Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2.Cl.Cl.[NH2:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][N:24]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]([NH:21][CH2:22][C:23]3[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][N:24]=3)=[O:14])[CH:10]=1)[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2
Reactant: COC(=O)c1ccnc(CN)c1
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CC(=O)O)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccnc(CNC(=O)Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
A mixture of compound 58 (0.155 g, 0.58 mmoles) and methyl 2-(aminomethyl)pyridine-4-carboxylate dihydrochloride (0.139 g, 0.58 mmoles) (see WO2003070732, example 6, step 2 for preparation, which is incorporated by reference in its entirety) in dichloromethane (20 ml) was treated with N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (0.264 g, 0.69 mmoles) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.133 g, 0.69 mmoles) and N-methylmorpholine (0.255 ml, 2.32 mmoles) then stirred at ambient temperature under a nitrogen atmosphere for 18 h. The mixture was washed with water (2×20 ml) and saturated brine (20 ml) then separated and dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound as a colorless oil (0.184 g 76%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([CH:11]([C:14]1[N:19]2[N:20]=[C:21]([CH3:28])[C:22]([C:23]3[S:27][CH:26]=[N:25][CH:24]=3)=[C:18]2[N:17]=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].[I:30]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1>[CH2:9]([CH:11]([C:14]1[N:19]2[N:20]=[C:21]([CH3:28])[C:22]([C:23]3[S:27][C:26]([I:30])=[N:25][CH:24]=3)=[C:18]2[N:17]=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(CC)c1cc(C)nc2c(-c3cncs3)c(C)nn12
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3cnc(I)s3)c(C)nn12
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Add a freshly prepared solution of lithium di-i-propylamide (150 ml; 62 4 mmol, 0.6 M in THF) to a mixture of 7-(1-ethyl-propyl)-2,5-dimethyl-3-thiazol-5-yl-pyrazolo[1,5-a]pyrimidine, (17.8 g, 62 4 mmol) in THF (100 mL) at −78° C. under a nitrogen atmosphere, keeping the temperature below −74° C. during the addition. Stir the mixture at −78° C. for one hour and then add a solution of N-iodosuccinimide (15 g, 63 mmol) in THF (100 mL) keeping temperature below −74° C. Warm the reaction gradually to 22° C. and then add a 10% aqueous solution of ammonium chloride (300 mL). Separate the organic layer and wash the aqueous layer with methyl-t-butyl ether (2×200 mL). Combine the organic layers, dry over sodium sulfate, filter, and evaporate the solvent. Purify the resulting residue by silica gel chromatography, eluting with hexanes/acetone (5/1) to afford the title compound (15 g, 60%). ES/MS m/z 427 (M+1)+.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][N:4]1[C:23]([CH3:25])([CH3:24])[CH2:22][C:7]2([NH:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]2=[O:21])[CH2:6][C:5]1([CH3:27])[CH3:26].[C:29]([OH:38])(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:3][N:4]1[C:5]([CH3:26])([CH3:27])[CH2:6][C:7]2([NH:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]2=[O:21])[CH2:22][C:23]1([CH3:25])[CH3:24])[CH2:28][O:35][C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:38][CH2:28][CH:2]([OH:1])[CH2:3][N:4]1[C:23]([CH3:25])([CH3:24])[CH2:22][C:7]2([NH:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]2=[O:21])[CH2:6][C:5]1([CH3:26])[CH3:27])=[O:37]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CCCCCCCCN1C(=O)NC2(CC(C)(C)N(CC3CO3)C(C)(C)C2)C1=O
Solvent: Cc1ccccc1C
Product: CCCCCCCCN1C(=O)NC2(CC(C)(C)N(CC(O)COC(=O)CCCCC(=O)OCC(O)CN3C(C)(C)CC4(CC3(C)C)NC(=O)N(CCCCCCCC)C4=O)C(C)(C)C2)C1=O

Procedure:
A mixture of 4.3 g of 8-(2,3-epoxypropyl)-7,7,9,9-tetramethyl-3-octyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 0.74 g of adipic acid in 20 ml of xylene was refluxed for 16 hours. After completion of the reaction, the xylene was distilled from the reaction mixture in vacuo and the residue was purified by column chromatography through silica gel eluted with ethyl acetate, giving the desired Compound No. 328 in the form of a pale yellow oil. The compound had an Rf value of 0.46 on thin-layer chromatography when developed with ethyl acetate.
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Br:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([Br:12])[CH:11]=1.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([O:13][CH2:2][O:3][CH3:4])[CH:9]=[C:10]([Br:12])[CH:11]=1
Reactant: COCCl
Reactant: Oc1cc(Br)cc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
Chloromethylmethyl ether (1.45 mL, 19.13 mmol) was added dropwise to a solution of 3,5-dibromophenol (4.38 g, 17.39 mmol) and diisopropylethylamine (3.63 mL, 20.90 mmol) in CH2Cl2 (40 mL) at 0° C. The mixture was warmed to RT, stirred for 16 h, and added to H2O (50 mL). The layers were separated, and the aqueous fraction was extracted with CH2Cl2 (2×50 mL). The combined organic fractions were washed with brine (25 mL), dried over anhydrous MgSO4, and the solvent was evaporated to provide 5.20 g (100%) of 1,3-dibromo-5-methoxymethoxy-benzene (113a).
Reaction SMILES: [OH2:1].C(Cl)Cl.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[O:22]=[C:23]([O-:34])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Na+]>C(N(CC)CC)C>[CH3:14][C:12]([C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:13].[C:23]([OH:34])([OH:22])=[O:1]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)O
Reaction time: 1 h

Procedure:
To a reactor fitted with a mechanical agitator were charged 5.5 liters of deionized water, 10 liters of methylene chloride, 2280 grams (10 moles) of bisphenol-A, 28 milliliters of triethylamine, 3.4 grams of sodium gluconate, and 0.40 mole of chain terminating agent. Phosgene was introduced at the rate of 18 grams/minute and phosgenation is continued for 60 minutes. The pH was maintained at between 8.0 and 10.0 by the addition of 25% aqueous sodium hydroxide. After phosgenation has ceased 4 liters of methylene chloride were added, the brine layer separated by centrifuge and the resin solution washed with aqueous acid water. The resin was steam precipitated and dried. To this resin product were added minor amounts (about 0.03 parts by weight per hundred parts by weight of resin) of a phosphite and of an epoxy stabilizer. This resin product was then fed to an extruder operating at a temperature of about 500° F. to extrude the resin into strands and the extruded strands chopped into pellets. The pellets were then injection molded at about 570° F. into test samples measuring about 21/2"×1/2"×1/8".
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)nc1CBr

Procedure:
50 g (0.23 mol) of methyl 2-methyl-6-trifluoromethylnicotinate and 49 g (0.28 mol) of N-bromosuccinimide are heated for 90 minutes at 50° C. in 500 ml of carbon tetrachloride in the presence of a catalytic amount of α,α-azaisobutyronitrile with illumination by a 150 watt lamp. Precipitated succinimide is filtered off, and the product methyl 2-bromomethyl-6-trifluoromethyinicotinate is then isolated as main component by means of column chromatography (mobile phase ethyl acetate/hexane 1:15), 1H-NMR (CDCl3): 4.01, s, 3H; 5.03, s, 2H; 7.72, d (J 8.2 Hz), 1H, 8.43 ppm, d, (J 8.2 Hz), 1H. 25.6 g (35 mmol) of the above product are taken up in toluene and treated with 10.6 g (40 mmol) of triphenylphosphine. After the mixture has been heated for 2 hours at boiling point, pure (3-methoxycarbonyl-6-trifluoromethylpyridine-2-ylmethyl)triphenylphosphonium bromide of melting point 215-217° C. crystallizes out upon cooling.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:15]3[N:16]([C:20]([O:22]C(C)(C)C)=O)[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[C:36]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:37][CH2:38]C([O-])=O.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:15]3[N:16]([C:20](=[O:22])[CH2:38][CH2:37][C:36]([O:43][CH2:44][CH3:45])=[O:42])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)CCC(=O)[O-]
Reactant: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3C(=O)OC(C)(C)C)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCC(=O)N1CCOc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc21
Yield: 38.3 %

Procedure:
The same operation as in Example (93a) was performed using tert-butyl 7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate obtained in Example (95c) (0.11 g, 0.27 mmol), a 4 N hydrochloric acid/ethyl acetate solution (8 ml, 32 mmol), monoethyl succinate (150 mg, 1 mmol), WSC hydrochloride (288 mg, 1.5 mmol), N,N-diisopropylethylamine (0.52 g, 4 mmol) and DMAP (10 mg). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1, 2/1, 2/3, 0/1) gave 45 mg of the title compound as a light yellow solid (38%).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[CH2:13][CH2:12][CH:11]([N:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:23]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)[CH2:10][CH2:9]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(C=NC2CCN(C(c3ccccc3)c3ccccc3)CC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(CNC2CCN(C(c3ccccc3)c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.55 parts of 1-(diphenylmethyl)-N-[(6-methyl-2-pyridyl)methylene]-4-piperidinamine, 1.9 part of sodium borohydride and 250 parts by volume of ethanol is stirred at room temperature for about two hours. The reaction mixture is evaporated to dryness in vacuo, the residue partitioned between 200 parts by volume of water and 150 parts by volume of methylene chloride and the layers separated. The aqueous layer is extracted with additional 125 parts by volume of methylene chloride. The methylene chloride fractions are combined, washed with 200 parts by volume of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo to yield, as a yellow oil, 1-(diphenylmethyl)-N-[(6-methyl-2-pyridyl)methyl]-4-piperidinamine. This compound has the following formula ##STR35##
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13].[H-].[Na+].[C:16]([NH:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)(OCC)=[O:17].NC1SC2C=CC=CC=2N=1>N1C=CC=CC=1.CCCCC>[CH3:13][C:12]1[NH:11][CH:10]=[N:9][C:8]=1[CH2:7][S:6][CH2:5][CH2:4][NH:3][C:16]([NH:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:17]
Reactant: CCOC(=O)Nc1nc2ccccc2s1
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: Nc1nc2ccccc2s1
Agent: [H-]
Solvent: c1ccncc1
Solvent: CCCCC
Product: Cc1[nH]cnc1CSCCNC(=O)Nc1nc2ccccc2s1
Yield: 16.4 %

Procedure:
The compound is prepared according to the method of Example 5 using 6.12 g (25.1 mmole) of 4-[(2-aminoethyl)thiomethyl]-5-methylimidazole dihydrochloride, and 2.29 g (50.2 mmole) of sodium hydride in oil in 100 ml of pyridine and 5.55 g (25.0 mmole) of 2-carbethoxyaminobenzothiazole, prepared from 2-aminobenzothiazole according to the method of Example 2. Chromatography, followed by trituration with pentane, affords the desired compound (1.43 g, 4.1 mmole). Structure assignment is supported by nmr.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH:19]=O)[CH:13]=1.S(=O)(=O)(O)O.C([BH3-])#N.[Na+]>O1CCCC1.O>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH2:19][NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:13]=1
Reactant: Cc1cc(C)nc(C=O)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)nc(CNc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
p-Nitroaniline (0.51 g, 3.7 mmol) was added to a solution of 4,6-dimethyl-pyridine-2-carbaldehyde (0.5 g, 3.7 mmol) in tetrahydrofuran (20 mL) at 0° C., followed by sulfuric acid and water (1 mL:1 mL). After stirring at 0° C. for 30 min. sodium cyanoborohydride (0.47 g, 7.4 mmol) was added portionwise at 0° C. The mixture stirred at room temperature for 1 h then concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic phase was washed with sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by column chromatography on silica gel (60-120 mesh) using 18% ethyl acetate/hexane as eluent to afford (4,6-dimethyl-pyridin-2-ylmethyl)-(4-nitro-phenyl)-amine (0.35 g, 37%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]I)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)CC.O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][C@@H:19]2[CH2:18][C@@H:17]([C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[O:21][C:20]2=[O:22])=[CH:37][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ICc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1

Procedure:
In analogy with Example 1h), 5.2 g (16.7 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]dihydrofuran-2-one (Example 12a)), dissolved in 50 ml of THF, are deprotonated, at -70° C., with 33.4 ml of a 1M solution of lithium is(trimethylsilyl)amide in THF, and alkylated (at -75° C. for 1 h) with 5.2 g (16.07 mmol) of p-benzyloxybenzyl iodide [preparation, see Example 1d)] in 15 ml of THF. Adding 6.2 ml (83.02 mmol) of propionic acid and water at -75° C., and further working up, affords the title compound after column chromatography (SiO2, hexane/ethyl acetate: 4:1). TLC Rf (hexane/ethyl acetate: 4:1)=0.27; tRet (II)=20.41 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1)#[N:2].[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>C(OCC)(=O)C.O>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=4)=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2C#N)ccn1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(C#N)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of acid 111-10 (150 mg crude from above containing about 25 mg, 0.1 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (22 mg, 0.1 mmol) 111-4, o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 40 mg, 0.105 mmol) were added DMF (1 mL) and diispropylethyl amine (DIEA, 38.7 mg, 0.3 mmol) and the mixture was stirred at room temperature overnight. Then it was redistributed between water (30 mL) and ethyl acetate (30 mL). The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The oily reside was subjected to both reverse phase preparative HPLC and silica gel chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-cyano-4-(2-methylpyridin-4-yl)phenyl)acetamide (Compound III) as a white solid. MS m/z 455.3 (M+1).
Reaction SMILES: [P:1]([O-:44])([O:37][CH2:38][CH2:39][N+:40]([CH3:43])([CH3:42])[CH3:41])([O:3][CH2:4][CH:5]([O:29]CC1C=CC=CC=1)[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2]>C(O)(=O)C.[Pd]>[P:1]([O-:44])([O:37][CH2:38][CH2:39][N+:40]([CH3:43])([CH3:42])[CH3:41])([O:3][CH2:4][CH:5]([OH:29])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[N+](C)(C)C)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(O)COP(=O)([O-])OCC[N+](C)(C)C

Procedure:
The benzyl compound (1.4 g) obtained in Example 27 was dissolved in 50 ml of acetic acid and hydrogenated on 100 mg of palladium-on-carbon. Then, the catalyst was removed and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (15 g) using chloroform-methanol-water (65:25:4) as the eluent to give the above-identified compound.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:20]=1[C:26]([F:29])([F:28])[F:27]>>[Br:18][C:19]1[C:20]([C:26]([F:27])([F:28])[F:29])=[C:21]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Product: Oc1ccc2ncn(-c3cccc(Br)c3C(F)(F)F)c2n1

Procedure:
From 5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine and 1-bromo-3-fluoro-2-(trifluoromethyl)benzene, prepared in a similar manner as the one described in Example 1.96, the title compound was obtained. LCMS m/z=358.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:37]5[CH:36]=[CH:35][N:34]=[C:33]([N:30]6[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]6)[CH:38]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3cc(N5CCN(C)CC5)nc(N)n3)CC4)ccn2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-methyl-4-[4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (Oadwood, Cat. No. 021854). LCMS (M+H)+: m/z=500.5.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[S:11][CH2:12][C:13]([CH3:21])=[C:14]2[C:18]([OH:20])=[O:19].Cl[C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C)C=O.C(Cl)(Cl)Cl>[C:18]([C:14]1[N:15]2[CH:10]([S:11][CH2:12][C:13]=1[CH3:21])[CH:9]([NH:8][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:16]2=[O:17])([OH:20])=[O:19]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2SC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.3 %

Procedure:
Triethylamine (55.6 cc) is added to a suspension of 7-amino-2-carboxy-3-methyl-8-oxo-5-thia-1aza-bicyclo[4.2.0]oct-2-ene (42.8 g) in dry N,N-dimethylformamide (250 cc), and after cooling the mixture to -20° C. a solution of chlorotriphenylmethane (55.8 g) in chloroform (250 cc) is added in the course of 2 hours. The reaction mixture is stirred for 24 hours at 25° C. and then poured into normal hydrochloric acid (400 cc). After filtration, the organic phase is separated off, concentrated to half its volume under reduced pressure (40 mm Hg) at 40° C., and taken up in ethyl acetate (400 cc). The aqueous phase is extracted with ethyl acetate (400 cc), and the combined organic phases are washed with normal hydrochloric acid (2×250 cc) and then extracted with a half-saturated sodium bicarbonate solution (4×500 cc). These combined aqueous phases are washed with ethyl acetate (300 cc), then acidified to pH 3 with 12 N hydrochloric acid and extracted with ethyl acetate (2×500 cc). The combined organic solutions are washed with a saturated sodium chloride solution (250 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. The residue is caused to solidify by adding isopropyl ether (250 cc). The solid is filtered off, washed with isopropyl ether (100 cc) and dried. A mixture (22.2 g) of 2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40%) and its oct-3-ene isomer (60%) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (12.2 g, 100 mmol), benzyl bromide (25.66 g, 150 mmol), and cesium carbonate (97.8 g, 300 mmol) in DMSO (200 mL) under nitrogen at room temperature was stirred overnight. The reaction was filtered to remove the solids, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting ethyl acetate:hexane (15:85, v:v) to give 4-benzyloxy-benzaldehyde (18.72 g, 80%) as a glass. MS found: (M+H)+=213.