Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[Si:33]([O:50][CH2:51][C@@H:52]([NH2:57])[CH2:53][CH:54]([CH3:56])[CH3:55])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:57][C@H:52]([CH2:51][O:50][Si:33]([C:46]([CH3:48])([CH3:47])[CH3:49])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:53][CH:54]([CH3:56])[CH3:55])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: CC(C)C[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(C)C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 0 °C
Yield: 64 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.00 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in benzene (100 ml) was added a solution of 0.67M (1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutylamine-trimethylaluminium in benzene (12.9 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux overnight. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred in the ice bath for 0.5 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→4:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.14 g, yield 64%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:25]5[CH:32]=[C:31]([C:33](=[O:43])[NH:34][CH2:35][CH2:36][N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)[N:30](COCC[Si](C)(C)C)[C:26]=5[N:27]=[CH:28][N:29]=4)=[C:19]([F:52])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[F:52][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:12][CH2:13]2)=[O:15])[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[C:25]2[CH:32]=[C:31]([C:33]([NH:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[O:43])[NH:30][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: C[Si](C)(C)CCOCn1c(C(=O)NCCN2CCOCC2)cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: O=C(NCCN1CCOCC1)c1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2[nH]1
Yield: 33 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[6-(2-morpholin-4-yl-ethylcarbamoyl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide (0.049 g, 0.07 mmol, 1.0 eq.) and a 1M tetrabutylammonium fluoride solution (5 ml). The reaction was heated to reflux for 1 hour. The reaction was diluted with ethyl acetate, and was washed with (2×) H2O (50 ml), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography using 3% methanol and DCM as the eluent, giving N-{3-fluoro-4-[(6-{[(2-morpholin-4-ylethyl)amino]carbonyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide as a white solid (0.014 g, 35% yield). 1H NMR (400 MHz, DMSO): 12.92 (s, 1H), 10.39 (bs, 1H), 10.36 (s, 1H), 10.04 (s, 1H), 9.11 (m, 1H), 8.37 (s, 1H), 7.83 (d, 1H), 7.66 (m, 2H), 7.46 (m, 1H), 7.40 (m, 1H), 7.15 (t, 2H), 3.98 (d, 2H), 3.77 (m, 3H), 3.56 (d, 2H), 3.16 (m, 2H), 3.02 (m, 3H), 1.59 (m, 2H), 1.36 (m, 2H); MS (ESI) for C30H29F2N7O5: 606 (MH+).
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])(=O)[CH3:2].[F:27][C:28]1[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=1[C:30]([NH:32][NH2:33])=O>C1(C)C(C)=CC=CC=1>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:5]1[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:7][N:8]2[C:4]=1[C:1]([CH3:2])=[N:33][N:32]=[C:30]2[C:29]1[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=1[F:27]
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1-c1ccccc1F
Reactant: NNC(=O)c1ccccc1F
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2-c2ccccc2F)cc1
Temperature: 180 °C

Procedure:
Toluene-4-sulfonic acid 5-acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl ester (8.26 g, 22.1 mmol) and 2-fluorobenzhydrazide (3.86 g, 25.0 mmol) were stirred together in xylene (250 ml) at reflux overnight. The solvent was removed in vacuo, and the residue was heated in Dowtherm A at 180° C. for 2 h. The mixture was poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 10% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a yellow solid (6.62 g). 1H NMR (400 MHz, CDCl3) δ 2.43 (3H, s), 2.53 (3H, s), 7.17-7.37 (6H, m), 7.41-7.51 (2H, m), 7.63 (1H, m), 7.69 (3H, m); MS (ES+) m/e 493 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:17](=[O:20])[CH2:18][CH3:19])C(OC)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl-].[Na+]>O.CS(C)=O>[Cl:1][C:2]1[C:3]([CH2:12][C:17](=[O:20])[CH2:18][CH3:19])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCC(=O)C(C(=O)OC)c1ncc(C(F)(F)F)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 130 °C
Reaction time: 8 h

Procedure:
2.08 g of methyl 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-3-oxopentanoate (0.00677 mol) and 0.12 g of sodium chloride are dissolved in a mixture of water (0.25 mL) and dimethylsulfoxyde (20 mL). The reaction medium is stirred at a temperature of 130° C. for 8 hours. After cooling, 100 mL of water are added to the reaction mixture which is extracted twice with 150 mL of ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)C(F)(F)F)=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[F:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[F:18]
Reactant: O=C(Nc1ccc(Br)c(F)c1[N+](=O)[O-])C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of N-(4-bromo-3-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.42 g, 10.3 mmol) and triphenylphosphine (3.79 g, 14.4 mmol) in tetrahydrofuran (31.0 mL) at 0° C. was treated with methanol (1.67 mL, 41.3 mmol) followed by dropwise addition of diisopropyl azodicarboxylate (2.84 mL, 14.4 mmol), and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with water (10 mL), concentrated in vacuo to remove most of the THF. Water (200 mL) was added and the resultant mixture was extracted with ethyl acetate (200 mL). Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 80% dichloromethane/hexanes) gave the desired product (2.46 g, 96%) as an orange solid. LCMS calculated for C7H7BrFN2O2 (M+H)+: m/z=249.0, 251.0. found: 248.9, 250.9.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.[CH3:28][O-:29].[Na+]>CO>[CH3:28][O:29][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: COc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(OC)c(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2-Chloro-6-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 8) (100 mg, 0.25 mMol) was added to freshly prepared sodium methoxide (0.27 mMol) in methanol and stirred at room temperature for 22 hours and then at 75° C. for 4 hours. The reaction solution was concentrated and the product was purified by silica gel chromatography to give a white solid. Anal. Calc'd. for C21H18N2O4S (394.45): C, 63.95; H, 4.60; N, 7.10. Found: C, 63.80; H, 4.71; N, 6.94.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 74.1 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 3.3 g.), conc. hydrochloric acid (2.80 g.), tetrahydrofuran (20 ml.) and methanol (50 ml.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.3 g.)
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=O)=O)=CC=1.C([O-])(=[O:25])C.[K+]>CCO.O>[N:18]1[C:19]2[CH2:20][CH2:21][CH2:22][C:13](=[O:25])[NH:12][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)ON=C2CCCc3ncccc32)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCCc2ncccc2N1
Temperature: 25 °C

Procedure:
A mixture of 1.0 eq of 95 and 2.3 eq of potassium acetate in 70 mL of EtOH and 140 mL of H2O was refluxed for 17 hrs. After cooling to rt and rotary evaporation of the EtOH, the solution was made alkaline with 10 N NaOH. The mixture was extracted with chloroform (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to yield 96.
Reaction SMILES: [CH:1]12[CH:8]([C:9]3[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>[OH-].[Na+].C(Cl)Cl>[CH2:27]([O:26][C:24]([N:3]1[CH2:4][CH:5]2[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[CH:1]([CH2:7][CH2:6]2)[CH2:2]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1cccc(C2C3CCC2CNC3)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2CCC(C1)C2c1cccc(O)c1
Reaction time: 8 h
Yield: 65 %

Procedure:
3-(3-Aza-bicyclo[3.2.1]oct-8-yl)-phenol as HCl salt (547 mg, 1.93 mmol) was stirred vigorously in 1N NaOH (10 mL), saturated aqueous Na2CO3 solution (20 mL) and CH2Cl2 (30 mL) then charged with benzyl chloroformate (5 mL, 35.0 mmol) slowly via syringe. After stirring overnight, the layers were separated and the product was extracted with CH2Cl2 (1×10 mL), washed with saturated aqueous NaHCO3 solution, dried through a cotton plug and concentrated to a brown liquid. Flash chromatography provided the desired product as a thick clear oil (420 mg, 65%). (TLC 30% EtOAc/hexanes Rf 0.34); 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 7.11 (t, J=7.9 Hz, 1H), 6.73 (d, J=7.9 Hz, 1H), 6.71 (s, 1H), 6.66 (d, J=7.9 Hz, 1H), 5.14 (s, 2H), 4.05 (dd, J=12.2 Hz, 2.7 Hz, 1H), 3.96 (dd, J=12.2, 2.7 Hz, 1H), 3.09 (m, 2H), 2.85 (s, 1H), 2.50 (br s, 1H), 2.46 (br s, 1H), 1.64 (m, 2H), 1.48 (m, 2H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:18]1[N:23]=[C:22]([NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:21]([NH2:33])=[N:20][CH:19]=1.[CH:34](O)=[O:35]>[Pd]>[C:1]1([C@@H:7]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:15]3[NH:16][C:34]2=[O:35])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([C@@H:25]([NH:24][C:22]2[C:21]([NH2:33])=[N:20][CH:19]=[CH:18][N:23]=2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](Nc1nc(Br)cnc1N)c1ccccc1
Reactant: O=CO
Agent: [Pd]
Agent: C[C@H](Nc1nccnc1N)c1ccccc1
Product: C[C@@H](c1ccccc1)n1c(=O)[nH]c2nccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-N2-(1-Phenylethyl)pyrazine-2,3-diamine. The title compound was prepared by dissolving (S)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine (1.00 g, 3.37 mmol) in neat formic acid (15 mL), and adding 10% Pd/C (0.34 mmol). This solution was purged with hydrogen gas at 1 atm., and stirred for 4 hours at room temperature. Upon completion, the reaction was filtered through celite and concentrated. The crude material was purified using silica gel chromatography (0-10% methanol in dichloromethane). Clean fractions were combined and condensed to afford 0.47 g (2.19 mmol, 65%) of (S)-N2-(1-phenylethyl)pyrazine-2,3-diamine. MS (ESI) m/z 215.4 [M+1]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]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.CN(C1C=CC=CN=1)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To 2.39 g (10 mmol) of 1-benzhydryl-3-hydroxyazetidine dissolved in 20 ml of pyridine were added 1.46 g (12 mmol) of dimethylaminopyridine. Thereto was added 12.10 g (11 mmol) of p-toluenesulfonyl chloride at -40° C., followed by gradual increase in the temperature and subsequent 1 day of stirring at room temperature. This was mixed with 150 ml of water, extracted with chloroform (100 ml×3) and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (250 ml, ethyl acetate:hexane 1:2) to yield 2.88 g (73%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13]C(=O)OCC1C=CC=CC=1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].C(O)C>[Si:1]([O:8][CH2:9][C:10]([NH2:13])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Yield: 83.4 %

Procedure:
A procedure similar to that described in Preparation 9 was repeated, except that 8.00 g of benzyl N-[2-t-butyldimethylsilyloxy-1,1-dimethylethyl]carbamate (prepared as described in Preparation 103), 1.60 g of 10% w/w palladium-on-carbon and 80 ml of ethanol were used, to give 4.02 g of the title compound having an Rf value of 0.14 (on silica gel thin layer chromatography, using ethyl acetate as the eluent).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:28][CH3:29])[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([O:33][C:34](=[O:43])[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40](Br)[CH:41]=1)[CH3:32]>>[CH2:31]([O:33][C:34](=[O:43])[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=2[CH2:8][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:30])[CH2:28][CH3:29])[CH:41]=1)[CH3:32]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1cncc(Br)c1
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid tert-butyl ester and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 8, Step 4 to provide (5-{2-[(N-tert-butoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O.C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Bromo-benzaldehyde (18.50 g, 99.99 mmol) was added to a stirred solution of concentrated nitric acid (70%, 13.09 mL, 199.98 mmol) in concentrated sulfuric acid (125 mL) at 0° C. After the addition was complete, the ice bath was removed and the reaction was allowed to stir for 5 hours at room temperature. Then, the mixture was poured into ice and the solid was collected by filtration. The filtrate was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was combined with the solid previously obtained via the first filtration and dissolved in diethyl ether. Hexanes were added and after crystallization 14.66 g (64%) of 5-bromo-2-nitro-benzaldehyde was collected by filtration and drying. 1H NMR (400 MHz, d6-DMSO): δ 10.19 (s, 1H), 8.10 (s, 2H), 8.02 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=[CH:19][CH2:20][CH2:21][C:22]([CH3:25])=[CH:23][CH3:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[CH:16][O:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13].[H][H]>CO.[Pd]>[CH3:1][CH:2]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH3:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[CH:16][O:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC=C(C)CCC=C(C)COc1ccccc1C(=COC)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(C)CCCC(C)COc1ccccc1C(=COC)C(=O)OC

Procedure:
3.2 g of methyl α-(2-(2,6-dimethylocta-2,6-dienyloxy)phenyl)-β-methoxyacrylate are dissolved in 70 ml of methanol, and 0.2 g of palladium on active carbon is added. At room temperature, hydrogen is passed with stirring through the suspension until no further gas is absorbed. The solution is separated from the catalyst and evaporated. This give 3.1 g of an oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([CH2:12][N:13]([CH2:26][CH3:27])[C:14]2[C:23]([C:24]#[N:25])=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1>[NH2:25][CH2:24][C:23]1[C:14]([N:13]([CH2:12][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:26][CH3:27])=[N:15][C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1C#N)CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC1CCCC1)c1nc2c(cc1CN)CCCC2
Yield: 65.6 %

Procedure:
To a suspension of LAH (0.600 g, 16 mmol) in THF (15 mL), was added a solution of 2-(cyclopentylmethyl-ethyl-amino)-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.300 g, 1.06 mmol) in dry THF. This reaction mixture was gently refluxed for 14 h. The unreacted LAH was then quenched with a saturated solution of sodium sulfate, and the residue was filtered off and washed with diethyl ether. The washings were collected, dried over sodium sulfate, and the solvent was evaporated to provide (3-aminomethyl-5,6,7,8-tetrahydro-quinoline-2-yl)-cyclopentylmethyl-ethylamine (0.2 g, yield: 65%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]=O>>[CH2:1]([NH:3][CH2:9][C:5]1[NH:4][CH:8]=[CH:7][N:6]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1ncc[nH]1
Product: CCNCc1ncc[nH]1

Procedure:
prepared by reaction of ethylamine with 1H-imidazole-2-carbaldehyde
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([C:22](O)=[O:23])=[CH:10]2)=[O:5].CN(C)CCCN=C=NCC.Cl.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:42][CH:41]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][C:2]([CH3:1])([CH3:26])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]([C:22]([NH:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[CH:44][CH:45]=1)=[O:23])=[CH:10]2)=[O:5]
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2-c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
75 mg (0.21 mmol) of 5-[(3,3-dimethylbutanoyl)amino]-1-phenyl-1H-indole-2-carboxylic acid from Example LIX, 61.55 mg (0.32 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 13.1 mg (0.11 mmol) of 4-dimethylaminopyridine are initially charged in 4 ml of dichloromethane. 44.6 mg (0.21 mmol) of tert-butyl 4-aminophenylcarbamate are added, and the mixture is stirred at RT for 3 hours. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C[O-].[Na+].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28]>CCOCC>[CH3:26][N:27]([CH3:28])[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: Oc1cccc(-c2nc3ncccc3o2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc(-c2nc3ncccc3o2)c1
Temperature: 25 °C

Procedure:
To a solution of 1.1 g. (0.005 mole) of 2-(3-hydroxyphenyl)oxazolo[4,5-b]pyridine in 15 ml. dried dimethylformamide is added 0.6 g. (0.011 mole) of sodium methoxide in portions over about 10 min. To the reddish-orange solution cooled in an ice-bath is added 0.72 g. (0.005 mole) of N,N-dimethyl-2-chloroethylamine hydrochloride in portions over 15 minutes. The resultant mixture is then stirred 10 minutes, set in an oil-bath at 75° C., and kept at 75-90° C. (bath) for 20 hours. After cooling to room temperature, 15 ml. of dried ether is added with stirring, and the resultant mixture is filtered. The filtrate is then stripped of solvent, and the residue distributed between methylene chloride and water. The organic layer is dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-[3-(2-dimethylaminoethoxy)phenyl]oxazolo[4,5-b]pyridine.