stirred at 100° C. for 3 h then cooled to 95° C. and transferred to a mixture of 6M HCl (200 mL) and a 6:4 mixture of ice and water (5994 g) at such a rate that the temperature stayed below 15° C. (about 35 min). The resulting brown solution was cooled to below 5° C. and taken to pH 4.15 by adding 33% aqueous NaOH (about 4.5 L), keeping the temperature below 5° C. The resulting beige precipitate was filtered and washed thoroughly with water (4×500 mL), sucking as dry as possible. The residue was suspended in water (1.5 L) and n-heptane (7 L) and stirred at 30° C. for 1 h. The aqueous phase was separated and extracted further with n-heptane (2×2 L), stirring for 30 min each time at 30° C. The combined heptane layers were combined, dried (Na2SO4, 136 g), filtered and the resulting solution was concentrated under reduced pressure to a weight of 1.9 kg (about 3 L), at which point the product began to crystallise. The mixture was cooled to 0° C., stirred for 1.5 h then the product was filtered, washed with cold n-heptane (2×125 mL) and dried at room temperature in a circulating air drier to give the product (129.08 g, 44.8%) as a crystalline solid; m.p. 73.4° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.CCOCC.O>[OH-].[Na+]>[C:22]([O:21][C:19]([NH:18][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[C:3]([OH:26])=[O:2])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
(S)-2-(t-butoxycarbonylamino-3-(biphenyl-4-yl)-propionic acid methyl ester (4.1 g, 11.5 mmol) is dissolved at room temperature in methanolic 1N sodium hydroxide (60 mL). The solution is stirred for 3 hours. Ether (30 mL) and water (30 mL) are added. The aqueous layer is separated and acidified with concentrated hydrochloric acid, then extracted with ether (2×20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gives (S)-2(-t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propionic acid as a white solid, m.p. 122°-123°.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[F:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)n1c(=O)sc2cc(F)ccc21
Agent: O=S(=O)(O)O
Product: CC(C)n1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
6-Fluoro-3-(1-methylethyl)-2(3H)-benzothiazolone (299 g) was dissolved in conc. sulfuric acid (8750 g), and the resultant mixture was cooled to a temperature of -5° to 0° C. 98% fuming nitric acid (d=1.52) (94.68 g) was dropwise added thereto while keeping the temperature at 0° C., followed by stirring for 1 hour. The reaction mixture was poured into ice-water (16 kg), and the precipitated crystals were collected by filtration. Crystals were washed with water and dried to give 325 g of 6-fluoro-3-(1-methylethyl)-5-nitro-2(3H)-benzothiazolone. m.p., 153°-153.5° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2OC(=O)[C:13](=[C:17]=[O:18])[CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:19][NH:20][NH2:21].[CH2:22]([OH:24])C>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]([CH2:22][OH:24])[CH2:13][C:17](=[O:18])[N:20]([CH3:19])[N:21]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C2CC(=C=O)C(=O)O2)cc1
Reactant: CCO
Reactant: CNN
Product: CC(=O)Nc1ccc(C2=NN(C)C(=O)CC2CO)cc1

Procedure:
7.4 g (0.03 mol) of 4-(4-acetylaminophenyl)-carbonyl-γ-butyrolactone and 2 ml (0.038 mol) of methylhydrazine in 30 ml of ethanol are heated at room temperature for 1 hour and then under reflux for 3 hours. After the mixture has been cooled, the precipitated product is filtered off with suction and washed.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[O:16][N:15]=1)=O)(C)(C)C.F[C:30](F)(F)[C:31](O)=O>ClCCl>[CH3:26][O:25][C:23]1[CH:22]=[C:21]([CH:20]=[C:19]([C:17]2[O:16][N:15]=[C:14]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[CH2:6][C:31]3[CH:30]=[CH:11][CH:10]=[CH:9][N:8]=3)[N:18]=2)[CH:24]=1)[C:27]#[N:28]
Reactant: COc1cc(C#N)cc(-c2nc(C3CCCCN3C(=O)OC(C)(C)C)no2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C#N)cc(-c2nc(C3CCCCN3Cc3ccccn3)no2)c1

Procedure:
To a solution of 2-[5-(3-cyano-5-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (162 mg, 0.42 mmol) in dichloromethane (4 mL) cooling in an ice-bath was added trifluoroacetic acid (2 mL). The ice-bath was removed after 30 min. and then left stirring for an additional hour. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and then washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo 113 mg (94%) of the title compound as a white solid. 1H NMR (CDCl3), δ(ppm): 7.99 (s, 1H), 7.84 (d, 1H), 7.35 (s, 1H), 5.56 (bs, 1H), 4.06 (m 1H), 3.93 (s, 3H), 3.01 (m, 1H), 2.84 (m, 1H), 1.92 (m, 1H), 1.70 (m, 2H), 1.49 (m 1H).
Reaction SMILES: C([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([Cl:14])[N:6]=1)(=O)C.C([O:18][C@@H:19]1[C@H:23]([O:24]C(=O)C)[C@@H:22]([CH2:28][O:29]C(=O)C)[O:21][C@H:20]1C1N=C2C(NC=N2)=CN=1)(=O)C.N>Cl[Hg]>[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:20]2[O:21][C@H:22]([CH2:28][OH:29])[C@H:23]([OH:24])[C@H:19]2[OH:18])=[C:7]([Cl:14])[N:6]=1
Reactant: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ncc3[nH]cnc3n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Hg]
Agent: N
Product: Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)c2n1

Procedure:
The chloromercury derivative of 2-acetamido-6-chloropurine is condensed with 2,3,5-tri-O-acetyl-β-D-ribofuranosylpurine utilizing the method of Lee et. al. (1971), J. Med. Chem., 14:819. The condensation product was treated with ammonia to yield 2-amino-6-chloro-9-(β-D-xylofuranosyl)purine. Further treatment with sodium hydroxyethylmercaptide gives the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:30]=[CH:29][O:28][CH:27]=1.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[O:28]1[CH:29]=[CH:30][C:26]([CH2:25][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:27]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: ClCc1ccoc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccoc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)-(1-ethoxycarbonyl-piperidin-4-yl)amine (1.5 g, 5.2 mmol) in tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice-bath. Add sodium hydride (0.25 g, 60% n in oil, 6.24 mmol). After 3.5 hours, add 3-(chloromethyl)furan (0.91 g, 7.8 mmol). Warm to ambient temperature. After 60 hours, quench by the addition of Glauber's salt (Na2SO4 10 H2O). Evaporate to remove most of the tetrahydrofuran, dilute with ethyl acetate, and extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine: Rf=0.32 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=1)=[O:5].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>ClCCl>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([N:6]([C:7]1[S:8][CH:9]=[C:10]([C:12]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:14])[N:11]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=1)=[O:5]
Reactant: C1CCNC1
Reactant: O=C(O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC(F)(F)F)cc2)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC(F)(F)F)cc2)n1)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of 250 mg (0.52 mmol) 2-[(2,4-dichloro-benzoyl)-(4-trifluoromethoxy-phenyl)-amino]-thiazole-4-carboxylic acid, 57 μL (0.68 mmol) pyrrolidine and 110 mg (0.68 mmol) 1,1′-carbonyldiimidazole in 10 mL dichloromethane was stirred for 16 h at room temperature. The mixture was poured onto 0.5 N hydrochloric acid and extracted with dichloromethane. Organic phases were pooled, washed with water and brine and dried with MgSO4. Volatiles were removed in vacuo and the residue was purified by silica gel chromatography (n-heptane/ethyl acetate 1:1) to yield 182 mg (65%) of the title compound as colorless solid. MS (m/e): 530.0 (MH+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](C2C=CC(CC3(OCCO3)C)=CC=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1.Cl.[CH3:40][C:41](C)=[O:42]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[CH:11][CH2:12][CH:13]1[C:31]1[CH:32]=[CH:33][C:28]([CH2:38][C:41](=[O:42])[CH3:40])=[CH:29][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(Cc2ccc(C3(O)CCN(Cc4ccccc4)CC3)cc2)OCCO1
Agent: Cl
Solvent: c1ccccc1
Product: CC(=O)Cc1ccc(C2CC=CCN2Cc2ccccc2)cc1

Procedure:
A mixture 1-benzyl-4-[4-(2,2-ethylene dioxypropyl)phenyl] piperidin-4-ol (3.0 g) and 4-toluenesulphonic acid (1.9 g) in benzene, was heated under reflux for 3 hr. using a Dean and Stark head. The cooled reaction mixture was washed with 1.2M sodium bicarbonate solution (1×50 ml) water, (2×50 ml , dried (magnesium sulphate), filtered, evaporated in vacuo, and chromatographed on silica. Elution with chloroform gave an oil which was dissolved in acetone and treated with 2M hydrochloric acid (5 ml) at room temperature for 4 h. The solvent was removed in vacuo, the residue dissolved in ether, washed with 1.2M sodium hydrogen carbonate (1×50 ml), water (2×50 ml), dried (magnesium sulphate), filtered and evaporated in vacuo to give 4-(1-benzyl-1,2,3,6-tetrahydropyridyl)phenyl propan-2-one, 1.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][CH2:21][NH:22][CH3:23])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[C:25]([OH:29])(=O)[CH2:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[OH:24])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][CH2:20][CH2:21][N:22]([CH3:23])[C:25](=[O:29])[CH2:26][OH:27])[N:12]=[CH:11][N:10]=1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: CN(CCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)C(=O)CO
Yield: 58 %

Procedure:
2-Chloro-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol was reacted with glycolic acid using an analogous procedure to that described in Example 3 to give N-[2-({4-[3-Chloro-4-hydroxyanilino]quinazolin-5-yl}oxy)ethyl]-2-hydroxy-N-methylacetamide in 58% yield; NMR spectrum (DMSO-d6) 2.96 (s, 3H), 3.90 (t, 2H), 4.05 (m, 3H), 4.41 (t, 2H), 6.97 (d, 1H), 7.14 (d, 1H), 7.34 (m, 2H), 7.70 (t, 1H), 7.79 (d, 1H), 8.40 (s, 1H), 9.64 (s, 1H), 10.00 (bs, 1H); Mass spectrum MH+ 403.