Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][NH:7][CH2:8][CH3:9])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[C:22](=[O:44])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34]2[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=2[C:36]([O:38][CH3:39])=[O:37])=[CH:27][CH:26]=1>C(#N)C>[CH2:8]([N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][CH:10]=1)[C:22](=[O:44])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][O:33][C:34]2[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=2[C:36]([O:38][CH3:39])=[O:37])=[CH:29][CH:30]=1)[CH3:9]
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)Cl)cc1
Reactant: CCNCc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(Cc1ccc(F)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
N-(4-Fluorobenzyl)ethanamine (0.114 g, 0.745 mmol) was dissolved in dry acetonitrile under N2 and N-ethyl-N,N-diisopropylamine (0.371 g, 2.867 nmol) was added. The mixture was stirred for 30 min and methyl 2-{2-[4-(2-chloro-2-oxoethoxy)phenyl]-ethoxy}benzoate (0.200 g, 0.573 mmol) was added. The solution was stirred overnight at room temperature. The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.223 g of methyl 2-[2-(4-{2-[ethyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (yield 83.5%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][CH2:10][CH2:11][C:12]([OH:14])=[S:13]>ClCCl.[I-].[Zn+2].[I-]>[O:14]=[C:12]1[S:13][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9][CH2:10][CH2:11]1
Reactant: O=Cc1ccccc1
Reactant: OC(=S)CCS
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: O=C1CCSC(c2ccccc2)S1
Temperature: 25 °C

Procedure:
To a solution of benzaldehyde (1.06 g, 10 mm) and 3-mercaptothiopropionic acid (1.22 g, 10 mm) in dichloromethane (25 cc) was added dry zinc iodide (1 mm, 320 mg) and the mixture was refluxed for 3.5 hrs. It was cooled to room temperature, diluted with dichloromethane and successively washed with IN HCl, brine and dried with sodium sulphate. Removal of the solvent yielded the essentially pure title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH2:24][C@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[N:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:46])[C:29]([C:31]1[N:40]([CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[C:34]2[N:35]=[C:36](Cl)[N:37]=[CH:38][C:33]=2[CH:32]=1)=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH2:24][C@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:36]4[N:37]=[CH:38][C:33]5[CH:32]=[C:31]([C:29](=[O:30])[N:28]([CH3:27])[CH3:46])[N:40]([CH:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)[C:34]=5[N:35]=4)=[CH:21][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]2(CC1)CN(c1ccc(N)nc1)C(=O)O2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@]5(CCCN(C(=O)OC(C)(C)C)CC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 35 %

Procedure:
Following general N—C coupling procedure 1, (S)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave (S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester as a white solid (0.075 g, 0.115 mmol) in 35% yield. MS m/z 619.5 (M+H)+.
Reaction SMILES: [CH2:1]([N:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=O)[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([N:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)/[C:16](=[N:33]/[NH:32][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)/[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCN1C(=O)C(=O)c2ccccc21
Product: CCCCCCCCCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccccc21
Yield: 100 %

Procedure:
The title compound was prepared as a pale orange solid, using 1-dodecyl-isatin and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 100%. 1H NMR (DMSO-d6): δ 0.82 (t, J=6.6 Hz, 3H), 1.20-1.28 (m, 18H), 1.62-1.66 (m, 2H), 3.77 (t, J=6.9 Hz, 2H), 7.16-7.24 (m, 2H), 7.48 (t, J=7.5 Hz, 1H), 7.60-7.73 (m, 4H), 7.92 (d, J=7.8 Hz, 2H), 13.91 (br s, 1H). 13C NMR (DMSO-d6): δ 14.38 (CH3), 22.53 (CH2), 26.67 (CH2), 27.38 (CH2), 29.07 (CH2), 29.14 (CH2), 29.32 (CH2), 39.36 (CH2), 29.43 (CH2), 29.45 (CH2), 31.73 (CH2), 39.75 (CH2), 110.68 (CH), 119.65 (C), 121.27 (CH), 123.70 (CH), 127.88 (CH), 129.65 (CH), 132.22 (CH), 132.41 (C), 133.40 (CH), 143.44 (C═N), 161.61 (C═O). HRMS (ES+) calcd for C27H36N3O2 (M+H+), m/e, 434.2812. found, 434.2802.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:21]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Cl:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
In a 150 mL round-bottomed flask, (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (5 g, 18 mmol) was dissolved in dimethylformamide (30 ml). N-Chlorosuccinimide (2.4 g, 18 mmol) was added and the mixture was stirred at 60° C. for 1 h. The reaction mixture was poured into ethyl acetate and extracted with saturated sodium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 30% ethyl acetate in heptane) to yield a light yellow solid (4.0 g, 71%) MS (ISP): 313.1 ([{35Cl}M+H]+), 315.1 ([{37Cl}M+H]+).
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)=[CH:14][C:13]=1[F:26])([CH3:11])[CH3:10])=O)(C)(C)C.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][CH2:33][OH:34])=[CH:30][CH:29]=1>>[NH2:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([CH2:32][CH2:33][OH:34])=[CH:30][CH:29]=3)[N:19]=2)=[CH:14][C:13]=1[F:26])([CH3:10])[CH3:11]
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1F
Product: CC(C)(N)c1ccc(-c2nc(Nc3ccc(CCO)cc3)ncc2Cl)cc1F

Procedure:
The title compound was prepared from 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)-3-fluorophenyl]-2,5-dichloropyrimidine (1.60 g, 4.0 mmol) and 4-aminophenethyl alcohol (826 mg, 6.0 mmol) following the method of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#N)[C:3]=1[C:10]1[NH:11][C:12](=[O:30])[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]1)=[O:17].C(O)(=O)C>[Zn].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:10]1=[C:15]([C:16]([N:18]3[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]3)=[O:17])[CH:14]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12](=[O:30])[N:11]1[CH2:8]2
Reactant: COC1CN(C(=O)c2cc(-c3ccccc3)c(=O)[nH]c2-c2c(Cl)cccc2C#N)C1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC1CN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2c(Cl)cccc2C3)C1
Yield: 2 %

Procedure:
A mixture of 1. 17 g of 1-[[2-(2-chloro-6-cyanophenyl)-1,6-dihydro-6-oxo-5-phenyl -3-pyridyl]carbonyl]-3-methoxyazetidine, 0.91 g of zinc powder and 25 ml of acetic acid was heated to boiling under reflux for 15 minutes under argon. The reaction mixture was then poured into 125 ml of water, whereupon the separated crystals were filtered off under suction and washed with water. The aqueous phase was exhaustively extracted with methylene chloride. The combined organic phases were evaporated and the residue was purified with the crystals obtained above. This material was chromatographed on silica gel with methylene chloride/acetone (9:1) and then recrystallized from toluene. There was obtained 0.33 g of 1-[(10-chloro-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-yl)carbonyl]-3-methoxyazetidine as yellow crystals with a m.p. of 235°-238°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10]([OH:17])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10]([O:17][CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccc(F)cc2)nc2ccsc12
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc(OCc3ccccn3)c3sccc3n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (30 mg, 0.09 mmol), 2-picolyl chloride hydrochloride salt (30 mg) and potassium carbonate (100 mg) in DMF (2 mL) is heated at 100° C. for 2 hours. The reaction solution is cooled to room temperature, quenched with aqueous sodium bicarbonate solution and extracted several times with ethyl acetate. The combined ethyl acetate layers are dried over Na2SO4, filtered and concentrated. The residue is purified by preparative thin layer chromatography to give 5-(4-Fluorophenyl)-7-[(2-pyridyl)-methyloxy]-thieno[3,2-b]pyridine as white solid (compound 1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:24]1)C[C:19]2=O.C(N(CC)CC)C>CC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:14][OH:15])[CH2:16][O:17][C:18]([CH3:24])([CH3:19])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CO)(CO)CCOCc1ccccc1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1(C)OCC(CO)(CCOCc2ccccc2)CO1
Yield: 164 %

Procedure:
543 mg of the crude 4-benzyloxy-2,2-dihydroxymethylbutanol product was dissolved in 3 mL of acetone, 232 mg (1.0 mmol equivalents) of 10-camphorsulfonic acid was added thereto, and a reaction was carried out at room temperature (25° C.) overnight. After completion of the reaction, triethylamine was added dropwise, and the mixture was concentrated under vacuum. The crude product thus obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=4/1) to give 459 mg (1.64 mmol equivalents) of 5-benzyloxyethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([NH2:22])=[O:21])=[O:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O>CO.[Pd]>[NH2:1][C@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([NH2:22])=[O:21])=[O:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)NCC(N)=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC[C@H](N)C(=O)NCC(=O)NCC(N)=O
Reaction time: 4 h
Yield: 96.8 %

Procedure:
940 mg (2.09 mmol) of Z-Glu(OtBu)-Gly-GlyNH2 was dissolved in 40 mL of 95:5 methanol:de-ionized water in a 250 mL glass PARR hydrogenation shaker flak. 222 mg of 10% palladium on carbon was added to the flask and the contents were hydrogenated with shaking under hydrogen (40 PSI) for 4 hours. The mixture was vacuum filtered though celite filter aid and solvent was removed from the filtrate by rotary evaporation to give 640 mg (94%) of the title compound. 1H NMR (400 MHz, DMSO) δ 4.03 (s, 1H), 3.75 (d, J=3.3, 2H), 3.63 (s, 2H), 3.30-3.22 (m, J=3.6, 1H), 3.14-3.10 (m, 1H), 2.27 (t, J=7.9, 2H), 1.84 (td, J=13.6, 7.4, 1H), 1.63 (td, J=15.0, 7.5, 1H), 1.39 (s, 9H). 13C NMR (101 MHz, MeOD) δ 176.53, 174.24, 172.00, 170.32, 81.82, 55.21, 43.64, 43.16, 40.44, 32.31, 30.45, 28.41. HRMS (M+H+) Calc. 317.1825 found 317.1800.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([NH:9][NH2:10])=[O:8])[C:5]=1[OH:14])([O-:3])=[O:2].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:18]1([C:15](=[N:10][NH:9][C:7](=[O:8])[C:6]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)[OH:14])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(=NNC(=O)c1cccc([N+](=O)[O-])c1O)c1ccccc1
Temperature: 22.5 °C
Reaction time: 14 h
Yield: 93.6 %

Procedure:
A solution of 1.0 g (5 mmol) of 3-nitrosalicylohydrazide in 50 ml of anhydrous ethanol were treated with 0.6 g (5 mmol) of acetophenone and with a catalytic amount of p-toluenesulfonic acid. After the mixture had been stirred for 14 hours at approximately 20 to 25° C. and the solvent had been distilled off, 1.4 g of the title compound (90% of theory) were obtained as colorless crystals of m.p.: 163-168° C.
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29]1([CH2:35][CH2:36]C=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:35][CH2:36][C:21]2[C:20]3[CH:19]=[CH:18][C:17]([F:22])=[CH:16][C:15]=3[N:14]=[C:13]3[C:23]4[N:10]([CH2:11][C:12]=23)[C:9](=[O:26])[C:8]2[CH2:7][O:6][C:5](=[O:27])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:28])[C:25]=2[CH:24]=4)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=CCCC1CCCCC1
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCC1CCCCC1

Procedure:
The product of Example 84 is treated with 3-cyclohexylpropanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[O:27]1[C:19]2[CH:18]=[CH:17][C:22](/[CH:23]=[CH:1]/[C:2]3[O:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:3]=3)=[CH:21][C:20]=2[O:25][CH2:26]1
Reactant: Cc1cc(OCc2ccccc2)cc(=O)o1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: O=c1cc(OCc2ccccc2)cc(/C=C/c2ccc3c(c2)OCO3)o1
Yield: 39 %

Procedure:
6-methyl-4-(phenylmethoxy)-2H-pyran-2-one (known) was reacted with piperonal in accordance with Method C described above under II to form E-6-[2-(1,3-benzodioxol -5-yl)ethenyl]-4-(phenylmethoxy)-2H-pyran-2-one: C21H16O5; yield 39%, melting point 150 to 152° C. (acetone). This condensation product was hydrogenated in accordance with Method A described above under I. For cleaning purposes the product was taken up in ethyl acetate, was extracted therefrom with 2 N potassium hydroxide solution and was precipitated from the latter by acidification: C14H12O5; yield 67%, melting point 200 to 201° C. (isopropanol/water).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]([CH3:37])=[C:33]([CH2:35]Cl)[N:34]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:29][CH:28]=3)[O:31][C:32]=2[CH3:37])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Reactant: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)c2ccoc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 120 f], 2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (example 120 e]) was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[F:18][C:19]([F:36])([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][NH:32][C:31]2=[O:35])=[CH:26][CH:25]=1)[CH:20]([F:22])[F:21].[H-].[Na+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:19]([F:36])([F:18])[CH:20]([F:22])[F:21])=[CH:29][CH:28]=2)[C:31]1=[O:35])[CH3:11]
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Reaction time: 20 h
Yield: 8.2 %

Procedure:
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.5 g), 2.66 g of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone and 0.386 g of 60% sodium hydride in oil were added to 25 ml of N,N-dimethylformamide. The mixture was stirred at 80° C. for 20 hours. After cooling, the reaction mixture was added to 100 ml of water and extracted with ethyl acetate (50 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/2) to give 0.27 g of 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone as a colorless powder.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH:14]1([N:19]2[C:23]([NH2:24])=[C:22]([C:25]#[N:26])[C:21]([CH2:27][CH3:28])=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([N:19]2[C:23]([NH:24][C:9]([CH2:8][C:5]3[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=3)=[O:11])=[C:22]([C:25]#[N:26])[C:21]([CH2:27][CH3:28])=[N:20]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(O)Cc1ccncc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccncc2)c1C#N
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a mixture of 4-pyridine acetic acid hydrochloride (4.3 g, 25 mmol) and DMF (50 ml) cooled in an ice bath was added NaH (1.0 g, 25 mmol, 60% dispersion in mineral oil). The resulting mixture was stirred for 30 minutes and then N,N'-carbonyldiimidazole (4.0 g, 24.6 mmol) was added followed 30 minutes later by 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carbonitrile (4.1 g, 20 mmol). The reaction mixture was stirred as such for 4 hours, then at room temperature for about 2 days, and then finally was heated on a steam bath for 2 hours. The reaction mixture was concentrated to dryness and water (50 ml) and acetic acid (5 ml) were added. The mixture was extracted with CH2Cl2 (300 ml), the organic layer was concentrated in vacuo and the resulting oil was crystallized from ether and purified by column chromatography on silica gel eluting with ether to afford 2.8 g (35%) of 1-cyclopentyl-3-ethyl-4-cyano-5-[(4-pyridinylmethyl)carbonylamino]-1H-pyrazole, as a viscous oil.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([N:17]3[CH:25]=[N:24][C:23]4[C:18]3=[N:19][CH:20]=[N:21][C:22]=4Cl)[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([N:17]3[CH:25]=[N:24][C:23]4[C:18]3=[N:19][CH:20]=[N:21][C:22]=4[NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc([C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O)o1
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nnc([C@H]2O[C@@H](n3cnc4c(NC5CCOCC5)ncnc43)[C@H](O)[C@@H]2O)o1
Yield: 77.1 %

Procedure:
(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-(6-chloro-purin-9-yl)-tetrahydro-furan-3,4-diol (41 mg) was heated under reflux with 4-aminotetrahydropyran hydrochloride (59 mg), diisopropylethylamine (0.11 ml), and isopropanol (5 ml) for 15 h. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel, eluting with ethyl acetate:methanol 100:0-90:10, to give the title compound (37 mg).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:26]([NH:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)=[O:27].[ClH:39].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:39].[NH2:31][CH2:30][CH2:29][NH:28][C:26]([C:8]1[N:9]=[N:10][N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[O:19])=[CH:16][CH:17]=2)[C:7]=1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][F:1])=[O:27]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1nnn(-c2ccc(C(=O)NCC(F)(F)F)cc2)c1CCCCCF
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNC(=O)c1nnn(-c2ccc(C(=O)NCC(F)(F)F)cc2)c1CCCCCF
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of tert-butyl [2-({[5-(5-fluoropentyl)-1-(4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazol-4-yl]carbonyl}amino)ethyl]carbamate (0.86 g) obtained in Example 219 in ethyl acetate (10 ml) was added 4N hydrochloric acid/ethyl acetate solution (10 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, diisopropyl ether was added to the obtained residue, and the resultant precipitate was collected by filtration to give the title compound as a white powder (0.76 g, 99%).