Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([O:21]CC)=[O:20])(=[O:3])[CH3:2].[OH-].[K+].CO.Cl>C(=O)(O)[O-].[Na+]>[C:1]([NH:4][C:5]1[C:10]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([OH:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1NC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1c(CC(=O)O)cccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-(2-acetamido-3-phenoxyphenyl)acetate (3.65 g.), potassium hydroxide (1.3 g.) and methanol (50 ml.) was stirred for 4 hours at ambient temperature and then for an hour at 40° C. Methanol was distilled off from the reaction mixture under reduced pressure and the residue was dissolved in water. The solution was washed with diethyl ether, adjusted to pH 1.0 with 5% sulfuric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated. The residue was recrystallized from a mixture of ethanol and n-hexane to give white needles of the captioned compound (3.1 g.). mp 155° to 156° C. Thus obtained product was dissolved in an aqueous solution of sodium bicarbonate and the solution was adjusted to pH 1.0 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give the pure compound (2.5 g.), mp 155° to 156° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([NH2:18])[CH3:17])=[O:5])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C@H:25]1[O:27][CH2:26]1>C(#N)C>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([NH:18][CH2:26][C@@H:25]([C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=1)[OH:27])[CH3:17])=[O:5])[CH3:20]
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N)c[nH]c12
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CC#N
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Yield: 38.8 %

Procedure:
A mixture of (R)-3-(2-aminopropyl)-1H-indole-7-carboxylic acid diethylamide (1.30 g, 4.76 mmol) and (R)-(+)-3-chlorostyrene oxide (1.21 mL, 9.52 mmol) in acetonitrile (15 mL) is refluxed for 10 hours. After cooling, the mixture is concentrated and the residue is purified by silica gel column chromatography (a saturated ammonia solution in chloroform) to give the desired 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-7-carboxylic acid diethylamide (0.79 g, yield: 39%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[O:12][CH3:13].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=2[O:12][CH3:13])[CH2:25][CH2:26]1)([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1c(F)cc([N+](=O)[O-])cc1Br
Product: COc1c(F)cc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The compound was prepared by analogy to Example 7, starting from commercially available 1-bromo-3-fluoro-2-methoxy-5-nitrobenzene, which was reacted with tert.butyloxycarbonyl-piperazine by analogy to preparation example 3.1 top yield 1-(N-boc-piperazin-4-yl)-3-fluoro-2-methoxy-5-nitrobenzene. Reduction of the nitro group to the corresponding aniline by analogy to preparation example 3.2, subsequent coupling with commercially available 3-difluoromethoxybenzenesulfonylchloride by analogy to preparation example 1.4, and final deprotection of the tert.-butoxycarbonyl group under acidic conditions by analogy to example 1 yielded the title compound.
Reaction SMILES: [F:1][C:2]1([F:23])[C:11]2[CH:10]=[N:9][C:8](S(C)(=O)=O)=[N:7][C:6]=2[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.CCN(C(C)C)C(C)C.[O:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>CC(O)C.CCOC(C)=O>[F:1][C:2]1([F:23])[C:11]2[CH:10]=[N:9][C:8]([NH:39][CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[N:7][C:6]=2[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(S(C)(=O)=O)ncc2C(F)(F)C1
Reactant: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1Cc2nc(NC3CCOCC3)ncc2C(F)(F)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirred suspension of 204 (349 mg, 1 mmol) in IPA (3 mL) at RT under nitrogen was added sequentially via syringe neat DIPEA (174 μL, 1 mmol) and neat tetrahydro-2H-pyran-4-amine (101 mg, 1 mmol). The mixture was heated to 90° C. and became homogeneous. Heating was continued for 60 min them cooled to RT, diluted to 30 mL with EtOAc and was washed sequentially with 10% citric acid solution (2×30 mL) and satd. aq. NaHCO3 (2×30 mL). The organic phase was isolated, dried (MgSO4), filtered and concentrated to a clear oil. The oil was triturated with hexane/EtOAc (4/1) with sonication to produce a precipitate that was filtered and rinsed with hexane/EtOAc (4/1). The mother liquor was recovered and re-precipitated. Both precipitated batches were combined to afford 215 mg (58%) of tert-butyl 5,5-difluoro-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (206) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[CH:37]/[CH2:38][CH3:39])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25]CC4C=CC(OC)=CC=4)=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].C1(OC)C=CC=CC=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+:65].[Na+].[Na+]>ClCCl.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[CH:37]/[CH2:38][CH3:39])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:65]
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
4-Methoxybenzyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-(Z)-pent-2-enamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (80 mg) in dichloromethane (2 ml) was added dropwise to a mixture of aluminium chloride (47 mg) and anisole (1.03 ml) in dichloromethane (2 ml) at -50° C. under argon. The mixture was stirred for 15 minutes at -40° C. and 0.5M trisodium citrate (3.42 ml) added, stirred at room temperature for 15 minutes then diluted with dichloromethane (10 ml) and water (10 ml). The aqueous layer was collected, washed with dichloromethane and chromatographed on HP20SS eluting with 0, 1, 2, 5 and 10% acetone in water. Fractions containing the product, h.p.l.c analysis, were combined, concentrated and freeze-dried to give the title compound (22 mg); νmax (KBr) 3407, 1757, 1609, 1527, 1375, 1338 and 1041 cm-1 ; δHD2O, 250 MHz) 1.03 (3H,t,J 7.5 Hz), 1.65-2.30 (6H,m), 3.32 and 3.51 (2H, ABq, J 7.7 Hz), 3.70-3.95 (2H,m), 4.65-4.80 (1H,m), 5.20 (1H,d,J 4.7 Hz), 5.74 (1H,d,J 4.7 Hz), 6.33 (1H,t,J 8 Hz) and 6.47 (1H,s). [Mass spectrum +ve ion (thioglycerol) MH+ (473)].
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>>[CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:19]([CH:16]1[CH2:18][CH2:17]1)=[O:20])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C1CC1
Reactant: C(=C/c1ccccc1)\CC1CCCCN1
Product: O=C(C1CC1)N1CCCCC1C/C=C/c1ccccc1

Procedure:
Stage a) The method is the same as that of Example 1.1, Stage a), the initial reactants being (E)-2-(cinnamyl)piperidine (Preparation 2A, Stage b) and cyclopropanecarboxylic acid chloride, yielding (E)-2-cinnamyl-1-cyclopropanecarbonylpiperidine (formula II; Ar=C6H5, m=1, n=2, R=cyclopropyl). Yield: 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([OH:22])=O)=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]=[CH:32][C:25]=12.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[N:30]([C:33]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[N:31]=[CH:32][C:25]=34)=[O:22])=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Nc1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(cc1C(=O)O)SCC[C@@H]2NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1cc2c(cc1C(=O)Nc1ccnc3c1cnn3C(c1ccccc1)(c1ccccc1)c1ccccc1)SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 72.8 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid (500 mg), 4-amino-1-triphenylmethylpyrazolo[3,4-b]pyridine (641 mg) and 2-chloro-1-methylpyridinium iodide (474 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-methyl-N-(1-triphenylmethylpyrazolo[3,4-b]pyridin-4-yl)thiochromane-7-carboxamide (767 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:3]1>C1COCC1.[Ni]>[CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH2:3]1
Reactant: CC1CN(c2ccc([N+](=O)[O-])nc2)CC(C)O1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1CN(c2ccc(N)nc2)CC(C)O1
Reaction time: 4 h
Yield: 87.3 %

Procedure:
2,6-Dimethyl-4-(6-nitro-pyridin-3-yl)-morpholine (4.00 g, 16.86 mmol) was dissolved in THF (100 mL) to which Raney Nickel (3.10 g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50 psi) for 4 hours. The catalyst was filtered and the solvent evaporated to give 5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamine as a purple solid (3.05 g, 87.4%). 1H NMR δ(400 MHz, CDCl3) 7.74 (d, J=2.4 Hz, 1H), 7.16 (dd, J=2.9, 8.8 Hz, 1H), 6.49 (dd, J=0.7, 8.8 Hz, 1H), 3.79 (m, 2H), 2.34 (dd, J=10.5, 10.5, 2H), 1.22 (d, J=6.3 Hz, 6H).
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[CH:33][CH:34]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 74.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-[(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)amino]benzoic acid (118 mg) as well as ethyl 3-(methylamino)propanoate (39 mg) to give the title compound (104 mg, 75%) as an amorphous compound.
Reaction SMILES: [CH2:1]([O-:3])C.[Na+].[I:5][C:6]1[C:7](Cl)=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1.O>CO>[Cl:12][C:9]1[N:8]=[C:7]([O:3][CH3:1])[C:6]([I:5])=[CH:11][N:10]=1
Reactant: CC[O-]
Reactant: Clc1ncc(I)c(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(Cl)ncc1I

Procedure:
Methanolic sodium ethanolate solution (88.00 mL, 15.31 mmol—from 0.7 g sodium and 100 ml dry methanol) is added dropwise with stirring at −5 to 0° C. to a solution of 5-iodo-2,4-dichloropyrimidine (4.00 g, 14.55 mmol) in dry methanol (50 mL). The reaction solution is warmed to RT overnight, during which the crude product precipitates. The product is isolated by filtration and then stirred thoroughly with water (ca 50 mL) for 30 mins, recrystallised from methanol and dried over phosphorus pentoxide in the desiccator under vacuum: 2.18 g (8.06 mmol, 55.39%) of a white product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH2:19][CH2:20][CH3:21])=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[C:6]([CH2:19][CH2:20][CH3:21])[CH:7]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(O)cc1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)COc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product from Step 8 (0.50 g, 1.4 mmol), p-methoxyphenol (2.8 mmol) and cesium carbonate (0.91 g, 2.8 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was evaporated and the residue was purified by chromatography on silica gel to give the title product as an oil.
Reaction SMILES: [CH2:1]([N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][CH2:21][N:22]([CH2:30][CH2:31][CH2:32][CH3:33])C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].Cl>CCO.CCOCC>[CH2:30]([NH:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN(CCCN(CCCCCCCCN(CCCN(CCCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCCNCCCNCCCCCCCCNCCCNCCCC
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Dissolve 1.32 gm (0.0017 mol) of the product of Step A of this example in 1.7 ml of EtOH, treat with 17 ml of 2N HCl in Et2O and stir the mixture overnight. Filter and wash the precipitate with Et2 O, recrystallize the washed material from isopropanol/water. Filter and dry the crystals (P2O5 at 79° C. at 0.1 mm) to yield 0.62 gm of the title compound, mp >300° C. Rf is 0.47 (silica gel plates eluted with 20% conc. NH3 /CH3OH).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[CH3:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([CH3:51])[C:37]=1[OH:52].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[CH:33][C:19]2[N:18]=[C:17]([C:4]3[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[N:7]=[C:2]([C:40]4[CH:39]=[C:38]([CH3:51])[C:37]([OH:52])=[C:36]([CH3:35])[CH:41]=4)[CH:3]=3)[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]=2[CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccc(Cl)cc3n2COCC[Si](C)(C)C)c1=O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(-c2cc(-c3nc4ccc(Cl)cc4n3COCC[Si](C)(C)C)c(=O)n(COCC[Si](C)(C)C)n2)cc(C)c1O
Temperature: 95 °C

Procedure:
6-Chloro-4-[6-chloro-1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one (100 mg; 0.185 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.15 equivalents) are dissolved in DME, and argon is passed in for 10 min. 2,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 equivalent) and 2M aqueous sodium carbonate solution (2 equivalents) are added and the mixture is heated at 95° C. for 5 hours. The volatile constituents are removed in vacuo, the residue is taken up in DMF, and the product the product is purified by column chromatography (RP-HPLC, gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid)).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[BH4-].[Na+].[NH4+].[Cl-]>CO>[F:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=Cc1c(F)cc2ncccc2c1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1c(F)cc2ncccc2c1F
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of 5,7-difluoroquinoline-6-carbaldehyde (4.00 g, 20.71 mmol) in MeOH (120 mL), was added NaBH4 (0.79 g, 20.71 mmol) in portions. After stirring for 15 min, saturated aqueous solution of NH4Cl was added. The aqueous phase was extracted with CH2Cl2 (4×25 mL). The organic layers were combined and dried over NaSO4. The product was purified by silica gel with hexane:EtOAc to afford (5,7-difluoroquinolin-6-yl)methanol (3.80 g, 94%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.97 (m, 1H), 8.42 (m, 1H), 7.63 (d, 1H), 7.46 (m, 1H), 4.99 (d, 2H), 2.07 (t, 1H). LCMS (method B): [MH]+=196.0, tR=1.67 min
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:12]([Cl:25])[N:11]3[CH:26]=2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([C:18]([OH:20])=[O:19])=[C:12]([Cl:25])[N:11]3[CH:26]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)c(Cl)n2cc(-c3cccc(Br)c3)nc2c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)c(Cl)n2cc(-c3cccc(Br)c3)nc2c1C
Yield: 80.2 %

Procedure:
A solution of tert-butyl 2-(3-bromophenyl)-5-chloro-7,8-dimethylimidazo[1,2-a]pyridine-6-carboxylate (1 g, 2.30 mmol, 1 equiv) in TFA (5 mL) was stirred 3 h. The reaction mixture was then concentrated in vacuo and the residue was triturated with ether. The solid was filtered and washed with ether to provide the product (0.70 g, 80%). LCMS (ESI, M+1): 379.0.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21](Cl)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.O(C(C)(C)C)[K]>>[Cl:11][C:12]1[C:21]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: OCCOc1ccccc1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: CC(C)(C)O[K]
Product: Clc1nc2ccccc2nc1OCCOc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step 1, starting from 2-phenoxyethanol (3.7 g, 26.8 mmol), 2,3-dichloroquinoxaline (1.33 g, 6.7 mmol) and KO-t-Bu (0.75 g, 6.7 mmol): yield 0.74 g (37%); mp 99.5-101.5° C.; HRMS m/z calcd for C16H13ClN2O2 (M)+ 300.0666, found 300.0672. Anal. (C16H13ClN2O2) C, H, N.
Reaction SMILES: [C:1]1([CH3:18])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH3:18])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1csc(Nc2ccccc2C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc(CO)cs1

Procedure:
Following a procedure similar to that described in Preparation 15, the desired compound was prepared from 10 g of ethyl 2-o-toluidinothiazole-4-carboxylate, 2.9 g of lithium aluminum hydride and 200 ml of tetrahydrofuran. The resulting product was a brown oil having the following physical properties.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:24])[CH:11]=[C:12]([CH2:16][NH:17][C@@H:18]([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[N:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:10](=[O:24])[CH:11]=[C:12]([CH2:16][NH:17][C@@H:18]([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[N:13]([CH3:15])[CH:14]=1
Reactant: CNC(=O)[C@H](C)NCc1cc(=O)c(OCc2ccccc2)cn1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@H](C)NCc1cc(=O)c(O)cn1C
Yield: 96 %

Procedure:
A mixture of (S)-2-((5-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide (7.04 g, 21.4 mmol) and 10% Pd/C (0.90 g) in MeOH (70 mL) was subjected to hydrogenation in a Parr apparatus at 50 psi of hydrogen pressure for 2 h. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo. The resulting solid was dried in a vacuum oven at 44° C. for overnight. Thus, (S)-2-((5-hydroxy-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide was obtained as an orange solid (4.90 g) in 96% yield. 1H NMR (CD3COOD) δ (ppm): 7.77 (s, 1H), 7.03 (s, 1H), 4.30-4.34 (m, 3H, OCH2+CHCH3), 3.98 (s, 3H), 2.80 (s, 3H), 1.56 (d, J=6.3 Hz, 3H, CHCH3); MS m/z 262 [M+Na]+, 240 (100%) [M+1]+, 138, 110.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15](ON1C(=O)CCC1=O)=[O:16]>CN(C=O)C>[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 18 h
Yield: 151.8 %

Procedure:
109.2 Grams (0.27 mol) of H-Arg-CHA.2HCl was dissolved in 290 ml of DMF and then 70.2 ml (0.54 mol) of NEM was added thereto, followed by further addition of 81.7 g (0.3 mol) of BOC-Gly-OSu at 0° to 5° C. and the reaction was carried out at room temperature for 18 hours. After the reaction was completed, the DMF was removed by evaporation under a reduced pressure and the residue was dissolved in 500 ml of MeOH and reprecipitated in 8 liters of AcOEt. The crystals precipitated were collected by filtration and dried to obtain 135.8 g (100%) of BOC-Gly-Arg-CHA.HCl. Rf1 =0.46. Melting point: 214.5° C. (decomposed). [α]D20 -22 (C=1, MeOH)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[CH:37][CH:38]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4I)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 682.1 (M+H)+.