Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C@@H:4]([C:10]([CH3:12])=[CH2:11])[C@@H:3]1[C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:19][O:1][C@H:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C@@H:4]([C:10]([CH3:12])=[CH2:11])[C@@H:3]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CI
Reactant: C=C(C)[C@@H]1CCC(C)(C)[C@H](O)[C@H]1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of the above alcohol (1.15 g) and sodium hydride (230 mg, 60% dispersion in oil) and methyl iodide (0.6 ml) in dry N,N-dimethylformamide was stirred for 3 hrs at room temperature. The mixture was cooled to 0° C., and reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give methyl (1S,2R,6R)-2-methoxy-3,3-dimethyl-6-(1-methylvinyl)-cyclohexane-1-carboxylate (1.12 g, 92% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:51])[C@@H:30]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:42][CH:41]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>ClCCl.CCN(C(C)C)C(C)C>[CH2:31]([C@H:30]([N:38]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:44][CH:45]=1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[C:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:28][CH2:27]1)=[O:51])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
In an inert atmosphere, trans-4-trifluoromethyl-cinnamic acid (21.4 mg, 0.099 mmol) was dissolved in 2 mL dichloromethane followed by the addition of 1-chloro-N,N-2-trimethylpropenyl amine (16.4 μl, 0.122 mmol). Stirring was continued at rt for 1 h. This solution was then added to a solution of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) in dichloromethane (1 mL) and Hünig's base (39 μl). The resulting mixture was stirred for 1 h at rt, followed by the addition of water (3 mL). The layers were separated. The aq. layer was extracted with dichloromethane (2×2 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by prep. TLC (silicagel, heptane/EtOAc=1/1) to give 36.1 mg (58%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=682.48.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][C:23](=[O:25])[CH2:22][O:21][C:18]1[CH:19]=[N:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Nc1ccccc1F
Reactant: O=C(O)COc1ccc(-c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccc(F)cc2)nc1)Nc1ccccc1F

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 43.8 mg (0.39 mmol) of 2-fluoroaniline. Yield: 9 mg.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][CH3:10].[CH2:11]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14]CC.O.CCCCCCC>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]#[C:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:18][CH:19]=2)=[C:3]([CH2:9][CH3:10])[CH:4]=1
Reactant: CCc1cc(Br)ccc1I
Reactant: C#Cc1ccc(CCCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C#Cc2ccc(Br)cc2CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 g (64.3 mmol) of 1-iodo-2-ethyl-4-bromobenzene and 12 g (64.3 mmol) of 4-n-hexylphenylacetylene are initially introduced in 300 ml of triethylamine, 250 mg (1.3 mmol) of copper(I) iodide and 900 mg (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and the mixture is stirred at RT for 3 h and subsequently refluxed for 1 h. The batch is cooled, water and heptane are added, and the phases are separated. The organic phase is washed with saturated sodium chloride soln., dried over sodium sulfate, filtered and evaporated in a rotary evaporator. The residue is purified by column chromatography (SiO2, heptane); the product is obtained as a colourless oil.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([C:15]#N)=[CH:11][CH:10]=1.Cl.C(OCC)(=[O:21])C>C1COCC1>[CH3:17][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: CCOC(=O)C[Zn]Br
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Yield: 91 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivlanet) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.17 g (10 mmol) of p-tolunitrile in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred 20˜25° C. for 46 hours. 15 mL of 10% hydrochloric acid was added dropwise at 20° C. or lower, and the mixture was stirred at 20˜25° C. for 1 hour, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 15 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.88 g of the desired product (yield 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[N:7]=[C:6]([NH2:13])[N:5]=1)C.Br[CH2:15][C:16](=O)[C:17]([O-:19])=[O:18].[CH2:21]1COC[CH2:22]1>>[CH2:21]([O:19][C:17]([C:16]1[N:13]=[C:6]2[N:7]([C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[C:4]([O:3][CH3:1])=[N:5]2)[CH:15]=1)=[O:18])[CH3:22]
Reactant: O=C([O-])C(=O)CBr
Reactant: CCOc1nc(N)nc2c1CCC2
Reactant: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(OC)nc2n1)CCC3
Temperature: 23 °C
Reaction time: 1 h

Procedure:
4.8 gram (29 mmol) 4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 100 ml dry THF. Bromopyruvate (5.4 ml,) was then added dropwise with in five minutes. The mixture was stirred at 23° C. for one hour. It was then filtered and washed with ether to give 8.7 gram of solid. This solid was then dissolved in 50 ml ethanol and refluxed for two hours. The reaction mixture was cooled to room temperature and partitioned between 350 ml chloroform and 200 ml saturated sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate. Filter off the drying agent and concentrate to give 5.3 gram of product (70% Yield). MP: 105–106° C. (M+H) 262.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[NH4+]>C(#N)C.C(OCC)C>[C:15]1([NH:14][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccccc1)c1cccc2ccccc12
Temperature: 82 °C
Yield: 82 %

Procedure:
4.77 g of 1-naphthoyl chloride (TCI America) was dissolved in 100 ml of anhydrous acetonitrile. To the solution so formed, 2.28 ml of aniline (Sigma-Aldrich) was added in a dropwise fashion over a period of c.a. 20 min. The reaction was then refluxed for 2 h at 82° C. 100 ml of distilled water and 5 ml of concentrated ammonium hydroxide were added along with 100 ml of diethyl ether in a separatory funnel. The phases were separated and the aqueous phase was washed with 100 ml of dichloromethane. The organic fractions were collected and dried with magnesium sulfate, filtered and the solvent was then removed under reduced pressure to yield a white solid 5.07 g (82%; 20.5 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:12]3[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[C:4]=2[O:3]1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=O.CC(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:31][C:2]1([CH3:1])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([N:25]3[CH2:26][CH2:27][N:28]([CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)[CH2:29][CH2:30]3)[C:12]3[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[C:4]=2[O:3]1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3c2OC(C)(C)C3)N2CCNCC2)cc1
Reactant: O=Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3c2OC(C)(C)C3)N2CCN(Cc3ccccn3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 1883 %

Procedure:
The title compound 9 was prepared by dissolving compound 5 (0.45 g, 0.98 mmol) in MeOH (10 mL) with 2-pyridine carboxaldehyde (110 μL, 1.18 mmol) and HOAc (3 μL, 50 μmol). Sodium cyanoborohydride (70 mg, 1.18 mmol) was added at 0° C. and reaction stirred 48 h at 25° C. Reaction was worked up by concentration in vacuo, extraction (CH2Cl2/K2CO3(aq)) and chromatography by reverse phase HPLC to give the title compound 9,461 mg(63%).
Reaction SMILES: C(N(C(C)C)C(C)C)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][C@H:26]4[C:25]=23)[N:17]=1>CN(C)C=O>[CH2:11]([NH: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][C@H:26]4[C:25]=23)[N:17]=1)[CH2:12][CH3:13]
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Reactant: CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Reaction time: 12 h
Yield: 57.5 %

Procedure:
0.87 ml of N-ethyldiisopropylamine and 0.28 ml (3 mmol) of 1-bromopropane were added to a solution of 0.500 g (1.52 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 15 ml of dimethylformamide, whereupon the mixture was stirred at 70° for 12 hours. The dimethylformamide was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was extracted twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 20:1) yielded 0.324 g (57%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.24 (silica gel, ethyl acetate/methanol 20:1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.C(Cl)(Cl)Cl.N>O1CCCC1>[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][C:13]([Br:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2nc(-c3cccnc3N)oc12
Agent: N
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3cc(Br)cnc3N)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
1-bromopyrrolidine-2,5-dione (233 mg) was added to a stirred solution of methyl 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carboxylate (335 mg) dissolved in tetrahydrofuran (10 ml) over a period of 5 minutes. The resulting solution was stirred at 25° C. for 2 hours. The solvent was evaporated and the mixture was washed with water and dried over phosphorus pentoxide under reduce pressure to afford a brown solid. The mixture was adsorbed on silica gel with chloroform and methanolic ammonia (7N). The crude product was purified by flash chromatography on silica gel eluting with 0 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazole-7-carboxylate (405 mg) as a pale brown solid. NMR Spectrum: (DMSOd6) 3.99 (s, 3H), 7.56 (dd, 1H), 7.85 (bs, 2H), 7.97 (d, 1H), 8.12 (d, 1H), 8.29 (s, 1H), 8.35 (s, 1H); Mass spectrum: M+H+ 348-350.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[NH:18][C:19]([CH3:38])([CH2:21][CH2:22][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:20].[C:39]([O:43][CH2:44]C)(=[O:42])[CH:40]=O.C1(C)C=CC=CC=1>CO>[CH3:44][O:43][C:39]([C:40]1[N:18]([C:19]([CH3:38])([CH2:21][CH2:22][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH3:20])[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])[CH:16]=[CH:17][C:2]=2[N:1]=1)=[O:42]
Reactant: CCOC(=O)C=O
Reactant: CC(C)(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Nc1cc(C(=O)OCc2ccccc2)ccc1N
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1nc2ccc(C(=O)OCc3ccccc3)cc2n1C(C)(C)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a stirred solution of crude benzyl 4-amino-3-({4-[bis(tert-butoxycarbonyl)amino]-2-methylbutan-2-yl}amino)benzoate (250 mg, 0.47 mmol) in methanol (10 mL) is added a 50% solution of ethyl glyoxalate in toluene (0.38 mL, 1.90 mmol). After 16 h, the solvent is evaporated to afford the title compound (295 mg, >99%), which is used in the next step without purification.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[C:40]([CH2:41][CH2:42]O)=[C:39]([F:44])[C:38]([F:45])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([F:45])=[C:39]([F:44])[C:40]=1[CH2:41][CH2:42][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCc1c(OCc2ccccc2)ccc(F)c1F
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(OCc2ccccc2)c(CCI)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A solution of Ph3P (697 mg, 2.66 mmol) and imidazole (181 mg, 2.66 mmol) in DCM (15 mL) was cooled to 0° C. Added to this was iodine (674 mg, 2.66 mmol) and the resulting mixture was stirred at 0° C. for 30 min. 2-(6-(benzyloxy)-2,3-difluorophenyl)ethanol (585 mg, 2.214 mmol) was added portionwise over several minutes and the resulting mixture was stirred at room temp. After 5 h, the mixture was filtered washing the solids with DCM. The filtrate was washed with aq Na2S2O3 and the organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane) to give 1-(benzyloxy)-3,4-difluoro-2-(2-iodoethyl)benzene (720 mg, 1.924 mmol, 87% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.52-7.35 (m, 5H), 7.03 (q, J=9.3 Hz, 1H), 6.69-6.52 (m, 1H), 5.10 (s, 2H), 3.37-3.29 (m, 4H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:10]([CH:12]1O[CH2:13]1)Cl.O>C(O)C.CO>[O:7]([CH2:10][CH2:12][CH3:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.840 g (0.008 mole) of 4- (2-nitroxy)ethoxymethyl!phenol, dissolved in a mixture of 10.6 ml of ethanol and 10 ml (0.010 mole) of 1N NaOH, were added slowly to a solution of 15.970 g (13.5 ml, 0.172 mole) of epichlorohydrin in 7 ml of methanol. The mixture was stirred for 16 hours at room temperature. 50 ml of water were added and the mixture was concentrated at reduced pressure at 40° C. The residue was extracted with a mixture of 100 ml of ethyl acetate and 100 ml of water. It was decanted and the aqueous phase was extracted a further two times with 25 ml of ethyl acetate. The organic extracts were pooled and washed with 75 ml of 1N HCl and 75 ml of water. It was dried over anhydrous sodium sulphate, was filtered and was concentrated at reduced pressure. 2.030 g (0.007 mole) of 2,3-epoxy-1- 4-(2-nitroxy)ethoxymethyl!phenoxy propane were obtained in the form of a yellowish oil which was mixed with 4.476 g (6.45 ml, 0.075 mole) of isopropylamine in 25 ml of anhydrous methanol and was heated under reflux for two hours. It was concentrated at reduced pressure at 40° C. 100 ml of water were added and it was extracted three times with 50 ml of ethyl acetate. The organic extracts were pooled and extracted three times with 100 ml of 1N HCl. The acid extracts were pooled and were alkalized to pH=12 by addition of 1N NaOH. It was extracted four times with 50 ml of ethyl acetate. The extracts were pooled and washed with 60 ml of water. It was dried over anhydrous sodium sulphate, was filtered and the solvent was removed at reduced pressure until a constant weight was obtained. 1.714 g (61%) of the product were obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].[CH2:14]([N:16](CC)[CH2:17]C)C.CNC.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:16]([CH3:17])[CH3:14])=[O:6]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Agent: CNC
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
Into a solution of 3 (1.50 g, 7.36 mmol) in CH2Cl2 (30 mL) at 0° C. was added triethylamine (1.5 mL, 10.9 mmol) and dimethylamine 40% in water (0.83 mL, 7.36 mmol) dropwise. The solution was stirred and allowed to warm to RT overnight before concentrating under reduced pressure and adding EtOAc. The solution was washed sequentially with saturated NaHCO3, water, and brine, before drying over MgSO4 and concentrating under reduced pressure to give impure 4 (0.78 g, 50%). MS: APCI (AP+): 213.1 (M)+, (AP−): 212.1 (M)−.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:10]1([C:23]([O:25][CH3:26])=[O:24])[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].ClC1[N:39]=[CH:38][C:37]([B:40]([OH:42])[OH:41])=[CH:36][N:35]=1>O1CCOCC1.C(O)C>[CH2:8]([C:10]1([C:23]([O:25][CH3:26])=[O:24])[CH2:11][CH2:12][N:13]([C:16]2[N:39]=[CH:38][C:37]([B:40]([OH:42])[OH:41])=[CH:36][N:35]=2)[CH2:14][CH2:15]1)[CH3:9]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCO
Product: CCC1(C(=O)OC)CCN(c2ncc(B(O)O)cn2)CC1
Reaction time: 2 h
Yield: 60.6 %

Procedure:
TFA (8 mL) was added to a stirred solution of 1-tert-butyl 4-methyl 4-ethylpiperidine-1,4-dicarboxylate (0.61 g, 2.25 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred for 2 h, then the volatiles were removed by rotary evaporation and the residue was left on a high vacuum line for 1 h. The syrupy material thus obtained was dissolved in ethanol (8 mL), anhydrous sodium carbonate (0.72 g, 6.79 mmol) was added and the mixture was stirred for 10 minutes. (2-Chloropyrimidin-5-yl)boronic acid (0.37 g, 2.3 mmol) was added and the mixture was stirred at 80° C. for 7 h. The reaction mixture was filtered through celite, then the solvent was removed under vacuum, and water was added. The mixture was decanted and washed again with water, then the residual gum was freeze-dried, to give the title compound (0.4 g, 60%) as a pale yellow lyophilised solid, which was used without further purification. LCMS (pH 10) MH+ 294, RT 1.15 minutes.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)c1ccccc1
Yield: 25 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and cyclohexyl chloroformate. Yield: 25% of theory, C34H38N6O5 (610.7) Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1) ##EQU64##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[O-:19][CH2:20][CH3:21].[Na+]>C(O)C>[CH2:20]([O:19][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1)[CH3:21]
Reactant: CC[O-]
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(OCC)cc(=O)[nH]1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.5 g) and sodium ethoxide (from 0.18 g sodium) in ethanol (25 ml) was heated in a pressure vessel at 125° C. for 24 hours. The residue left after evaporation was dissolved in water (20 ml), acetic acid was added to precipitate a gum, and the mixture was extracted with chloroform. Evaporation of the extract gave a solid which was recrystallized from ether to yield the title compound, 0.07 g, m.p. 95.5°-97° C.