Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:34]=2[N:35]=1>>[Cl:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:17][CH2:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][C:2]([CH3:8])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:15][CH:14]=3)[S:32][C:33]=2[CH:39]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc3ccc(Cl)cc3s2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate and 2,6-dichloro benzothiazole. 1H NMR (CDCl3) δ 7.55 (d, 2H, J=8.0), 7.52 (d, 1H, J=2.0), 7.47 (d, 1H, J=8.0), 7.32 (d, 2H, J=8.0), 7.24 (dd, 1H, J=8.0; 2.0), 7.07 (d, 2H, J=8.6), 6.86 (d, 2H, J=8.6), 4.67 (s, 2H), 3.65 (t, 2H, J=7.2), 2.93 (t, 2H, J=7.2), 1.53 (s, 6H). MS: m/z 549 (M+1).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]([O-])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CS(Cl)(=O)=O.N1C=CC=CC=1.[NH2:63][C@@H:64]1[C:95](=[O:96])[N:66]2[C:67]([C:79]([O:81][CH:82]([C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=3)[C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)=[O:80])=[C:68]([S:71][CH2:72][C:73]3[C:74](=[O:78])[O:75][CH2:76][CH:77]=3)[CH2:69][S:70][C@H:65]12>CN(C)C=O>[O:78]=[C:74]1[C:73]([CH2:72][S:71][C:68]2[CH2:69][S:70][C@@H:65]3[C@H:64]([NH:63][C:27](=[O:28])/[C:26](/[C:24]4[N:25]=[C:21]([NH:20][C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[S:22][CH:23]=4)=[N:30]\[O:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:95](=[O:96])[N:66]3[C:67]=2[C:79]([O:81][CH:82]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:89]2[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=2)=[O:80])=[CH:77][CH2:76][O:75]1
Reactant: O=C([O-])C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CCOC3=O)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C1OCC=C1CSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of sodium 2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetate (420 mg) in dimethylformamide (5 ml) was cooled to -50° C. whilst under an inert atmosphere. Methanesulphonyl chloride (0.047 ml) was added and the reaction stirred at -50° C. for 30 min. Pyridine (0.049 ml) was added followed by a solution of diphenylmethyl 7β-amino-3-(2,5-dihydro-2-oxofuran-3-ylmethylthio)ceph-3-em-4-carboxylate (300 mg) in dimethylformamide (3 ml) and the reaction was allowed to warm to 0° C. After stirring at 0° C. for 90 min the mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed twice with water followed by saturated sodium bicarbonate and finally brine. After drying over magnesium sulphate and evaporation of solvent the residue was purified by chromatography on silica gel (Keiselgel, 2:3 ethyl acetate:hexane rising to 7:3 ethyl acetate:hexane). The title compound was isolated as a foam (422 mg). υmax (CH2Cl2) 3380, 1785, 1760 and 1725cm-1 ; δ H (CDCl3) 3.25 (1H, d, J 17.3Hz), 3.49-3.56 (3H, m), 4.68 (2H, s), 5.08 (1H, d, J 4.9Hz), 6.00 (1H, dd, J 8.8Hz, 4.9Hz), 6.44 (1H, s), 6.74 (1H, bs), 6.98 (1H, s), 7.12 (1H, s), 7.16-7.49 (41H, m). [mass spectrum: +ve ion (3NOBA, Na+) MNa+ 1170].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.C1CCN2C(=NCCC2)CC1.CN(C)C=O.[F:39][C:40]1[CH:41]=[C:42]2[C@:49]3([C:53](=[O:54])[NH:52][C:51](=[O:55])[NH:50]3)[CH2:48][C@@H:47]([C:56](Cl)=[O:57])[O:46][C:43]2=[CH:44][CH:45]=1>>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]2[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:56]([C@@H:47]3[CH2:48][C@@:49]4([C:53](=[O:54])[NH:52][C:51](=[O:55])[NH:50]4)[C:42]4[C:43](=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=4)[O:46]3)=[O:57])[CH2:9][CH2:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)NCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)Oc3ccc(F)cc32)N1
Temperature: -30 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
A mixture of 1-(2-aminoethyl)-4-diphenylmethylpiperazine (10.0 g, 33.9 mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (10.9 g, 71.7 mmol) and N,N-dimethylformamide (90.0 ml, 1.16 mol) was chilled to -30° C. To the mixture was added over 30 minutes a solution of (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1, 10.0 g, 33.5 mmol) in N,N-dimethylformamide (90.0 ml, 1.16 mol) and the mixture was stirred for 15 hours at temperature of 15°-25° C. After distilling off the solvent, the reaction mixture was chromatographed on silica gel, eluted with CH2Cl2 /MeOH (9/1) and evaporated in vacuo to dryness to give the desired compound (12.2 g, 65.2%) as colorless amorphous substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[N+:18]([O-:27])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC1CCc2ncccc2C1)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCc2c(ccc[n+]2[O-])C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To a stirred solution of 6-benzyloxycarbonylamino-5,6,7,8-tetrahydroquinoline (1.66 g, 5.87 mmol) in chloroform (13 mL) at 0° C. under nitrogen was added 3-chloroperoxybenzoic acid (1.06 g net, 6.16 mmol). The reaction mixture was then slowly warmed to room temperature. After 1 d, the reaction mixture was chromatographed on basic alumina (eluted with a 0–3% step-wise gradient of methanol in methylene chloride). The title compound (1.16 g, 66.5%) was obtained as a light yellow solid. 13C NMR (400 MHz, CDCl3) δ 155.7, 147.2, 137.3, 136.3, 133.5, 128.5, 128.1, 128.0, 126.5, 122.6, 66.8, 45.4, 36.7, 27.3, 22.9. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=6.2 Hz, 1H), 7.31 (m, 5H), 7.00 (m, 2H), 5.07 (s, 2H), 3.98 (br s, 1H), 3.12 (m, 2H), 2.95 (m, 1H), 2.70 (dd, J=7.9, 16.0 Hz, 1H), 2.11 (m, 1H), 1.86 (br s, 1H). HPLC/MS [M+H]+, 299.
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25]Br.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25][N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:11]2[CH:19]=[CH:20][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:18][CH2:17]1
Reactant: c1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Reactant: COC(=O)CCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCN1CCC(Oc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
To a solution of 4-(4-Phenoxy-phenoxy)-piperidine (152 mg, 0.5 mmol) in anhydrous CH2Cl2 (0.5 mL) was added methyl-3-bromopropionate (91 mg, 0.55 mmol) in CH2Cl2 (0.5 mL) and triethylamine (101 mg, 1.0 mmol). The resulting mixture was purged with nitrogen and stirred at rt for 48 h. CH2Cl2 was removed in vacuo and crude mixture was partioned between EtOAc and water. EtOAc layer was removed, washed with saturated NaHCO3, dried over anhydrous MgSO4 and concentrated. The crude mixture was purified by silica gel flash chromatography (50% EtOAc/Hexane) to obtain the product (146 mg, 82%): MS; m/z 356.5 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.56-1.60 (m, 2H), 1.89-1.92 (m, 2H), 2.19-2.49 (m, 2H), 2.46-2.49 (m, 2H), 2.58 (t, 2H, J=6.8Hz), 2.60-2.69 (m, 2H), 3.59 (s, 3H), 4.28-4.30 (m, 1H), 6.91-6.96 (m, 6H), 7.04-7.08 (m, 1H), 7.32-7.36 (m, 2H); HPLC (UV); 94.7%.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:10]=2)[C:5]2[N:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1.[Br:30]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:30][CH2:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:10]=2)[C:5]2[N:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1
Reactant: Cc1nc2cccnc2n(-c2cccc(NC(=O)c3cc(Cl)cc(Cl)c3)c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Yield: 26.8 %

Procedure:
The mixture of 2-methyl-4-[3-(3,5-dichlorobenzoylamino) phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.4 g), N-bromosuccinimide (2.39 g) and benzoylperoxide in chloroform (40 ml) was refluxed for 3 hours. The mixture was washed with water and extracted by chloroform (80 ml), and evaporated. The crude product was purified by chromatography to obtain 2-bromomethyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.4 g).
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([OH:27])=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:38][CH3:39])(=O)=O.O>CN(C)C=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([O:27][CH2:38][CH3:39])=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1

Procedure:
In 10 ml of N,N-dimethylformamide were stirred 0.50 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, 0.20 g of anhydrous potassium carbonate and 0.22 ml of diethyl sulfate at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:7) to give 0.50 g of N-acetyl-N-(2-ethoxycarbonylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[N:6]([C:12](=[O:14])[NH:9][N:8]=2)[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1ncc(Br)nc1Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Cl)nc(Br)cn12

Procedure:
A solution of 2.50 g of the product of Step C in THF (60 mL) was stirred as 3.32 g of triphosgene was added in portions to provide a tan suspension. A homogeneous solution was obtained after 30 min. and the excess phosgene was destroyed by the careful addition of water and the mixture was extracted with EtOAc. The organic extracts were washed with sat. sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to afford 6-bromo-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a light yellow solid. MS (M+H−)=280.1.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[C:15]([C:21]([OH:23])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:23])[CH2:29][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.8 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-isobutyl-1H-1,2,3-triazole-4-carboxylic acid (510 mg, 1.61 mmol) obtained in Example 93b), HOBt (110 mg, 0.806 mmol, 0.5 eq.) and cyclopropylamine (0.150 ml, 2.10 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8.0 ml), WSC (378 mg, 1.93 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate-hexane (4:1, 50 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate and diethyl ether were added to the residue. The precipitate was collected by filtration, washed with ethyl acetate-diethyl ether (1:3) and diethyl ether and dried to give the title compound as a white powder (559 mg, 1.57 mmol, 98.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.[N+:32]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:34])=[O:33]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][CH:35]([N+:32]([O-:34])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1CCBr
Reactant: O=[N+]([O-])Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1CCCC1CCC(c1ccccc1)[N+](=O)[O-]
Temperature: -2 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. solution of 200 mg (1.460 mmol) 2-(2-bromo-ethyl)-pyrrolidine-1-car boxylic acid tert-butyl ester (CAS: 958026-65-8) in 4.3 ml tetrahydrofuran over mol-sieves and 851.0 ul HMPA, was added drop-wise 1.92 ml (3.064 mmol) n-BuLi (1.6 M in hexane). After 45 minutes at −78° C., a solution of 406.2 mg (1.460 mmol) nitromethyl-benzene in 0.6 ml tetrahydrofuran over mol-sieves was added drop-wise. After 1 hour at −78° C., the reaction mixture was allowed to warm up slowly (during 5 hours) to −2° C. The mixture was then cooled again to −78° C. and quenched at this temperature with 0.4 ml of acetic acid, then with 8 ml saturated ammonium chloride. Back to room temperature, the aqueous phase was extracted 2 times with ethylacetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude yellow oil (993 mg) was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 15%) to provide 242 mg (y: 49.6%) of the title compound as a colorless oil. MS (m/e): 335.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[C:19]#[N:20])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1.CN1C2C(=[O:39])C3C=C(CC4C=C(C=CC=4)C#N)C=CC=3NC=2C=N1>>[CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[C:19]([NH2:20])=[O:39])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2[nH]c3ccc(Cc4ccccc4C#N)cc3c(=O)c21
Reactant: Cn1ncc2[nH]c3ccc(Cc4cccc(C#N)c4)cc3c(=O)c21
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4C(N)=O)cc3c(=O)c21

Procedure:
The title compound was prepared according to the procedure of EXAMPLE 29 using 2-[(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]benzonitrile (EXAMPLE 32, step 2), instead of 3-[(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]benzonitrile.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[SH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([CH2:2][S:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:4]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: O=C(O)CCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)CCCCSCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of bromomethyl-2-naphthyl ketone (2 g, 8.00 mmol) in anhydrous THF (50 mL) was added 5-mercaptovaleric acid (1.07 g, 8.00 mmol), followed by potassium carbonate (5.71 g, 41 mmol). The suspension was refluxed for 1 hour, cooled to the room temperature and filtered. The solid was collected, dissolved in a 1:1 mixture water-THF and acidified with HCl (pH 1-2). The acidic solution was extracted with ether, dried (MgSO4), filtered and evaporated to produce the title compound 225a (1.21 g, 50% yield). 1H NMR: (300 MHz, DMSO-d6) δ 11.98 (br s, 1H), 8.69 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 8.00-7.98 (m, 3H), 7.67-7.61 (m, 2H), 4.09 (s, 2H), 2.52 (t, J=6.6 Hz, 2H), 2.19 (t, J=6.6 Hz, 2H), 1.56-1.53 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C@H:26]([C:32]#[C:33][CH3:34])[CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH:15]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C@H:26]([C:32]#[C:33][CH3:34])[CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC#C[C@H](CC(=O)OC)c1ccc(OC2CCc3cc(-c4cccc(OCC)c4)ccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#C[C@H](CC(=O)O)c1ccc(OC2CCc3cc(-c4cccc(OCC)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 59.3 in THF/MeOH (1:1, 2 mL), was treated with 2N NaOH aqueous solution (1 mL) and stirred for overnight at room temperature. The reaction mixture was acidified with aqueous 4N HCl and extracted with EtOAc to obtain 59, which was purified by preparative HPLC, eluting with 5˜95% ACN in water containing 0.1% TFA. MS ESI (neg.) m/e: 439.1 (M−H). 1HNMR (MeOD-d4) δ 7.65 (br, 1H), 7.48 (s, 1H), 7.38 (d, 1H, J=7.02 Hz), 7.32 (t, 1H, J=7.12 Hz), 7.18 (d, 1H, J=6.57 Hz), 7.14 (s, 1H), 7.06 (m, 2H), 6.99-6.86 (m, 2H), 6.78 (m, 1H), 4.79 (m, 1H), 4.12 (q, 2H, J=6.50 Hz), 3.86 (m, 1H), 3.15-3.01 (m, 2H), 2.54-2.42 (m, 2H), 2.03 (m, 1H), 1.74 (ss, 3H), 1.42 (t, 3H, J=6.74 Hz).
Reaction SMILES: [OH-].[Na+].C(O)C.[C:6]([NH:14][C:15]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(OCC)(=O)C>[C:6]([NH:14][C:15]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:22]=[CH:21][C:16]=1[C:17]([OH:19])=[O:18])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2nccs2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Nc1cc(-c2nccs2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 96 %

Procedure:
0.35 mL of 10% aqueous sodium hydroxide was added to 5 mL of ethanol suspension containing 0.25 g of methyl 2-(benzamido)-4-(thiazol-2-yl)benzoate at room temperature, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.23 g of 2-(benzamido)-4-(thiazol-2-yl)benzoic acid as white solid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:25]([O:27][C:28](=[O:41])[CH2:29][C:30]1[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][NH:33][CH:34]=1)[CH3:26].O>CN(C)C=O>[CH3:18][C:17]1[O:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][N:33]2[CH:34]=[C:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:41])[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (513 mg, yield: 58%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 90 °C
Yield: 81.5 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]propylamine (70 mg, 0.24 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (57 mg, 0.24 mmol) and DIPEA (84 μL, 0.48 mmol) in IPA (3 mL) was heated for 24 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-7% MeOH in DCM) to afford the title compound as a pale brown oil (96 mg, 82%). LCMS (Method J): RT=3.03 min, [M+H]+=491.