Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1.CN(C)C1N=CC(C2SC3C=C(O)C=CC=3N=2)=CN=1.B(Br)(Br)Br>CO>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(Br)sc2c1
Agent: BrB(Br)Br
Agent: CN(C)c1ncc(-c2nc3ccc(O)cc3s2)cn1
Solvent: CO
Product: Oc1ccc2nc(Br)sc2c1
Yield: 76.7 %

Procedure:
2-Bromo-6-methoxy-1,3-benzothiazole (0.832 g, 3.41 mmol) was subjected to the procedure used for the preparation of 2-[2-(dimethylamino)pyrimidin-5-yl]-1,3-benzothiazol-6-ol, with the following exceptions: 4.4 equiv BBr3-solution was used, and after being stirred on, the mixture was poured into MeOH and then concentrated under reduced pressure. A slurry of this residue in EtOAc was filtered through silica and eluted with EtOAc/DCM/MeOH 10:10:1 and DCM/MeOH 9:1. The crude product was recrystallized from EtOAc to give 2-bromo-1,3-benzothiazol-6-ol (0.602 g). 1H NMR δ 10.00 (br s, 1H) 7.77 (d, 1H) 7.39 (d, 1H) 6.97 (dd, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[O:13]([CH2:20][CH2:21]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C(OCC)C>[O:13]([CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCOc1ccccc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCCOc3ccccc3)ccc21
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (2.5 g), 2-phenoxyethyl bromide (3.4 g) and cesium carbonate (5.5 g) were stirred in N,N-dimethylformamide (15 cm3) and heated at 100° C. for 2.5 h. The reaction mixture was allowed to cool to room temperature and then diluted with water (150 cm3). The aqueous mixture was extracted with ethyl acetate (2×50 cm3) and the organic extracts were washed with aqueous sodium hydroxide (1 M, 50 cm3), water (50 cm3) and then hydrochloric acid (2 M, 50 cm3). The organic extracts were dried (Na2SO4) and the solvent removed under reduced pressure to afford the crude product which was suspended in diethyl ether and filtered to yield the title compound (3.2 g).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]([C:31]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH2:26]([O:28][C:29]([C:31]1([C:36]2[CH:41]=[CH:40][C:39]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CCCC1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (0.077 g, 0.19 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopentanecarboxylic acid ethyl ester (0.079 g, 0.23 mmol), and potassium carbonate (0.066 g, 0.48 mmol) were combined in 2:1 DME:H2O (3 mL). The solution was purged with N2 for 5 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.02 mmol) was added. The mixture was purged with N2 for an additional 5 minutes, and then the reaction was stirred at 90° C. in a sealed tube for 1.5 hours. Aqueous work-up, followed by silica gel chromatography, provided the title compound.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>C1COCC1.ClCCl.C(OCC)(=O)C.C(O[Cu]OC(=O)C)(=O)C>[O:16]=[C:7]1[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]1[C:32]1[CH:33]=[CH:34][C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2C(=O)c3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 23.4 %

Procedure:
To a suspension of dibenzo[b,f][1,4]oxazepin-11(10H)-one (0.623 g, 2.95 mmol) in THF (10.0 mL), dichloromethane (10.0 mL) and triethylamine (2.0 mL, 14.7 mmol) was added diacetoxycopper (0.587 g, 3.25 mmol) followed by 4-(ethoxycarbonyl)phenylboronic acid (1.15 g, 5.91 mmol). The reaction mixture was stirred at room temperature for 5 days. It was diluted with ethyl acetate and this organic layer was washed with 10% HCl (2 times), water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (a 1st one with 20% ethyl acetate in hexanes and second one with 0.5% methanol in dichloromethane) to afford title compound 465 (248 mg, 23%) as a white solid. MS (m/z): 360.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:18])=[N:6][CH:5]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2CO)nc1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of 6-(5-formyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (0.25 g, 0.74 mmol) in methanol (10 mL) was treated at room temperature with sodium borohydride (0.03 g, 0.74 mmol) and stirred for 1 h. After quenching with aqueous citric acid (5 mL of a 10% solution) and extraction with ethyl acetate the organic phase was dried (Na2SO4) filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetete=90:10 to 40:60) afforded the title compound as a white solid (0.22 g, 89%). MS: m/e=341.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Na:19].OC1C2C(C(O)=C3C=1CC=CC3)=CC=CC=2.C1(=O)C2C(=CC3C(C=2)=CC=CC=3)C=CC1=O>O>[Na:19].[CH:10]1[C:9]2[C:14](=[C:15]([OH:17])[C:16]3[C:7]([C:8]=2[OH:18])=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=C1C=Cc2cc3ccccc3cc2C1=O
Agent: Oc1c2c(c(O)c3ccccc13)CC=CC2
Agent: [Na+]
Solvent: O
Product: Oc1c2ccccc2c(O)c2ccccc12
Temperature: 87.5 °C

Procedure:
A three necked flask having a capacity of 300 ml and equipped with a stirrer, a thermometer, a heating jacket and a charge inlet, 32 g of a 30% sodium hydroxide aqueous solution and 57 g of water were charged, and with stirring, 25 g of 9,10-anthracenedione was charged and suspended, whereupon air in the flask was substituted by nitrogen. While stirring the content in this flask, 130 g of an aqueous solution of a sodium salt of 1,4-dihydro-9,10-dihydroxyanthracene (22% as the concentration of anthracenedione) was added, and the mixture was maintained at an internal temperature within a range of from 85 to 90° C. for 4 hours to obtain an aqueous solution of a sodium salt of 9,10-anthracenediol.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.Br[C:10]1[CH:18]=[C:17]2C(C[C:15]3(CCC(=O)CC3)[C:16]2=[O:19])=C[CH:11]=1.CON(C)C(C1[N:32]=[N:33]C=CC=1)=O>C1COCC1>[N:32]1[CH:11]=[CH:10][CH:18]=[C:17]([CH:16]([OH:19])[CH3:15])[N:33]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cccnn1
Temperature: -60 °C
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a solution of LDA (23.4 mL, 42.1 mmol, 1.8 M in THF) in THF (150 mL) was added slowly a solution of compound 1 (3.6 g, 21.05 mmol) in THF (77 mL) at −60° C. under a N2 atmosphere. After being stirred at −60° C. for 1 h, a solution of compound 2 (7.05 g, 18.9 mmol)) in THF (23 mL) was added slowly to the above solution. The resulting mixture was stirred at −60° C. for 2 h. The reaction mixture was quenched with water (15 mL). The aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel (petroleum:ethyl acetate, 10:1) to give compound 3 (2.5 g, yield 26%) as a yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2scnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: BrCCCCOc1ccc2scnc2c1
Reaction time: 8 h
Yield: 27 %

Procedure:
A mixture of intermediate 25 (206 mg, 1.4 mmol), 1,4-dibromobutane (0.5 mL, 4.2 mmol) and anhydrous K2CO3 (193 mg, 1.4 mmol) in EtOH (20 mL) was heated to reflux and stirred overnight. The yellow solid was filtered and purified by column chromatography (elution with PE/EtOAc=4:1) to afford 5-(4-bromobutoxy)benzo[d]thiazole (intermediate 26) (108 mg, 39%) as a yellow oil. HPLC: 99%, RT 3.426 min. MS (ESI) m/z 288.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][S:5][CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl.CO>[NH2:1][CH2:2][C:3]1([N:8]([CH3:10])[CH3:9])[CH2:4][S:5](=[O:19])[CH2:6][CH2:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)C1(CN)CCSC1
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1(CN)CCS(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(aminomethyl)-N,N-dimethyltetrahydrothiophen-3-amine (160 mg, 0.998 mmol) in DCM: MeOH (4:1, 10 mL) was added MCPBA (246 mg, 1.098 mmol) at 0° C. The reaction was slowly warmed to room temperature and stirred overnight. The crude was purified by cation exchange resin to give the title compound without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.550 g of 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 3 ml of N,N-dimethylformamide; 0.058 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. Under ice cooling, 0.160 ml of ethyl bromoacetate was added, followed by stirring at room temperature for 2 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.332 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:11]=3[O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([S:20]([NH:23][C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:22])=[O:21])=[C:15]([F:29])[CH:14]=3)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.Cl[CH2:36]Cl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(C(C)=O)C(C)C.C(O)(=O)C.O.C(OCC)(=O)C>[Cl:34][C:32]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([S:20]([NH:23][C:24]3[S:28][N:27]=[CH:26][N:25]=3)(=[O:21])=[O:22])=[C:15]([F:29])[CH:14]=2)=[C:10]([C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH3:36])[CH2:4]3)[N:6]=[CH:7][CH:8]=2)[CH:33]=1
Reactant: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnn2C2CNC2)cc1F
Reactant: ClCCl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: CCOC(C)=O
Product: CN1CC(n2nccc2-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncns3)cc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Example 801, 54 mg, 0.1 mmol) was stirred with dichloromethane (2 mL) methanol (0.2 mL) and 37% w/v aqueous formaldehyde solution (0.025 mL, 0.34 mmol) at room temperature for 15 minutes. Sodium triacetoxyborohydride (68 mg, 0.32 mmol) was added at the reaction stirred at room temperature for 18 hours. 37% wt/vol aqueous formaldehyde solution (0.025 mL, 0.34 mmol) was added and the reaction stirred for 15 minutes then sodium triacetoxyborohydride (68 mg, 0.32 mmol) was added at the reaction stirred at room temperature for 3 hours. The mixture was evaporated and the residue dissolved in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate solution (2×10 ml) and saturated aqueous sodium chloride solution (2×10 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give a solid. The solid was suspended in methyl isobutyl ketone:acetic acid:water 2:1:1 and eluted through a silica column (5 g) with methyl isobutyl ketone:acetic acid:water 2:1:1. The appropriate fractions were combined and concentrated in vacuo to give a film. This was scratched with ethyl acetate then diethyl ether and dried in vacuo to give the title compound as a white solid. Yield 30 mg. 54%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH:33]=O)=[CH:23]2)=[CH:19][CH:18]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:24](/[CH:33]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:23]2)=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
Sodium hydride (60%, oily, 222 mg) was added to a mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenylpyrrole-3-carbaldehyde (2.37 g), ethyl diethylphosphonoacetate (1.1 ml) and tetrahydrofuran (30 ml) at 0° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propenoate (2.13 g, yield: 78%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 120–121° C.
Reaction SMILES: [CH3:1][C:2](=O)[CH3:3].C(=O)=O.BrCC=C.[Mg].[CH:13]1([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])[CH2:15][CH2:14]1.[Cl-].[NH4+]>O(CC)CC>[CH:13]1([C:16]([CH2:3][CH:2]=[CH2:1])([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[OH:17])[CH2:14][CH2:15]1
Reactant: O=C(c1ccc(F)cc1)C1CC1
Reactant: CC(C)=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCC(O)(c1ccc(F)cc1)C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a stirred and cooled (2-propanone/CO2 -bath)Grignard complex previously prepared starting from 254.1 parts of 3-bromo-1-propene, 54.7 parts of magnesium and 1540 parts of anhydrous 1,1'-oxybisethane was added dropwise, during a 1 hour-period, a solution of 330 parts of cyclopropyl (4-fluorophenyl)methanone in 280 parts of anhydrous 1,1'-oxybisethane at a temperature below -5° C. The reaction mixture was allowed to reach room temperature and stirring was continued overnight at room temperature. The mixture was cooled to 0° C. and decomposed with 350 parts of a saturated ammonium chloride solution. The 1,1'-oxybisethane was decanted and the residual salts were suspended twice in 140 parts of 1,1'-oxybisethane. The latter was decanted and the combined 1,1'-oxybisethane-phases were washed with 500 parts of water. The organic phase was dried, filtered and evaporated. From the residue, the forerun was distilled off by "Spinning Band". The distillation residue yielded 255.7 parts (62 %) of α-cyclopropyl-4-fluoro-α-(2-propenyl)benzenemethanol (intermediate 1).
Reaction SMILES: OCC1C2SC(S)=NC=2C=CC=1.[F:13][C:14]([S:17]([O-:20])(=[O:19])=[O:18])([F:16])[F:15].[C:21]([CH2:24][N+:25]12[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2)(=[O:23])N>>[F:13][C:14]([S:17]([O-:20])(=[O:19])=[O:18])([F:16])[F:15].[OH:23][CH2:21][CH2:24][N+:25]12[CH2:32][CH2:31][N:28]([CH2:27][CH2:26]1)[CH2:29][CH2:30]2
Reactant: NC(=O)C[N+]12CCN(CC1)CC2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: OCc1cccc2nc(S)sc12
Product: OCC[N+]12CCN(CC1)CC2

Procedure:
Starting with the product of Example 5, Step 2 (64 mg) and following the procedure of Example 4, Step 3, but substituting 1-carbamoylmethyl-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethylsulfonate, with 1-(2-hydroxyethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethylsulfonate one obtains the desired product (76.4 mg).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH:15]=O)[C:10]([O:12]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24](=[NH:26])[NH2:25])[CH:21]=[CH:20][N:19]=1>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([OH:12])=[N:25][C:24]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:17])[CH:23]=2)=[N:26][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C=O)OCc1ccccc1
Reactant: N=C(N)c1ccnc(Cl)c1
Solvent: CCO
Product: Oc1nc(-c2ccnc(Cl)c2)ncc1OCc1ccccc1
Yield: 66 %

Procedure:
A mixture of crude ethyl 2-(benzyloxy)-3-oxopropanoate (all from previous step), 2-chloropyridine-4-carboximidamide (9.57 g, 50 mmol) and 100 mL of anhydrous ethanol was refluxed for 4 h under nitrogen. The mixture was then cooled and the volatile solvents were removed by rotary-evaporator. The residue was re-dissolved in water and filtered. The filtrate was acidified by HCl (4N aq) in an ice bath and the white precipitate was filtered, washed with water, and dried to give 5-(benzyloxy)-2-(2-chloropyridin-4-yl)pyrimidin-4-ol (10.4 g, 66%). 1HNMR δ (400 MHz, d6-DMSO): 13.12 (s, 1H), 8.58 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.51-7.34 (m, 5H), 5.20 (s, 2H); MS (ESI) m/z (M+H)+ 314.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:29])[C@H:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16])[CH3:9].C(N(CC)CC)C.[C:37]([O:41][C:42]([NH:44][C@H:45]([C:48](O)=[O:49])[CH2:46][Cl:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH2:8]([O:10][C:11](=[O:29])[C@H:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:16][C:48](=[O:49])[C@H:45]([CH2:46][Cl:47])[NH:44][C:42]([O:41][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:43])[CH3:9]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of 0.42 g (1 mmol) of L-phenylalanyl-L-leucine ethyl ester trifluoroacetate, 0.14 mL (1 mmol) of triethylamine and 0.26 g (1 mmol) of N-(tert-butoxycarbonyl)-3-chloro-L-alanine in 8 mL of chloroform, 0.21 g (1 mmol) of dicyclohexylcarbodiimide was added at 0° C. The resultant reaction mixture was stirred overnight at room temperature. The precipitate which formed was removed by filtration and the filtrate was washed successively with 0.5 N hydrochloric acid, water, 3% aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate. Removal of the solvent afforded a white solid, which was mixed with 4 mL of a 1:1 mixture of ethyl acetate and n-hexane. Insoluble materials were removed by filtration and the filtrate was evaporated. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 0.367 g (66.5%) of the desired product. The product, which has the structural formula ##STR75## melted at about 110° C. Its identity was further confirmed by IR and NMR analyses and by thin layer chromatography (Rf =0.34 in 5:1 chloroform/ethyl acetate).