Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13])=[O:7].CO.O1CCCC1.[CH3:27][S-:28].[Na+]>O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][S:28][CH3:27])=[C:12]([CH3:13])[C:11]=2[CH:14]=1
Reactant: C[S-]
Reactant: COc1ccc2oc(C(=O)CCCCCl)c(C)c2c1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)CCCCSC)c(C)c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a mixture of 5-chloro-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentan-1-one (1.30 g) synthesized above, methanol (15 mL) and tetrahydrofuran (15 mL) was added a 15% aqueous solution (4.33 mL) of sodium methanethiolate, and the mixture was stirred at room temperature for 1 hr and at 50° C. for 1 hr. Sodium methanethiolate (325 mg) was additionally added and the mixture was stirred at 50° C. for 1 hr. Sodium methanethiolate (325 mg) was additionally added again, and the mixture was stirred at 50° C. for 1 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (492 mg, 36%) as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([C:32]([N:8]2[CH2:13][CH2:12][C@H:11]([N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C@H:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9]2)=[O:33])[CH:35]=[C:36]([Cl:38])[CH:37]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Product: CN1CCN([C@H]2CCN(C(=O)c3cc(Cl)cc(Cl)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=432.2 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-phenyl-piperidin-4-one, N-methyl-piperazine and 3,5-dichloro-benzoyl chloride.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.N1CCCCC1.C([OH:30])C>>[OH:30][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH:2]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: CCO
Reactant: O=C(CO)c1ccccc1
Reactant: COc1cc(C=O)ccc1O
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)c2ccccc2O)ccc1O

Procedure:
2-hydroxyacetophenone (6.8 g, 50 mmol) was condensed with vanillin (7.7 g, 50 mmol) in ethanol (100 ml) and piperidine (8.5 g) at room temperature (20° C.) under nitrogen for 4 days to give 2′,4-dihydroxy-3-methoxychalcone. The crude mixture was filtered and the filter residue was washed with ethanol. The crude product (9.8 g) was stirred up with ethyl acetate and the intermediate product was filtered off (yield 8.3 g, 61% of theoretical). The intermediate product (2.73 g, 10 mmol) was then hydrogenated in ethanol (60 ml) using hydrogen at atmospheric pressure with the aid of a palladium catalyst on activated carbon (0.3 g, 10 wt. % Pd content, moist, water content ca. 50 wt. %), then filtered and the filtrate was evaporated to dryness, wherein compound 5 was obtained as a colourless crystalline material (2.3 g, purity >95%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH3:11])[C:5]=1[CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CO>[CH2:18]([O:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH3:11])[C:5]=1[CH:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ccc(=O)c(OCc2ccccc2)c1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of NaOH (1.77 g dissolved in 20 mL, 44.4 mmol) in de-ionized water was added dropwise to a suspension of 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (9.00 g, 40.3 mmol) in methanol (100 mL), and followed by benzyl bromide (5.28 mL, 44.4 mmol) at room temperature. The resulting suspension was refluxed for 3.5 h, and then stirred at RT for overnight. Methanol was removed under vacuum using the rotary evaporator, and the residue was diluted with water and extracted two times with CH2Cl2 (2×100 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of methanol and ethyl acetate (10/90, v/v) as eluant. Fractions rich in the product were pooled together and evaporated to dryness to give 4 g of 3-benzyloxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[N:11][C:6]=2[CH:5]=[N:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN1C(=O)CCC1.O>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][N:4]=[CH:5][C:6]=2[N:11]=1
Reactant: Fc1ccc(Nc2ccc3c(Cl)nncc3n2)c(F)c1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Nc2ccc3c(N4CCOCC4)nncc3n2)c(F)c1
Reaction time: 0.08 h

Procedure:
A solution of 5-chloro-N-(2,4-difluorophenyl)pyrido[3,2-d]pyridazin-2-amine (80 mg, 0.27 mmol) and morpholine (238 mg, 2.73 mmol) in 0.4 mL of NMP was heated in a microwave at 150° C. for 30 min. It was diluted with 1 mL of water and stirred for 5 min. The precipitated solid was filtered, rinsed sequentially with 2×2 mL of water, 2×2 mL of ether and 2 mL of EtOAc, then dried in a vacuum oven at 45° C. for 18 h to give the title compound as a tan solid. MS (ESI, pos.ion) m/z: M+1=344.0
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].C(O[C:36]([N:38](C)[CH2:39][C:40](O)=[O:41])=O)(C)(C)C.C(Cl)C[Cl:46].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[ClH:46].[CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][C:24]3([OH:30])[CH2:29][CH2:28][N:27]([C:40](=[O:41])[CH2:39][NH:38][CH3:36])[CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: ClCCCl
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/CC2(O)CCNCC2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/CC2(O)CCN(C(=O)CNC)CC2)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-{(E)-3-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-allyl}-piperidin-4-ol (example 3) (150 mg, 0.371 mmol), 2-(tert-butoxycarbonyl (methyl)amino) acetic acid (70.2 mg, 0.371 mmol), EDC (107 mg, 0.556 mmol), HOBT (68.1 mg, 0.445 mmol) and NEt3 (0.067 ml, 0.482 mmol) were dissolved in 8 ml of DMF and stirred for 3 h at 60° C. Then the mixture was diluted with EtOAc, washed with NaCl-solution and dried over Na2 SO4. Evaporation gave a brown oil. The crude product was purified by chromatography (silicagel, EtOAc/cyclo hexane).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[N:23]=[C:22]([Cl:29])[N:21]=1>CN(C)C=O>[ClH:29].[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:22]1[N:21]=[C:20]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]2[CH3:9])[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[N:23]=1
Reactant: CNc1ccccc1
Reactant: CCCc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCc3ccccc3C2C)nc(N(C)c2ccccc2)n1
Product: Cl
Yield: 73.7 %

Procedure:
After N-methylaniline(0.27 ml, 2.49 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-6-propyl-2-chloropyrimidine(0.5 g, 1.66 mmol) and dimethylformamide (5 ml), 0.5 g of the title compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[CH3:11]O>>[CH3:11][O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: OCCc1ccc(O)cc1
Product: COCCc1ccc(O)cc1
Temperature: 100 °C
Yield: 40 %

Procedure:
A solution of twenty (20) grams 4-hydroxyphenethyl alcohol in 150 ml methanol containing 36.75 grams sulfuric acid (catalyst) were loaded into a 300 cc autoclave. The autoclave was then sealed and purged with nitrogen and pressurized with nitrogen gas to 500 psig. The autoclave was then heated to 100° C. with stirring at 300 rpm. The reaction was allowed to take place for approximately twenty-four (24) hours. The autoclave was then purged with nitrogen, cooled to 5° C., and vented slowly. The resultant material was 90 ml of a dark, greenish-black solution. An aliquot was treated with base and analyzed by gas chromatography (GC). A 40% yield of 4-(2'-methoxyethyl)phenol was obtained.
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.Br[CH2:11][CH2:12][CH3:13].[NH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][CH2:37][C@H:26]4[C:25]=23)[N:17]=1>CN(C)C=O>[CH2:11]([N:14]([CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][CH2:37][C@H:26]4[C:25]=23)[N:17]=1)[CH2:5][CH2:4][CH3:6])[CH2:12][CH3:13]
Reactant: CCCBr
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)no1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)no1
Reaction time: 12 h
Yield: 38 %

Procedure:
1.74 ml (10 mmol) of N-ethyldiisopropylamine and 0.55 ml (6 mmol) of 1-bromopropane were added to a solution of 340 mg (1 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one in 10 ml of dimethylformamide and the mixture was stirred at 70° for 12 hours. The reaction solution was subsequently evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 240:10:1). There were obtained 162 mg (38%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one, Rf=0.26 (silica gel, ethyl acetate/methanol 40:1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C([Sn]([N:53]=[N+:54]=[N-:55])(CCCCCCCC)CCCCCCCC)CCCCCCC>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:55][N:54]=[N:53][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCCCCCC[Sn](CCCCCCCC)(CCCCCCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
A mixture of 2.11 g of 2-butyl-4-chloro-5-formyl-1-(2'-cyanobiphenyl-4-yl)methylimidazole, 8.38 g of trioctyltin azide (tri-n-octyltin azide) and 10 ml of toluene was stirred at 120° C. for 18 hours. After cooling, the reaction mixture was concentrated. To the residue was added 10 ml of ethanol as well as an aqueous solution of sodium nitrite (1.3 g/5 ml) and the mixture was adjusted to pH 3.3 with concentrated hydrochloric acid. The mixture was diluted with 20 ml of water and extracted with two 20 ml portions of ethyl acetate. The ethyl acetate solution was concentrated and the residue was purified by chromatography on 30 g of silica gel (CH2Cl2 -MeOH). The active fraction was concentrated to provide 1.82 g of 2-butyl-4-chloro-5-formyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole. Yield 73%. 1H NMR (CDCl3) δ: 0.78-1.80 (9H), 2.53 (3H, t), 5.51 (2H, s), 6.9-8.0 (12H, m), 9.66 (1H, s) IR(KBr): 2964, 1668, 1518, 1466, 1382, 1280, 758 cm-1
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:10]=[CH:11][C:3]=12.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C([O-])(O)=O.[Na+]>C1COCC1.O.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>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:4]2=[N:5][C:6]([NH2:8])=[N:7][C:2]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[C:3]2[CH:11]=[N:10]1
Reactant: OB(O)c1cccs1
Reactant: Nc1nc(Cl)c2cnn(Cc3ccccc3F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(-c2cccs2)c2cnn(Cc3ccccc3F)c2n1
Yield: 19.7 %

Procedure:
A stirred solution of 4-chloro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine(139 mg, 0.5 mmol) in dry THF (10 mL) was treated with 2-thiopheneboronic acid (128 mg, 1.0 mmol), Pd(PPh3)4 (50 mg, 10 mol %) and saturated aqueous NaHCO3 solution (2 mL), refluxed for 30 min, diluted with H2O, extracted with EtOAc, dried MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by chromatography [SiO2; heptane:EtOAc (1:1) then (1:3)] to give the title compound (32 mg, 20%) as a cream solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42]>CS(C)=O.O>[NH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH:42][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: NCc1cccc(N)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(N)c4)n3Cc3ccccc32)cc1C
Yield: 57.2 %

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 (0.125 g; 0.275 mmol), and 3-aminobenzylamine (0.071 g; 0.577 mmol), in dimethylsulfoxide (5 mL) was stirred at 80° C. for 18 hours. The solution was diluted with water and extracted into dichloromethane. The extracts were dried over anhydrous sodium sulfate and evaporated to yield the title compound as an amorphous white solid (0.085 g; 57%), m.p. 105-115° C. MS [(+)ESI, m/z]: 541.2 [M+H]+
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15]=4[N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=O.[Li+].[BH4-].CO.Cl>CCOC(C)=O.C1COCC1>[OH:2][CH2:3][C:5]12[CH2:10][CH2:9][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15]=4[N:14]=3)([CH2:11][CH2:12]1)[CH2:7][CH2:6]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane 1-carboxylic acid methyl ester (Example 14) (1.40 g, 3.48 mmol) was combined with LiBH4 (0.379 g, 17.4 mmol), MeOH (0.141 ml. 3.48 mmol), and 100 ml of THF and the resultant mixture was brought to reflux for 18 h. After cooling to rt, 50 ml of 1 M HCl were added and the mixture conc'd in vacuo. The residue was dissolved in EtOAc and washed with 1 M HCl, sat'd NaHCO3, brine, and dried over Na2SO4. The EtOAc solution was conc'd in vacuo to give 1.15 g (88% yield) of a white solid. (MH+=375.50)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[OH:36][CH:37]([CH:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[CH2:38][NH2:39]>C(OCC)(=O)C>[OH:36][CH:37]([CH:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[CH2:38][NH:39][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:22])([F:23])[F:24])[CH:13]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)OCC(C(O)CNC(=O)c2cccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)c2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.63 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzoic acid is suspended in 36 ml of ethyl acetate, 2.38 g (20 mmol) of thionylchloride is added and the suspension is heated to boiling temperature. After 15 minutes, a clear solution is present, after 1 hour the formation of the acid chloride is complete. The solution is evaporated to dryness under reduce pressure, the residue is concentrated by evaporation in a vacuum twice with 50 ml of dichloromethane each and then dissolved in 36 ml of dioxane. 1.21 g (12 mmol) of triethylamine and 1.93 g (12 mmol) of 2-hydroxy-2-(2,2-dimethyl-I,3-dioxolan-4-yl)-ethylamine are added to this solution and it is stirred for 5 hours at room temperature. The reaction mixture is then evaporated to dryness in a vacuum, the residue is extracted with ethyl acetate, the ethyl acetate extract is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 3.42 g (6.75 mmol) =67.5% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([CH3:16])[C:7]1[N:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)[CH3:2].[C:17]1([C:23]2[O:24][C:25]([C:31]([F:34])([F:33])[F:32])=[C:26]([C:28](O)=[O:29])[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([CH3:16])[C:7]1[N:12]=[CH:11][C:10]([NH:13][C:28]([C:26]2[N:27]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:24][C:25]=2[C:31]([F:33])([F:34])[F:32])=[O:29])=[CH:9][N:8]=1)[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCOCCN(C)c1ncc([N+](=O)[O-])cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCOCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 2.1 %

Procedure:
(2-Ethoxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine (150 mg, 0.663 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (179 mg, 0.696 mmol), Et3N (466 uL, 3.3 mmol) and BOP (308 mg. 0.696 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-ethoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide as a yellow solid (6 mg). ES-MS calcd for C20H20F3N5O3 (m/e) 435.41, obsd 436.1 (M+H).
Reaction SMILES: [C:1]([C:4]1([CH2:7][CH2:8][C:9]([O:11]C)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+]>O1CCCC1.CN(C)C=O>[CH2:5]1[C:4]2([CH2:7][CH2:8][C:9](=[O:11])[CH2:2][C:1]2=[O:3])[CH2:6]1
Reactant: COC(=O)CCC1(C(C)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CCC2(CC2)C(=O)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
74.5 g of methyl 3-(1-acetylcyclopropyl)propionate (0.32 mol) are dissolved in 1 l of tetrahydrofuran and the solution is treated portionwise with 14.3 g of sodium hydride (55% suspension in oil, 0.32 mol) at room temperature. After 1 hour, the reaction mixture is diluted with 200 ml of dimethylformamide and warmed to 70° C. After 8 hours, tetrahydrofuran is removed in vacuo, and the residue is poured into 2 N hydrochloric acid and extracted with diethyl ether. The organic phase is dried over sodium sulfate and concentrated, and column chromatography over silica gel (methylene chloride:ethanol 9:1 as eluent) gives spiro[2.5]octane-4,6-dione in the form of white crystals of melting point 116-118° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[O:22][CH2:23][CH:24](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:25].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>CN(C)C=O.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]2[N:9]([CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:24]([CH3:25])[CH2:23][O:22][C:3]=2[C:2]=1[F:1]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OCC
Temperature: 80 °C

Procedure:
To a solution of 791 mg of the compound obtained in Example 4 in 5 ml of anhydrous N,N-dimethylformamide (hereinafter abbreviated as DMF), 207 mg of potassium carbonate and a catalytic amount of 18-crown-6-ether were added, and the mixture was heated at 80° C. for 8.5 hours. To the mixture were added ethyl acetate and water. The mixture was shaken, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield the titled compound as crystals in quantitative yield. The physical data of the product were identical to those of the authentic specimen as described in Reference Example B-1.