Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:14]([O:16]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:7])([CH3:4])[CH3:3].[NH2:37][C@H:38]([C:41]([NH:43][C@H:44]([C:50]([NH:52][C@H:53]([C:57]([N:59]1[CH2:100][CH2:99][CH2:98][C@H:60]1[C:61]([NH:63][C@H:64]([C:69]([NH:71][C@H:72]([C:76]([NH:78][C@H:79]([C:83]([NH:85][C@H:86]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][CH:88]([CH3:90])[CH3:89])=[O:84])[C@@H:80]([CH3:82])[OH:81])=[O:77])[CH:73]([CH3:75])[CH3:74])=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])=[O:62])=[O:58])[C@@H:54]([CH3:56])[OH:55])=[O:51])[CH2:45][CH2:46][C:47](=[O:49])[NH2:48])=[O:42])[CH2:39][OH:40]>CN(C=O)C>[NH:26]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C@H:13]([C:14]([NH:37][C@H:38]([C:41]([NH:43][C@H:44]([C:50]([NH:52][C@H:53]([C:57]([N:59]1[CH2:100][CH2:99][CH2:98][C@H:60]1[C:61]([NH:63][C@H:64]([C:69]([NH:71][C@H:72]([C:76]([NH:78][C@H:79]([C:83]([NH:85][C@H:86]([C:91]([O:93][C:94]([CH3:96])([CH3:95])[CH3:97])=[O:92])[CH2:87][CH:88]([CH3:89])[CH3:90])=[O:84])[C@@H:80]([CH3:82])[OH:81])=[O:77])[CH:73]([CH3:74])[CH3:75])=[O:70])[CH2:65][CH:66]([CH3:67])[CH3:68])=[O:62])=[O:58])[C@@H:54]([CH3:56])[OH:55])=[O:51])[CH2:45][CH2:46][C:47](=[O:49])[NH2:48])=[O:42])[CH2:39][OH:40])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CO)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@@H](C)O)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@@H](C)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.35 g Z-Lys(Boc)-ONp (2.7 mmol) and 2.42 g (2.64 mmol) H-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OtBu (F. 1) are dissolved in 35 ml DMF. After stirring at room temperature for 18 hours the reaction mixture is evaporated to dryness.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:13][N:12]([C:14]3[N:15]4[C:19]([N:20]=[C:21]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=35)=[CH:18][CH:17]=[N:16]4)[CH2:11]2)=[O:9])[CH2:4]1)#[CH:2].C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:11][N:12]([C:14]3[N:15]4[C:19]([N:20]=[C:21]5[CH2:27][CH2:26][N:25]([CH3:30])[CH2:24][CH2:23][C:22]=35)=[CH:18][CH:17]=[N:16]4)[CH2:13]2)=[O:9])[CH2:4]1)#[CH:2]
Reactant: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCN(C)CC4)C2)C1
Reaction time: 8 h

Procedure:
To 50 mg (0.14 mmol) of (3-Ethynyl-pyrrolidin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone in 2 mL of THF and 1 mL of puffer solution (pH 5) was added 11.3 μL (0.15 mmol) of formaldehyde (37% in water) and 35 mg (0.17 mmol) of sodium triacetoxyborohydride. Stirring was continued overnight, the reaction mixture diluted with 1 mL of water, filtered and purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].[CH3:27][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([O:21][CH3:27])[C:8]=2[C:7]1=[O:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (208 g, 0.55 mol) in a mixture of dichloromethane (830 mL) and methanol (410 mL) at 10° C., a solution of (trimethyl-silyl)diazomethane (600 mL, 1.2 mol; 2M) in hexanes was added over a period of 1 hour with the reaction temperature maintained below 15° C. The reaction mixture (unstirred) was allowed to stand at 10° C. overnight, and then at 20° C. for additional 4 hours. The reaction mixture was cooled back to 10° C. and quenched with acetic acid (˜75 mL). The product mixture was concentrated under vacuum and the residue recrystallized from boiling methyl tert-butyl ether and heptane. The solid recrystallized was collected by filtration, washed with a mixture of methyl tert-butyl ether and heptane (1:1, v/v), and air dried to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22].[Cl-].[Na+]>CCOCC>[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1)[OH:22]
Reactant: COC1CCCCC1=O
Reactant: Brc1cncc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COC1CCCCC1(O)c1cncc(Br)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A solution of 3,5-dibromopyridine (30.45 g, 0.13 mol) in anhydrous ether (400 ml) was added dropwise to a stirred solution of n-butyllithium (1.6M in hexane, 88.3 ml) and anhydrous ether (40 ml) over 0.5 hours at -70° C. The pale yellow suspension was stirred at -70° C. for 1 hour, and a solution of 2-methoxycyclohexanone (16.5 g, 0.13 mol) in anhydrous ether (60 ml) was added dropwise. The reaction mixture was stirred at -70° C. for 2 hours and allowed to warm to room temperature. The reaction mixture was poured onto ice/water (11); sodium chloride (50 g) was added and the ether layer separated. The aqueous layer was extracted with ether (2×200ml). The combined ether layers were extracted with 2N hydrochloric acid (2×250 ml). The acid extract was washed with ether (200 ml), basified with 4N aqueous sodium hydroxide solution at room temperature (pH11), sodium chloride (50 g) was added and the precipitated oil was extracted with ether (2×400 ml). The combined extracts were dried over magnesium sulphate and concentrated in vacuo to give 2-methoxy-1-(5-bromopyrid-3-yl)cyclohexanol (30.6 g). The cyclohexanol was added in small portions to stirred sulphuric acid (114 ml). The reaction exothermed to 50° C., but no external cooling was applied. When the addition was completed after 20 minutes the red/brown solution was stirred at room temperature for 4 hours. The reaction mixture was poured onto ice/water (11) and basified to pH8 with sodium carbonate. The product was extracted with ether (2×300 ml). The ether extracts were combined, dried with magnesium sulphate and evaporated to give a pale orange oil. The oil was purified by flash chromatography over silica gel eluting with hexane/ethyl acetate 6.4 to give 2-(5-bromopyrid-3-yl)cyclohexanone (15.1 g) m.p. 67°-9° C. NMR(CDCl3). 1.6-2.1(m,4H); 2.1-2.4(m,2H); 2.4-2.6 (m,2H); 3.6-3.66(dd,1H); 7.6(s,1H); 8.18(s,1H); 8.38(s,1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)n1
Temperature: 40 °C
Yield: 96.5 %

Procedure:
A mixture of 2-chloro-6-methoxy-3-nitropyridine (5.9 g; commercial), N-(tert-butoxycarbonyl)-1,3-propanediamine (4.48 g; commercial) and K2CO3 (3.55 g) in MeCN (90 mL) and DMF (25 mL) was heated at 40° C. for 30 min. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was taken up in EA, sequentially washed with water and brine and evaporated under reduced pressure, affording 8.1 g (96% yield) of a crude yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH:6]=[O:7].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:6][OH:7]
Reactant: CCCOc1c(OC)cc(C=O)cc1SC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1c(OC)cc(CO)cc1SC
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
15.5 g (0.065 mole) of 3-methoxy-5-methylthio-4-propoxybenzaldehyde in 300 ml of methanol was cooled in ice bath. 1 g (0.026 mole) of sodium borohydride was added in 3 portions to the above solution. The mixture was stirred for 10 minutes in ice bath. MeOH was removed, and the residue was purified by flash column chromatography to afford 15.45 g (95% yield) of 3-methoxy-5-methylthio-4-propoxybenzyl alcohol as a light yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11].[NH2:22][CH2:23][C:24]([N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][N:33]([C:24]([CH2:23][NH:22][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:14][CH:15]=2)([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH2:34][CH2:35]1)=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: CC#CCOc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(CN)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
2 ml (14.2 mmol) of triethylamine then 2.9 g (14.2 mmol) of 4-but-2-ynyloxybenzoyl chloride diluted in 30 ml of tetrahydrofuran are added to a solution of 4 g (11.6 mmol) of dimethyl 2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate (prepared as described in example 1-3) in 40 ml of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 1 h, then hydrolysed and the product is extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. The crude product obtained is purified by chromatography over silica gel eluted with a 5/5 heptane/ethyl acetate mixture. 4.2 g (70%) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzoylamino)methyl]malonate are obtained in the form of a beige solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]3(C#N)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[C:13]2[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=2[NH:11]1.[NH4+].[Cl-].O>C1COCC1>[C:1]1([C:21]2([N:18]3[CH2:19][CH2:20][CH:15]([N:14]4[C:13]5[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=5[NH:11][C:10]4=[O:9])[CH2:16][CH2:17]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CCCCC1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.1 %

Procedure:
To a solution of phenylmagnesium bromide (3M solution in diethyl ether, 0.75 ml, 2.25 mmol) in THF (1 ml) was added a suspension of 1-[4-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidino]-1-cyclohexanecarbonitrile (230 mg, 0.71 mmol) in THF (2 ml) at 0° C. Then the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture was added sat.NH4Cl aq. solution (1 ml) followed by addition of water (5 ml). The white precipitate appeared was collected by filtration, washed faith water and CH2Cl2, and dried to give 75 mg (28.1%) of title compound. The filtrate of CH2Cl2 wash was concentrated to give 171 mg of title compound and the starting material mixture, which was purified by column chromatography (silica gel:30 g, CH2Cl2/MeOH:50/1 to 15/1) to give 60 mg(22.5%) of title compound as white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH:3]1[CH2:6][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([SH:14])[CH2:11][N:10]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[O:8])[CH2:4]1.C(N(C(C)C)CC)(C)C.C1(P(O[C:53]2[C@H:54]([CH3:77])[C@@H:55]3[C@@H:72]([C@H:73]([OH:75])[CH3:74])[C:71](=[O:76])[N:56]3[C:57]=2[C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=2)=[O:59])(C2C=CC=CC=2)=O)C=CC=CC=1>C(#N)C>[CH3:1][N:2]([CH3:28])[CH:3]1[CH2:4][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14][C:53]3[C@H:54]([CH3:77])[C@@H:55]4[C@@H:72]([C@H:73]([OH:75])[CH3:74])[C:71](=[O:76])[N:56]4[C:57]=3[C:58]([O:60][CH2:61][C:62]3[CH:63]=[CH:64][C:65]([N+:68]([O-:70])=[O:69])=[CH:66][CH:67]=3)=[O:59])[CH2:11][N:10]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[O:8])[CH2:6]1
Reactant: CN(C)C1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(N(C)C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A solution of 0.98 g of (2S,4S)-2-(3-dimethylaminoazetidin-1-ylcarbonyl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 121) dissolved in 20 ml of dry acetonitrile and 0.418 ml of diisopropylethylamine were added dropwise at the same time, whilst ice-cooling, to a solution of 1.43 g of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) in 25 ml of dry acetonitrile. The mixture was then stirred at the same temperature for 2 hours, after which it was left to stand in a refrigerator overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was diluted with ethyl acetate; the resulting mixture was washed with water and then with an aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography and the fractions obtained by elution with a 75:25 by volume mixture of ethyl acetate and methanol were combined and concentrated by evaporation under reduced pressure, to obtain 1.16 g of the title compound, as a powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[C:25]([F:24])=[CH:30][CH:29]=[CH:28][C:27]=2[F:31])=[N:3][CH:4]=1
Reactant: Oc1c(F)cccc1F
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2c(F)cccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 48 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,6-difluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 8.05–7.94 (3H, m), 7.48–7.42 (2H, m), 7.33–7.23 (1H, m), 7.12–7.02 (2H, m), 5.45–5.33 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 447 (M+H)+, 445 (M−H)−.
Reaction SMILES: [C:1]1([B:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[B:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:23])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][CH:31]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32]O>C(#N)C>[C:1]1([B:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[B:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:23][CH2:32][CH:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH2:30])[O:8][CH2:32][CH:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH2:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)c1ccccc1Oc1ccccc1B(O)c1ccccc1
Reactant: NC(CO)Cc1ccccc1
Solvent: CC#N
Product: NC(COB(c1ccccc1)c1ccccc1Oc1ccccc1B(OCC(N)Cc1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
The entitled compound (73 mg) was obtained by allowing 77 mg of bis(4,4′-(phenylhydroxyboryl)phenyl) ether and 75 mg of 2-amino-3-phenylpropanol to act in 1 mL of acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[Cl:39])[C@@H:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[C@@:13]3([CH3:40])[O:14][CH3:15])[C:6]=2[N:7]=1.Cl.[O:43]1CCOCC1>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:43])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[Cl:39])[C@@H:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[C@@:13]3([CH3:40])[O:14][CH3:15])[C:6]=2[N:7]=1
Reactant: C1COCCO1
Reactant: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(C)c2c(Cl)nc(N)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(C)c2c(=O)[nH]c(N)nc21
Temperature: 135 °C

Procedure:
A mixture of the product from Step B (200 mg, 0.3 mmol) in 1,4-dioxane (15 mL) and aqueous NaOH (2N, 15 mL) in a pressure bottle was heated overnight at 135° C. The mixture was then cooled to 0° C., neutralized with 2N aqueous HCl and evaporated to dryness. The crude product was suspended in MeOH, filtered, and the solid thoroughly washed with MeOH. The combined filtrate was concentrated, and the residue purified on a silica gel column (5×5 cm) using CH2Cl2/MeOH (40/1, 30/1 and 20/1) as eluent to give the desired compound (150 mg) as a colorless foam.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45](Cl)=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:45]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=1)=[O:46])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: O=C(Cl)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)c1ccccn1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and pyridine-2-carbonyl chloride as the starting materials in 35% yield. LCMS for C24H20ClN6O (M+H)+: m/z=443.2. 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.51 (s, 2H), 8.72 (m, 1H), 8.16 (s, 1H), 8.13 (m, 1H), 8.05 (m, 1H), 7.92 (m, 1H), 7.75 (m, 1H), 7.66 (m, 1H), 7.49 (m, 1H), 7.45 (m, 1H), 7.11 (dd, 1H), 6.89 (m, 1H), 6.84 (m, 1H), 2.89 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:22]([Cu])#[N:23].[OH-].[NH4+].Cl>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:22]#[N:23])[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c1ccccc1n2C
Temperature: 120 °C
Yield: 38.8 %

Procedure:
A mixture of 1-bromo-4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (256 mg), CuCN (132 mg) in NMP (N-methyl 2-pyrrolidinone, 2 mL) was heated at 120° C. for 67 min. The mixture was poured into a stirring mixture of EtOAc and diluted ammonium hydroxide solution, then acidified with conc. HCl; then the organic phase was separated from aqueous and washed with sat. NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated; the residue was purified with column to give the desired product (84 mg). The title compound, ESI MS (m/z): 296 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][N:18]([CH3:33])[C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]([CH3:33])[CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CN(C)c1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].CCCCCC.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:22](=[O:24])[CH3:23])[S:5][C:6]=1[CH3:7]
Reactant: CON(C)C(C)=O
Reactant: Cc1ncsc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1nc(C)c(C)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Commercially available 4,5-dimethyl-1,3-thiazole (453 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution which was then cooled to −78° C. A hexane solution (1.56 M) (2.8 ml) of n-butyllithium was slowly added over a period of 10 min, and the mixture was stirred at −78° C. for 2 hr. N-Methoxy-N-methylacetamide (454 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution which was then slowly added over a period of 10 min, and the mixture was stirred at −78° C. for 2 hr. The cooling bath was removed, an aqueous saturated ammonium chloride solution (10 ml) was added, and the mixture was stirred for 30 min. Further, water (10 ml) was added, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate. The solvent was removed, and the residue was purified by chromatography on silica gel using hexane/ethyl acetate for development to give the title compound (609 mg, 98%).