Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[NH:12][C:8]=2[CH:7]=1.[Na+].[I-].Cl.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]3[NH:10][C:11](=[O:13])[NH:12][C:8]=3[CH:7]=2)[CH2:29][CH2:28]1
Reactant: O=c1[nH]c2ccc(OCCCBr)cc2[nH]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=c1[nH]c2ccc(OCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
A mixture of intermediate 39 (126 mg, 0.47 mmol) and NaI (140 mg, 0.93 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 41 (188 mg, 0.71 mmol) and anhydrous K2CO3 (259 mg, 1.88 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=15:1) to give 5-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)-1H-benzo[d]imidazol-2(3H)-one (compound 34) (54 mg, 27%). 1H NMR (300 MHz, DMSO): δ 10.60 (s, 1H), 10.36 (s, 1H), 7.32 (d, J=5.1 Hz, 2H), 7.16-7.18 (m, 1H), 6.80 (d, J=9.6 Hz, 1H), 6.51-6.53 (d, J=6.6 Hz, 2H), 3.99-3.95 (m, 2H), 2.81-3.26 (s, 5H), 2.80-2.60 (m, 5H), 1.80-2.01 (m, 2H). HPLC: 99%, RT 2.228 min. MS (ESI) m/z 421.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:33]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(C)c3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (152 mg, 343 μmol) produced in Example D5(i) in pyridine (4 mL) was added acetyl chloride (74 μL, 1.03 mmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (102 mg, 61%) as a pale-purple solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(OCCO)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CCOCCO
Product: N#Cc1cnc2c(oc3ccccc32)c1Nc1cccc(Br)c1
Yield: 63.4 %

Procedure:
A solution of 300 mg (1.30 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 0.160 mL (1.43 mmol) of 3-bromoaniline in 8 mL of 2-ethoxyethanol is heated at reflux temperature for 24 hours. The reaction mixture is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with saturated sodium bicarbonate, followed by brine, then dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo. The resultant solid is collected by filtration to give 300 mg (42%) of a beige solid, mp 242–245° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[CH2:10][CH2:11][CH2:12][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2c(c1O)CCC2
Product: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A solution of 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-ol (1.424 g, 7.904 mmol) in phosphoryl chloride (11.0 mL, 118 mmol) was heated at 110° C. in a sealed flask under nitrogen for 2 h. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 50% aq. NaOH to pH 7. The resulting mixture was extracted three times with EtOAc, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a brown solid (0.82 g, 52%). LCMS calc. for C8H8N2O2(M+H)+: m/z=199.3. Found: 199.2.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cc(OC)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-methoxypyridine hydrobromide*.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][C:21](Cl)=[O:22].O1CCCC1.[H-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:20][C:21]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(O)c(CNCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CN(Cc1ccccc1)C(=O)CO2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of 2.43 g of 2-(benzylamino-methyl)-4-methoxy-phenol and 20 mL of toluene was cooled to 5° C. and a solution of chloroacetyl chloride (0.88 ml) in 5 mL of toluene slowly added while stirring. Stirring was continued for 2 hours at room temperature. Dry tetrahydrofuran (25 mL) was added and 3.4 g of sodium hydride (95%; dispersion in mineral oil) were added in small portions under a nitrogen atmosphere. The mixture was allowed to stir at room temperature for 24 h. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent removed in vacuo yielding 2.0 g of 4-benzyl-7-methoxy-4,5-dihydro-benzo[f][1,4]oxazepin-3-one as an oil. EI-MS: 283 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[CH2:17]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)[CH3:18]
Reactant: CCI
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 2-(4-piperidinyl)ethanol (Ig, 7.74 mmol) and potassium carbonate (2.67 g, 19.35 mmol) in dry DMF (10 ml) was added iodoethane (0.687 ml, 8.51 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours. The solvent was partially removed in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The aqueous was washed with further ethyl acetate and the combined organics dried (hydrophobic frit) and concentrated in vacuo to give the title compound as a mixture with residual DMF as a clear oil, 1.55 g
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH2:10])=[N:8][CH:7]=[N:6][C:5]=2[N:11]=1.N(O)=O.[NH2:15][C:16]1[C:17]2[S:24][C:23]([Cl:25])=[N:22][C:18]=2[N:19]=[CH:20][N:21]=1>CN(C=O)C>[NH2:15][C:16]1[C:17]2[S:24][C:23]([Cl:25])=[N:22][C:18]=2[N:19]=[CH:20][N:21]=1.[NH2:10][C:9]1[C:4]2[S:3][C:2](=[S:24])[NH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1nc2ncnc(N)c2s1
Agent: Nc1ncnc2nc(Cl)sc12
Agent: O=NO
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]c(=S)sc12

Procedure:
This was circumvented by the synthesis of the adenosine analog from its preformed heterocycle in the same manner as that used to obtain the guanosine analog. The known 2,7-diaminothiazolo[4,5-d]pyrimidine (27) served as the starting material (Scheme V). Treatment of 27 with nitrous acid under conditions similar to those used to prepare 13 provided 7-amino-2-chlorothiazolo[4,5-d]pyrimidine (28). The structure of compound 28 was verified by single-crystal X-ray analysis. Treatment of 28 with NaSH in DMF at 0° C. yielded the 2-mercapto derivative, 7-aminothiazolo[4,5-d]pyrimidine-2(3H)-thione (29). The conversion of the 2-thioxo function in 29 to a 2-oxo function was accomplished using cold alkaline hydrogen peroxide to yield 7-aminothiazolo[4,5-d]pyrimidin-2(3H)-one (30). Reaction of 30 with the benzoyl-protected sugar, 5, under the same glycosylation conditions (at room temperature) as used to produce the blocked guanosine analog, 6, resulted in the formation of the unexpected blocked 4-ribofuranosyl isomer, 7-amino-4-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidin-2(3H)-one (31), as the only isomer detected and isolated. If, however, the same reaction was carried out at elevated temperature (80° C.), the predominant product obtained was the desired 3-ribofuranosyl isomer, 7-amino-3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidin-2-(3H)-one (32). Both isomers, 31 and 32. were deprotected using sodium methoxide in dry methanol to obtain 7-amino-4-β-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (33) and 7-amino-3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (34), respectively.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5])[CH3:2].[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.N1C=CC=CC=1>C(Cl)Cl>[C:11]12([C:21]([O:10][C:8]3[CH:7]=[CH:6][C:4]([OH:5])=[C:3]([CH2:1][CH3:2])[CH:9]=3)=[O:22])[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]3)[CH2:12]1)[CH2:20]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCc1cc(O)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(OC(=O)C23CC4CC(CC(C4)C2)C3)ccc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Ethylhydroquinone (1.85 mmol) and 1-adamantanecarbonyl chloride (1.4 eq.) were suspended in CH2Cl2 (3 mL/mmol), pyridine (1 mmol) was added, and the mixture stirred at r.t. for 48 h.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C1COCC1>[NH2:19][CH2:18][C:10]1([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[N:9][CH:8]=2)[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1
Reactant: CC(=O)c1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(C2(CN)CCC(F)(F)CC2)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
To a solution of 1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (80 mg, 0.30 mmol) in THF (4.0 mL) at room temperature was added sodium borohydride (23 mg, 0.60 mmol) and the reaction was stirred at room temperature for 2.5 hours. The reaction was quenched with methanol and the volatiles were then removed under reduced pressure. The residue was taken up in AcOEt (about 10 mL) and washed with saturated aqueous sodium bicarbonate (about 10 mL). The layers were separated and the aqueous layer was extracted again with AcOEt (2×5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then dissolved in a 7 N ammonia solution in methanol (6.7 mL) and treated with the tip of a spatula of Raney-nickel. The flask was purged three times then left to stir under one atmosphere of hydrogen for 15 hours. The catalyst was removed by filtration through celite and washed with methanol. The solvent was then removed under reduced pressure to afford 1-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-ethanol as a white solid (64 mg, 78%). LC-MS (m/z) 271.1 (MH+); tR=0.55.
Reaction SMILES: [BrH:1].N[C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH3:19].C1C2=C3C(CC4C2=CC=CC=4)N(C)CCC3=CC=1>C(OCC)(=O)C.Br>[BrH:1].[OH:16][C:13]1[C:14]2=[C:15]3[CH:6]([CH2:5][C:4]4[C:3]2=[CH:23][C:22]([O:24][CH3:25])=[CH:21][CH:20]=4)[N:7]([CH3:19])[CH2:8][CH2:9][C:10]3=[CH:11][C:12]=1[O:17][CH3:18]
Reactant: COc1ccc(CC2c3cc(O)c(OC)cc3CCN2C)c(N)c1
Agent: Br
Agent: CN1CCc2cccc3c2C1Cc1ccccc1-3
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)-c1c(O)c(OC)cc3c1C(C2)N(C)CC3
Yield: 47 %

Procedure:
The diazotization and cyclization of 1-(2'-amino-4'-methoxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (4f) was carried out as in Example XVIII, except that the only residue containing the crude aporphine was quickly passed through a short column of silica gel (10 g, backed in chloroform) and eluted with 5% methanol-chloroform. Evaporation of the organic solvents gave a residue which was dissolved in ethyl acetate and heated with a few drops of 48% hydrogen bromide to give 1-hydroxy-2,10-dimethoxyaporphine hydrobromide (5f) in 47% yield, mp 219-221.
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH3:18])[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH3:18])/[C:10](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1N(CCN(C(C)C)C(C)C)C(=O)C2=O
Reactant: NNC(N)=O
Agent: Cl
Product: Cc1cccc2c1N(CCN(C(C)C)C(C)C)C(=O)/C2=N/NC(N)=O
Yield: 75.7 %

Procedure:
By using 1-(2-diisopropylaminoethyl)-7-methylisatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-1-(2-diisopropylaminoethyl)-7-methylisatin 3-semicarbazone having a melting point of 194°-195° C. (yield: 75.7%).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([O:13]CC)=[O:12])[O:9][C:8]([CH:28]([Br:30])[CH3:29])([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)[O:7]1)=[O:5])C.[OH-].[Na+].C(COC)OC>O>[Br:30][CH:28]([C:8]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)[O:7][C@@H:6]([C:4]([OH:5])=[O:3])[C@H:10]([C:11]([OH:13])=[O:12])[O:9]1)[CH3:29]
Reactant: CCOC(=O)[C@@H]1OC(c2ccc3cc(OC)ccc3c2)(C(C)Br)O[C@H]1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2cc(C3(C(C)Br)O[C@@H](C(=O)O)[C@H](C(=O)O)O3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A mixture of the two diastereoisomers of 2-(1-bromoethyl)-2(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid diethyl ester 3 and 4 (prepared in a similar manner as described in Example 1) (21.18 g, 0.044 mol, ratio 3:4=1:1), sodium hydroxide (3.52 g, 0.088 mol), dimethoxyethane (35 ml) and of water (35 ml) was kept, under stirring, at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with diethylether. The aqueous phase was acidified with concentrated hydrochloric acid to pH 1 and extracted with diethylether. The organic phase was washed with water and dried over sodium sulphate. Evaporation of the solvent under reduced pressure gave the two diastereoisomers of 2-(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 5 and 6 (16 g, 0.0367 mol; yield 85.5%) in ratio 5:6=1:1 (determined by 1H-NMR 200 MHz).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:28][NH2:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH2:28][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:16]([Cl:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: NCc1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (134 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (148 mg, 0.57 mmol, Amine-23) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[NH2:25])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.C(N(CC)CC)C>C1COCC1.[Pd]>[F:26][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C:8]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH2:25])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Nc1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ccccc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1cnccc1Nc1cc(-c2ccccc2F)nc2ccccc12

Procedure:
353 mg N*4*-[2-(5-Chloro-2-fluoro-phenyl)-quinolin-4-yl]-pyridine-3,4-diamine (cf. Example 7) dissolved in 60 ml THF and 330 mg triethylamine were hydrogenated over 1.8 g Pd—C (52% water) over night, at normal pressure and ambient room temperature to give after filtration, evaporation and subsequent digeration with ether 238 mg yellow powder product with correct mass M+H+331 and >90% HPLC purity with a Rt˜1.23 min in LC-MS system 1. TLC on silica in CH2Cl2/MeOH 1:1 showed one product at Rf˜0.21.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[C:27]([OH:33])[NH:28]3)O1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:3]1[C:4]2[N:5]3[CH2:15][CH2:14][O:13][CH2:12][CH:6]3[CH2:7][NH:8][C:9]=2[CH:10]=[N:11][C:2]=1[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([OH:33])[NH:28]2
Reactant: CC1(C)OB(c2cccc3[nH]c(O)cc23)OC1(C)C
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Oc1cc2c(-c3ncc4c(n3)N3CCOCC3CN4)cccc2[nH]1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 50 mg, 0.221 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-ol (30 mg, 0.116 mmol), and PdCl2(dppf) (12.91 mg, 0.018 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 2.95-3.03 (m, 2H), 3.20-3.30 (m, 3H), 3.77-3.83 (m, 2H), 3.88-3.95 (m, 1H), 4.00-4.08 (m, 1H), 4.36-4.45 (m, 1H), 6.01-6.15 (m, 1H), 6.78-6.85 (m, 1H), 7.18-7.26 (m, 1H), 7.62-7.68 (m, 1H), 7.74-7.80 (m, 1H), 10.23-10.52 (m, 1H), 12.27-12.56 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C17H17N5O2, 323.14. found 324.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[O:24][C:25]=1[CH3:26].ClC1C=C(C=C(Cl)C=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2cc(Cl)cc(Cl)c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1cc(Cl)cc(Cl)c1
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(3,5-dichloro-phenyl)-5-methyl-oxazole (prepared from 3,5-dichloro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 2 a] and b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-3-{4-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C:12]1([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46].N>C(OCC)(=O)C>[CH2:2]([O:9][C:10]([C:12]1([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:23][CH:24]=2)[C:42](=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CNC2(C(=O)OCc3ccccc3)CCCC2)cc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCC1
Reaction time: 15 h

Procedure:
A solution of 2.9 g (6.5 mmol) of N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyano-biphenyl-4-ylmethyl)-amine hydrochloride and 4.4 ml (26 mmol) of Hunig base in 50 ml of ethyl acetate is treated with 1.1 g (9 mmol) of pentanoyl chloride, and the mixture is stirred for 15 hours at 25°-30°. After the addition of a further 0.5 g of pentanoyl chloride the mixture is stirred for a further 8 hours. The reaction mixture is then treated with 10 ml of aqueous ammonia solution (5%) and stirred for 0,5 hours. The ethyl acetate phase is separated, washed in succession with 2 N-hydrochloric acid, water and sodium hydrogencarbonate solution, dried and evaporated. The N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine is thus obtained in the form of a brown oil [Rf : 0.53 (system B7)], which is used for further reactions in crude form.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a solution of 3-(benzyloxy)aniline (5.00 g) in DMF (50% mL) were added sodium acetate (2.10 g) and ethyl bromoacetate (4.20 g), and the mixture was stirred at room temperature for 12 hr. Water was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.80 g) as orange crystals.