Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>C1COCC1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:9][CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH3:8])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(O)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC(C)c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 1-(pyridine-4-yl)ethanol (400 mg, 3.25 mmol) in THF (10 mL) was added sodium hydride (301 mg, 12.54 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. 4-methylbenzene-1-sulfonyl chloride (744 mg, 3.90 mmol) was added and the mixture was stirred at room temperature for 4 hr. Water (10 mL) was added and THF was removed under reduced pressure. The residue was extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=2/1) to give 1-(pyridine-4-yl)ethyl 4-methylbenzenesulfonate (0.56 g, 62.2%). LCMS 278 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][C@@H:26]1[C@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28](=[O:37])[NH:27]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][N:27]2[C@H:26]([CH3:25])[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(2-bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [C:1]([CH:3]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][N:12]=1)C(OC(C)(C)C)=O)#[N:2].Cl.CC(=O)OCC>CO>[N+:21]([C:14]1[CH:15]=[C:16]([C:17]([F:20])([F:18])[F:19])[C:11]([CH2:3][C:1]#[N:2])=[N:12][CH:13]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)C(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (7 g, 21.13 mmol) in MeOH (100 mL) was added aqueous HCl (40 mL, 1316 mmol). The resulting mixture was stirred at 100° C. overnight. After TLC analysis (PE/EA=10/1) showed the starting material was consumed, the solvent was removed in vacuo. The residue was dissolved in H2O (50 mL) and extracted by EA (100 mL). The organic layer was washed with aqueous NaHCO3 and brine and then dried over Na2SO4. After filtration, the filtrate was concentrated to give the crude product, which was purified by column chromatography (PE/EA=10/1) to yield a brown solid of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (4.3 g, 17.77 mmol, 84% yield): 1H NMR (400 MHz, CD3OD) δ 9.59 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 4.86 (s, 2H); ES-LCMS m/z: 232.1 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([N+:22]([O-])=O)[CH:7]=1.[H][H]>[Pt].CO>[NH2:22][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Temperature: 25 °C
Yield: 92.3 %

Procedure:
In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 2,328 g (6.78 moles) of the ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate prepared in the Synthesis Example 2, 2 wt. % platinum per 118 g of carbon (50 wt. % product, N.E. Chemcat Corporation, 6.0 mmoles in terms of platinum metallic atom) and 9,440 mL of methanol were placed. The mixture was allowed to react at 50 to 60° C. for 6 hours in an atmosphere of hydrogen while stirring. After the reaction was complete, the reaction solution was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to obtain 1,960 g of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as an orange liquid (isolation yield: 92%).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19]OS(C)(=O)=O)[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:26])([CH3:25])[N:4]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[C-:34]#[N:35].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:34]([CH2:19][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C@H:7]3[O:6][C:5]([CH3:26])([CH3:25])[N:4]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:3]3[CH2:2][F:1])=[CH:13][CH:12]=2)[O:18][N:17]=1)#[N:35]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CC#N)no3)cc2)OC1(C)C
Yield: 55.8 %

Procedure:
The product of step 1 of Example 10 (200 mg, 0.41 mmol), potassium cyanide (111 mg, 1.65 mmol), and 18-crown-6 (23 mg, 0.08 mmol) in acetonitrile (8 mL) are stirred at room temperature for 16 hours then the mixture is concentrated and purified by column chromatography on silica gel eluting with a gradient of ethyl acetate/heptane to afford the title compound (95 mg). m/z (Cl) 416 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[N:16][C:17]([O:20]CC4C=CC=CC=4)=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][N:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N2CCN(c3ccc(OCc4ccccc4)nn3)CC2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc(N2CCN(c3ccc(=O)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of 6 parts of 3-[4-(3-methylphenyl)-1-piperazinyl)-6-(phenylmethoxy)pyridazine and 60 parts of concentrate hydrochloric acid was stirred and refluxed for 3 hours. The whole was allowed to stand overnight and treated With concentrate ammonium hydroxide. The product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2.2'-oxybispropane. The product was filtered off and dried, yielding 4.5 parts (98%) of 6-[4-(3-methylphenyl)-1-piperazinyl]-3(2H)-pyridazinone; mp. 209.8° C. (compound 271).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+].ClCCl>O>[C:16]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CNc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CNc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 2.7 parts of ethyl 2-[(4-aminophenyl)amino]acetate hydrochloride, 1.1 parts of acetic acid anhydride, 0.98 parts of sodium hydrogen carbonate, 65 parts of dichloromethane and 50 parts of water was stirred for 30 minutes at room temperature. The organic phase was separated, washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 1.9 parts (68%) of ethyl 2-[[4-(acetylamino)phenyl]amino]acetate; mp. 119.5° C. (12).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:39])[CH2:15][C@@H:16]([C:22]1[CH:38]=[CH:37][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>O.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]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:39])[CH2:15][C@@H:16]([C:22]1[CH:38]=[CH:37][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([C:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=3)[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=C(C[C@@H](c1ccc(OCc2cccc(B(O)O)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)c2)CC1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 7.8 %

Procedure:
To a sealed tube flushed with nitrogen and including DMF (0.5 mL), were added boronic acid 34.1 (90.0 mg, 0.171 mmol), triflate 34.3 (56.6 mg, 0.171 mmol), a 1 M sodium carbonate solution (0.48 mL, 0.480 mmol), lithium chloride (21.7 mg, 0.513 mmol), and Pd(dppf)Cl2 (13.9 mg, 0.0170 mmol). The reaction was heated and stirred at 85° C. for 1.5 hours. The reaction was then cooled and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The organic layers were combined and washed with 1M lithium chloride (1×30 mL) and brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 0 to 40% EtOAc:hexanes) to give 34.4 (8.90 mg). MS ESI (pos.) m/e: 664.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (1H, d, J=1.6 Hz), 7.35 (1H, s), 7.09-7.30 (10H, m), 6.86 (2H, d, J=8.6 Hz), 6.06 (1H, d, J=1.6 Hz), 5.98 (1H, s), 4.95 (2H, s), 4.64-4.73 (1H, m), 4.49-4.60 (1H, m), 4.07 (2H, d, J=5.1 Hz), 3.99-4.03 (2H, m, J=2.7 Hz), 3.95 (1H, dd, J=17.6, 8.6 Hz), 3.56 (2H, t, J=5.7 Hz), 3.45 (1H, dd, J=17.4, 6.5 Hz), 3.13 (1H, dd, J=13.3, 3.1 Hz), 2.69 (1H, dd, J=13.5, 9.6 Hz), 2.42-2.50 (2H, m), 1.42 (9H, s).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(N2C(=O)C(=O)c3ccccc32)c1
Reaction time: 24 h
Yield: 80.7 %

Procedure:
Using a method similar to Preparation 38, with isatin (2.94 g, 20 mmol), 3-methoxyphenylboronic acid (6.08 g, 40 mmol), copper (II) acetate (3.63 g, 20 mmol), pyridine (3.2 ml, 40 mmol) and powdered 4A sieves (15-25 g) in dichloromethane (60 mL). Follow reaction by TLC (50% ethyl acetate/hexane). Stir mechanically for 1 day and add more powdered 4A sieves (10-15 g). Stir for 3 days and add 3-methoxyphenylboronic acid (1.52 g, 10 mmol), copper (II) acetate (1.82 g, 10 mmol), pyridine (1.6 ml, 20 mmol) and powdered 4A sieves (10-15 g). Workup and purify by flash chromotagraphy (dichloromethane) to provide 4.09 g (81%) of an orange solid. MS (ES): m/z=254 (M+1); 1H NMR (DMSO-d6): δ7.66-7.58 (m, 2H), 7.51 (t, 1H), 7.19 (t, 1H), 7.09-7.04 (m, 3H) 6.85 (d, 1H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.[F-].[Cs+].C(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3[C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)cc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.112 g, 0.209 mmol), pyridine-3-boronic acid (0.077 g, 0.626 mmol), and cesium fluoride (0.111 g, 0.731 mmol) in dry ACN (7 mL) is purged with N2 and then treated with 1,1′-bis(diphenylphophino)-ferrocene palladium (II) chloride complex with DCM (0.031 g, 0.042 mmol). The mixture is heated to 100° C. and stirred for 5 hours under N2. The reaction is cooled, and the crude mixture is absorbed on silica gel and purified by flash chromatography using 2/1 hexanes/ethyl acetate to afford 0.089 g (79%) of the title compound. Rf=0.33 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C31H28O4NF3 535, found 536 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[H-].[Na+].CN(C)C=O.Br[CH2:35][C:36]1[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=1[C:38]([O:40][CH3:41])=[O:39]>C(OCC)(=O)C>[C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:5]2[C:4](=[O:26])[N:3]([CH2:35][C:36]3[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=3[C:38]([O:40][CH3:41])=[O:39])[C:2]([CH3:1])=[N:7][C:6]=2[CH2:8][CH2:9][CH3:10])=[CH:13][CH:14]=1)#[N:25]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(Cc2ccccc2C(=O)OC)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2 g), sodium hydride (0.28 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 10 min, methyl 2-(bromomethyl)benzoate (1.6 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.15 g, 40%).
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.[CH:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(C(CCCC)CO)C>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:32]([CH:48]([CH2:47][CH2:46][CH2:45][CH3:44])[CH2:43][O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:33]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: CCCCC(CC)CO
Product: CCCCC(CC)COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of 2-ethylhexanol was heated for 30 minutes at 100°C. To the thus otained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 10 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine 2-ethylhexyl ester di(p-toluenesulfonate) in 91% yield; mp. 170°-174°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:16][C@@H:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:18]1[NH:26][C:27](=[O:29])[CH3:28]>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C@@H:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:18]2[NH:26][C:27](=[O:29])[CH3:28])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1c2ccccc2C[C@H]1Nc1nc(Cl)ncc1Cl
Temperature: 55 °C
Reaction time: 3 h

Procedure:
2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) is suspended in 35 mL iso-PrOH and combined with K2CO3 (5.28 g, 38.16 mmol). Then N-((1R,2R)-2-amino-indan-1-yl)-acetamide B-4-b (570 mg, 2.99 mmol) is added and the reaction mixture is stirred for 3 h at 55° C. The reaction mixture is evaporated down, mixed with water and extracted with EtOAc. The organic phase is dried on magnesium sulphate and evaporated down in vacuo. The crude product of A-2b (HPLC-MS: tRet.=1.24 min; MS (M+H)+=337/339) is used in the subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1([C:15]2[CH:16]=[C:17]([S:21]([C:24]3[CH:25]=[C:26]([C:31]([NH2:33])=[NH:32])[S:27][C:28]=3[S:29][CH3:30])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[H-].[Na+].IC>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:2][O:8][C:9]1([C:15]2[CH:16]=[C:17]([S:21]([C:24]3[CH:25]=[C:26]([C:31]([NH2:33])=[NH:32])[S:27][C:28]=3[S:29][CH3:30])(=[O:22])=[O:23])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(C2(O)CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Product: COC1(c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)CCOCC1
Reaction time: 0.33 h

Procedure:
To a solution of the BOC-protected amidine (46 mg, 0.09 mmol) (prepared in example 149) in 0.2 mL of DMF at 25° C. was added NaH (60% oil dispersion, 5.7 mg, 0.14 mmol). The reaction was allowed to stir for 20 mins then iodomethane (6 uL, 0.09 mmol) was added and the reaction stirred for additional 12 hrs. The solvent was evaporated and the crude material purified by flash chromatography to give the title compound as a BOC protected amidine, which was deprotected in 2 mL of 50% TFA/DCM (25° C., 1 hr) to give the title compound (11.5 mg, 20%) as a yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.14 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H), 7.66 (m, 1H), 3.89 (m, 4H), 3.00 (s, 3H), 2.74 (s, 3H), 2.02 (m, 4H). Mass spectrum (ESI, m/z) calcd. for C18H22N2O4S3 426.1, found 427.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[C:41]=5[Cl:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(Cl)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-dichlorophenylboronic acid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)[CH3:15].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=2)=[CH:36][CH2:37]O)=[CH:31][CH:30]=1>C1COCC1>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:37][CH:36]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][CH:33]=2)[C:39]2[CH:40]=[CH:41][C:42]([Br:45])=[CH:43][CH:44]=2)=[C:21]([Cl:26])[CH:20]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(O)c(Cl)c1
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c(Cl)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A solution of tributylphosphine (955 μl, 3.0 mmol), 3-chloro-4-hydroxyphenylacetic acid ethyl ester (472 mg, 2.2 mmol) and 3,3-bis-(4-bromophenyl)prop-2-en-1-ol (736 mg, 2.0 mmol) in dry THF (15 ml) was stirred at 0-5° C. for 30 min, under a atmosphere of nitrogen. Azodicarboxylic dipiperidide (756 mg, 3.0 mmol) was added the mixture stirred at 0-5° C. for 2 h, and at room temperature over night. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product was then purified by column chromatography on silica (eluent graduated from heptane to toluene) to give 1.0 g (89%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](Br)[CH:12]=[CH2:13].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[CH2:13]([C:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:12]=[CH2:11]
Reactant: COC(=O)C1CCCCC1
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC1(C(=O)OC)CCCCC1
Temperature: 50 °C
Reaction time: 64 h
Yield: 18.7 %

Procedure:
To a solution of methyl cyclohexylcarboxylate (1.42 g) and allyl bromide (3.02 g) in N,N-dimethylformamide (20 mL) was added potassium tert-butoxide (1.68 g, 15.0 mmol) under ice cooling. The solution was stirred at room temperature for 16 hours, at 50° C. for 8 hours and further at room temperature for 64 hours. Water and 3N hydrochloric acid were then added to the solution, and it was extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=97:3) to give the title compound (340 mg).