Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23][N:24]1[C:28]([CH2:29]Cl)=[N:27][CH:26]=[N:25]1.O>CN(C=O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([O:20][CH2:29][C:28]4[N:24]([CH3:23])[N:25]=[CH:26][N:27]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=[C:10]3[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ncnc1CCl
Reactant: COC(=O)c1cc2nnn(-c3ccccc3)c2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nnn(-c3ccccc3)c2nc1OCc1ncnn1C
Temperature: 25 °C
Yield: 26.6 %

Procedure:
A mixture of 3-phenyl-5-oxo-6-methoxycarbonyl-4H-1,2,3-triazolo[4,5-b]pyridine (0.10 g, 0.37 mmol) and sodium hydride (55% in oil, 0.018 g, 0.40 mmol) in dry DMF (2 ml) was stirred at room temperature under nitrogen until all effervescence had ceased. A solution of 2-methyl-3-chloromethyl-1,2,4-triazole (0.065 g, 0.50 mmol) in dry DMF (0.5 ml) was added and the mixture was stirred for 4 days. Water was added and the aqueous solution was extracted with dichloromethane. The extracts were dried (Na2SO4), filtered and concentrated. Preparative thin-layer chromatography on silica gel, eluting with 5% methanol-dichloromethane, gave the alkylation product which was washed with hot ethyl acetate to give 3-phenyl-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-methoxycarbonyl-1,2,3-triazolo[4,5-b]pyridine (0.036 g, 27%) as an off-white, crystalline solid, m.p. 188-190° C. Found: C, 55.97; H, 4.17; N, 26.93. C17H15N7O3 requires C, 55.89; H, 4.14; N, 26.84%. δH (360 MHz; CDCl3) 3.96 (3H, s), 4.08 (3H, s), 5.76 (2H, s), 7.50 (1H, t, J=7.5), 7.63 (2H, dd, J=7.5 and 7.5), 7.89 (1H, s), 8.23 (2H, d, J=7.5) and 8.96 (1H, s); m/z (ES+) 366 (M+H+).
Reaction SMILES: OC(CC(O)CCCCCCCC)C(C1C=CC=CC=1)=O.C(Br)CCCCCCC.C(=O)([O-])[O-].[K+].[K+].Cl.NO.C([O-])(=O)C.[K+].[CH2:45]([O:55][CH:56]([CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:57][CH:58]([OH:68])[C:59](=[N:66][OH:67])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]CC>CC(C)=O.C(O)C.CCCCCCC>[CH2:45]([O:55][CH:56]([CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:57][CH:58]([OH:68])[C:59](=[N:66][OH:67])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCCCOC(CCCCCCCC)CC(O)C(=NO)c1ccccc1
Agent: CC(=O)[O-]
Agent: CCCCCCCCC(O)CC(O)C(=O)c1ccccc1
Agent: Cl
Solvent: CCCCCCC
Solvent: CCO
Solvent: CC(C)=O
Product: CCCCCCCCOC(CCCCCCCC)CC(O)C(=NO)c1ccccc1

Procedure:
29.2 g (0.1 Mol) of 2,4-dihydroxylaurophenone together with 28 g (0.145 Mol) of n-octylbromide and 14 g of anhydrous potassium carbonate in 150 ml of dried acetone, as in Example 11, are converted to ketone, 56° C. to 57° C. in flash point (ethanol), and, subsequently, with hydroxylamine hydrochloride in the presence of potassium acetate in ethanolic solution, converted to oxime, between 60° C. and 63° C. in flash point (ethanol, n-heptane). The following example was obtained in the same way: 4-decyloxy-2-hydroxy-laurophenone-oxime, between 64° C. and 69° C. in flash point (n-heptane, ethanol).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][CH2:9][C:10](=[CH2:13])[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:27][CH2:11][C:10]([CH2:9][O:8][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:13]
Reactant: C=C(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(CBr)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.2 %

Procedure:
To a solution of 10 (2.56 g; 7.74 mmol) in CH2Cl2 (75 ml), CBr4 (3.63 g; 10.83 mmol) and triphenylphosphine (2.47 g; 9.31 mmol) were added respectively at 0° C. and the reaction was stirred at room temperature for 40 min. Cooled to 0° C., ethyl acetate (100 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was separated and washed by saturated aqueous NaCl, and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using CH2Cl2-hexane (1:5) as the eluent to afford 11 as white solid (3.02 g; 92% yield): 1H NMR (400 MHz, CDCl3) δ 7.42-7.48 (m, 6H, six of ArH), 7.27-7.33 (m, 6H, six of ArH), 7.20-7.27 (m, 3H, three of ArH), 5.37 (s, 1H, one of C═CH2), 5.31 (s, 1H, one of C═CH2), 4.01 (s, 2H, CH2Br), 3.75 (s, 2H, Ph2COCH2); 13C NMR (100 MHz, CDCl3) δ 143.6, 142.6, 128.4, 127.6, 126.9, 115.8, 86.9, 64.2, 33.5, (9).
Reaction SMILES: C(OC(CCCCC([O:17][C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:20][C:19]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O)=O)C1C=CC=CC=1.C1COCC1>[OH-].[OH-].[Pd+2].CCO>[OH:17][C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:20][C:19]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(CCCCC(=O)Oc1c(-c2ccccc2)oc2ccccc2c1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1c(O)c(-c2ccccc2)oc2ccccc12
Yield: 126.5 %

Procedure:
A mixture of 3-(benzyloxycarbonylbutylcarbonyloxy)flavone (312 mg, 0.7 mmol) and Pd(OH)2 (49.4 mg) in 9:1 THF:EtOH+0.05% acetic acid (15 mL) was treated with H2 for 5 h. The crude product was filtered (Celite), the filtrate was concentrated and the residue was purified by flash chromatography (10-25% EtOAc in toluene+1% acetic acid) to give the hemiadipate as a light yellow solid (0.211 g, 89%). A small portion was crystallized from EtOAc/petroleum spirits, mp=118-121° C.; 1H NMR (399.7 MHz, CDCl3) δ 1.66-1.83 (m, 4H, CH2CH2CO2); 2.38 (t, J=6.8 Hz, 2H, CH2CO2); 2.63 (t, J=6.8 Hz, 2H, CH2CO2); 7.42 (dd, 1H, J5,6=8.0 Hz, J6,7=8.0 Hz, H6); 7.47-7.53 (m, 3H, H3′,4′, 5′); 7.54 (d, 1H, J7,8=8.4 Hz, H8); 7.70 (ddd, 1H, J5,7=1.6 Hz, J6,7=8.0 Hz, J7,8=8.4 Hz, H7); 7.81-7.86 (m, 2H, H2′, 6′); 8.24 (dd, 1H, J5,6=8.0 Hz, J5,7=1.6 Hz, H5). 13C NMR (100.5 MHz, CDCl3) δ 25.01, 25.20 (2C, CO2CH2CH2); 34.57 (2C, CO2CH2); 119.20, 124.66, 126.33, 127.21, 129.41, 129.76, 131.04, 132.40, 134.70, 135.10, 156.74, 157.60 (14C, Ar); 171.52, 173.38, 179.36 (3C, C═O). Anal. Found: C, 68.89; H, 4.91; C21H18O6 requires C, 68.85; H, 4.95%. HRMS (ESI+) m/z 389.1000, C21H18NaO6 [M+Na]+ requires 389.1001].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][CH:12]([CH:20](O)[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:42](C(OCC)=O)=NC(OCC)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[NH2:42][CH:20]([CH3:21])[CH:12]([CH2:11][C:9]1[O:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)O)o1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)N)o1
Temperature: 25 °C

Procedure:
To 1.65 g of tert-butyl (2RS,3SR)-2-{5-(ethoxycarbonyl)-2-furylmethyl}-3-hydroxybutanoate in 40 ml of tetrahydrofuran, 2.32 g of triphenylphosphine, 1.40 ml of diethyl azodicarboxylate and 2.43 g of diphenylphosphoryl azide were added successively under cooling with ice under stirring, and the resulting reaction solution was stirred at room temperature for 18 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [hexane/ethyl acetate=12/1→3/1]. The resulting azide was refluxed together with 2.33 g of triphenylphosphine in 33 ml of 10% hydrous tetrahydrofuran under heating for 3 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=1/1→ethyl acetate/methanol=10/1] to give 686 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C@@H:26]([C:31](=[O:33])[NH2:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:15]([C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:31]([NH2:32])=[O:33])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 92, 2.6 grams, 5.2 mmol) in CH2Cl2 (25 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at rt for 1 h and then was concentrated to give a white solid (1.6 grams, 84%). MS (ESI), (M+H)+ 402.15; 1H NMR (DMSO-d6, 500 MHz), δ 7-87 (d, 2H, J=8.5), 7.66 (d, 2H, J=8.6), 7.41 (s, 1H), 7.04 (s, 1H), 4.17 (t, 1H, J=7.3), 3.40-3.50 (m, 1H), 3.20-3.25 (m, 1H), 3.03-3.10 (m, 1H), 2.65-2.80 (m, 2H), 1.85-2.00 (m, 1H), 1.20-1.85 (m, 2H), 1.45-1.60 (m, 1H), 1.30-1.40 (m, 1H), 1.10-1.30 (m, 4H), 0.75-0.90 (m, 1H), 0.82 (d, 3H, J=7.3), 0.80 (d, 3H, J=7.0).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1
Temperature: 100 °C
Yield: 51.7 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (21.0 mg, 0.08 mmol) in DMF (1 mL) was added Pd(PPh3)2Cl2 (5 mg, 0.007 mmol), 2-chlorophenyl boronic acid (15 mg, 0.096 mmol), and Na2-CO3 (21.0 mg in 0.5 mL water). The reaction mixture was heated at an oil bath temperature of 100° C. for about 12 hours. The mixture was cooled to RT and water (20 mL) was added. The aqueous layer was washed with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (30% EtOAc/hexanes) to give the title compound as a brown solid (15 mg, 55%). 1H-NMR (300 MHz, CDCl3) δ 9.14 (d, 1H, J=9.2 Hz), 8.52 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 7.74-7.71 (m, 1H), 7.56-7.52 (m, 2H), 7.46-7.42 (m, 2H), 5.61 (bs, 1H), 2.88 (m, 1H), 0.89 (m, 2H), 0.66 (m, 2H); MS (ESI) (M+H)+ 363.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][SH:10].II>C(O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][S:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: SCCCCCCCCBr
Agent: II
Solvent: CCO
Product: BrCCCCCCCCSSCCCCCCCCBr
Yield: 80 %

Procedure:
A solution of 8-bromo-1-octanethiol (0.7 g, 3.1 mmol) in 20 mL ethanol was titrated with a 65 mM solution of iodine in ethanol (˜23 mL) until a light yellow color persisted (Bain, C. D. et al., Langmuir, 5:723-727. (1989). The ethanol was removed at 40° C. by rotary evaporation, The dark-maroon colored oil was dissolved in 40 mL ether and extracted with distilled water (4×50 mL). The ethereal layer was dried over anhydrous sodium sulfate and the solvent removed under vacuum at 30° C. Flash chromatography (80:20 hexanes:methylene chloride) afforded di(8-bromooctyl)disulfide, a yellowish oil, in 80% yield, 1H NMR (CDCl3) δ 3.41 (t, 4H), 2.68 (t, 4H), 1.86 (m, 4H), 1.67 4 m H), 1.20-1.50 (m, 16H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][CH:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[C:9](=[O:19])[CH2:8]1.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15]([CH:7]([CH3:6])[CH2:8][C:9]2=[O:19])=[CH:14][CH:13]=1
Reactant: CC1CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CC1CC(=O)c2cc(N)ccc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
As presented in the following reaction formula, tin chloride (SnCl2; 26.5 g, 0.117 mol) was added at room temperature to a mixture of 3-methyl-6-nitro-2,3-dihydro-1-H-inden-1-one (5.0 g, 0.026 mol), hydrochloric acid (HCl; 90 mL) and water (H2O; 30 mL), and the reaction mixture was stirred at 40° C. for 0.5 hours. After the completion of reaction, the mixture was treated with saturated, anhydrous potassium carbonate (K2CO3; 300 mL) and then extracted three times with 100 mL of dichloromethane. The combined organic phase was concentrated to give 6-amino-3-methyl-2,3-dihydro-1-H-inden-1-one (3.8 g, yield: 92%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]3[C:30](=[O:33])[CH2:31][CH2:32][C:28]=3[N:27]=[C:26]2[CH:34]([CH3:36])[CH3:35])=[CH:20][CH:19]=1>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]2[C:29]3[C:30]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])([OH:33])[CH2:31][CH2:32][C:28]=3[N:27]=[C:26]2[CH:34]([CH3:36])[CH3:35])=[CH:22][CH:23]=1
Reactant: CCOC(C)=O
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl acetate (0.234 mL) in dry THF (1 ml) was added dropwise to a stirred solution of LiHMDS, 1M in THF (2.389 mL) cooled to −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 30 minutes. Then, Intermediate 18 (230 mg) in THF (2 ml) was added dropwise. The RM was stirred at −78° C. under nitrogen for 1 hour.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:47]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)[CH2:48]1>CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:47]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)[CH2:48]1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnoc1Cc1ccccc1
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1Cc1ccccc1)N1CCC(c2cccnc2)C1
Reaction time: 2 h
Yield: 18 %

Procedure:
A solution of 5-benzylisoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 3-pyrrolidin-3-yl-pyridine (7 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1477.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])=O.[CH3:9][S:10][C:11]1[N:20]=[C:19]([N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)N=CC)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.Cl.O>CCOCC>[CH3:32][O:31][C:28]1[CH:27]=[C:26]2[C:25](=[CH:30][CH:29]=1)[N:21]([C:19]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([S:10][CH3:9])[N:20]=1)[C:2]([CH3:1])=[C:4]2[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC=NN(c1ccc(OC)cc1)c1nc(SC)nc2ccccc12
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1nc(SC)nc2ccccc12

Procedure:
A mixture of laevulinic acid (7 g.), acetaldehyde N1 -(2-methylthioquinazolin-4-yl)-p-methoxyphenylhydrazone (3.5 g.) and a saturated solution of hydrogen chloride in ether (2 ml.) was heated at 95° - 100° C. for 22 hours. The mixture was poured into water (300 ml.), and the precipitated brown solid was collected by filtration and dissolved in chloroform (100 ml.). The solution was filtered and the filtrate was extracted with 2 N- ammonia solution (4 × 50 ml.). The extracts were combined and acidified to pH3 with glacial acetic acid. The mixture was filtered, and the solid crystallised from methanol to give 5-methoxy-2-methyl-1-(2-methylthioquinazolin-4-yl)indol-3-ylacetic acid, as a pale yellow crystalline solid, m.p. 175°-178° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9](OCC)=[O:10])=[C:4]([CH3:14])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:10][CH2:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([CH3:1])=[N:3][C:4]=1[CH3:14]
Reactant: CCOC(=O)c1c(C)nc(C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CO)c(C)n1

Procedure:
(a) Ethyl 2,4,6-trimethylpyrimidine-5-carboxylate [11.0 g; prepared according to Urban & Shnider, Helv. Chim Acta, 41, 1806 (1958)] was stirred with a slight excess of lithium aluminium hydride in dry tetrahydrofuran (100 ml) at room temperature for 2 hr. The solvent was evaporated and the residue was shaken with a little water. The dried (MgSO4) ethyl acetate extract was evaporated and the residue was purified by column chromotography over alumina with ethyl acetate elution to give 5-(hydroxymethyl)-2,4,6-trimethylpyrimidine as white crystals, mp 68° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(Cl)nn2)CC1

Procedure:
2.0 g (13.4 mmol) of 3,6-dichloropyridazine, 2.3 g (14.8 mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine were stirred in 20 ml of DMF at 50° C. for 4 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 4-Fluoro-phenylamine to produce 4-Chloro-N-(4-fluoro-phenyl)-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: Cl.C([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])C1C=CC=CC=1.C([O:32][CH2:33][CH3:34])(=O)C>CN(C)C=O.C(N(CC)CC)C>[NH:18]1[C:22](=[O:26])[CH2:23][CH2:25][C@H:34]1[C:33]([NH:24][C@H:23]([C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([OH:9])=[O:28])=[O:27])=[O:26])[CH3:25])=[O:32]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
L-alanyl-L-prolyl-L-proline benzylester hydrochloride (2.46 g, 6 m mole) was dissolved in dimethylformamide (10 ml, and triethylamine (0.84 ml, 6m mole) was added thereto under cooling to neutralize it and then benzyloxycarbonyl-L-pyroglutamic acid N-hydroxysuccinimide ester (2.38 g, 6.6 m mole) was added thereto. The mixture was stirred for 2 days while the solution had been adjusted to a pH of about 7 with triethylamine and then ethyl acetate (150 ml) was added thereto. The solution was washed with 1N hydrochloric acid, 5% aqueous sodium bicarbonate and water in order. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. To the thus obtained residue, n-hexane was added to form a powder. This powder was purified by column chromatography. (Silica gel, developing solvent; chloroform:ethanol:ethyl acetate=5:1:5). The fractions of the main ingredient were collected together and then concentrated. To the residue, n-hexane was added to precipitate the powder. They were dissolved in methanol (50 ml) and then hydrogen gas passed through the solution in the presence of palladium-carbon as a catalyst for 4 hours. The catalyst was separated by filtration and the solvent was distilled off. The thus obtained residue was recrystallized with methanol-ether to give L-pyroglutamyl-L-alanyl-L-prolyl-L-proline (880 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH3:47])=[CH:45][N:44]=[C:43]([CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH3:47])=[CH:45][N:44]=[C:43]([CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)cn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)c(C)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K17) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (300 mg, 64%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CCO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1cccc(-c2nccs2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(-c2nccs2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl 6-(thiazol-2-yl)picolinate (230 mg; 1.04 mmol) in anh. EtOH (3 ml) was treated with NaBH4 (197 mg; 5.22 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 17 h. After concentration to dryness under reduced pressure, the resulting residue was treated with water, and extracted with DCM. The organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded (6-(thiazol-2-yl)pyridin-2-yl)methanol as an orange solid. LC-MS (conditions A): tR=0.45 min.; [M+H]+: 193.05 g/mol.