Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].B([O-])([O-])[O-].C([N:26]([CH2:31][C:32]([OH:34])=[O:33])CC(O)=O)C[N:17](CC(O)=O)[CH2:18][C:19](O)=[O:20]>>[NH2:17][CH2:18][C:19]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:20].[CH3:2][O:34][C:32](=[O:33])[CH2:31][NH2:26]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [O-]B([O-])[O-]
Product: COC(=O)CN
Product: NCC(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
The synthesis reaction was carried out by incubating a reaction liquid containing 100 mM test amino acid methyl ester, 150 mM L-glutamine, 100 mM borate buffer (pH 9.0), 10 mM EDTA and enzyme (0.05 U/ml) for 3 hours at 25° C., followed by determination of the quantity of the produced peptides by HPLC. As a result, 52.19 mM glycyl-L-glutamine was produced in the case of using glycine methyl ester as the L-amino acid methyl ester, 5.94 mM L-valyl-L-glutamine was produced in the case of using L-valine methyl ester, 0.59 mM L-isoleucyl-L-glutamine was produced in the case of using L-isoleucyl-L-glutamine, 4.31 mM L-methionyl-L-glutamine was produced in the case of using L-methionine methyl ester, 3.67 mM L-phenylalanyl-L-glutamine was produced in the case of using L-phenylalanine methyl ester, 40.44 mM L-seryl-L-glutamine was produced in the case of using L-serine methyl ester, 3.85 mM L-threonyl-L-glutamine was produced in the case of using L-threonine methyl ester, 0.23 mM L-glutaminyl-L-glutamine was produced in the case of using L-glutamine methyl ester, 1.24 mM L-tyrosyl-L-glutamine was produced in the case of using L-tyrosine methyl ester, 6.52 mM L-arginyl-L-glutamine was produced in the case of using L-arginine methyl ester, and 8.22 mM L-aspartyl-α-L-glutamine was produced in the case of using L-aspartic acid-α-methyl ester. In addition, peptides composed of the corresponding amino acids and L-glutamines were also confirmed to be produced in the case of using L-leucine methyl ester, L-asparagine methyl ester, L-lysine methyl ester, L-aspartic acid-β-methyl ester, L-aspartic acid-α,β-dimethyl ester or L-glutamic acid-γ-methyl ester as the amino acid methyl ester (determination of quantity of these was not performed since no standard preparation was available).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:21][CH:22]=[O:23])[CH:6]=[C:7]([CH2:19]Br)[CH2:8][CH2:9][O:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[P:25]([O:34]C(C)C)([O:30][CH:31]([CH3:33])[CH3:32])[O:26][CH:27]([CH3:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:21][CH:22]=[O:23])[CH:6]=[C:7]([CH2:19][P:25]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])=[O:34])[CH2:8][CH2:9][O:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CCOC(=O)c1ccccc1)NC=O
Product: CCOC(=O)C(C=C(CCOC(=O)c1ccccc1)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
8.4 g (21 mmol) of 6-benzoyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 23 ml (84 mmol) of triisopropyl phosphite (90%) are heated to 80° C. and stirred under a pressure of ~130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 6-benzoyloxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brown oil.
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO.O>CC(C)=O>[O:1]=[C:2]([CH3:14])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1
Reactant: CCOC(=O)c1cc(CC(C)O)on1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(CC(C)=O)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Ethyl 5-(2-hydroxypropyl)isoxazole-3-carboxylate (1.5 g, 7.53 mmol) was dissolved in acetone (40 ml) and cooled to 0° C. Jones' reagent (5.90 ml, 7.91 mmol) was added dropwise and the reaction mixture was stirred at 0 C for 30 min. Then the reaction mixture was allowed to warm up to RT and stirred 18 h. Mixture of methanol (30 ml) and water (30 ml) was added and then the volatiles were evaporated. The residue was extracted with DCM, dried with Na2SO4 and evaporated to dryness to afford 1.38 g (93%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): 6, 1.32 (t, 3H), 2.22 (s, 3H), 4.29-4.44 (m, 2H), 4.22 (s, 2H), 6.67 (s, 1H).
Reaction SMILES: C(N([P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[Cl:9])C(C)C)(C)C.P(Cl)(Cl)[Cl:18]>C(#N)C>[CH:11]([N:10]([P:8]([Cl:18])[Cl:9])[CH:14]([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Reactant: ClP(Cl)Cl
Solvent: CC#N
Product: CC(C)N(C(C)C)P(Cl)Cl
Temperature: 25 °C
Yield: 81 %

Procedure:
Bis-(N,N-Diisopropylamino) chlorophosphine, 10 grams (37 mmols), was dissolved in 500 ml of anhydrous acetonitrile. Phosphorus trichloride, 5.16 grams (37 mmols), was added to the solution and the reaction was allowed to stir over-night at room temperature. The reaction was assayed for completion by 31 P NMR of an aliquot of the reaction using an external lock. Complete conversion of the starting material at δ 134 ppm to the product at δ 165 ppm was observed. The solvent was evaporated from the reaction mixture on a rotary evaporator and the resulting oil distilled under vacuum yielding 5.7 grams of product (81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][CH:16]=1)=[O:8].C[N:25]=[C:26]=[S:27].Cl.[CH3:29]N(C=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:17]([N:18]([CH3:29])[C:26]([NH2:25])=[S:27])(=[O:19])=[O:20])=[CH:15][CH:16]=1)=[O:8]
Reactant: CN(C)C=O
Reactant: CN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(N)(=O)=O)s1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)N(C)C(N)=S)s1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
375 mg of 2-[2-(5-chloro-2-methoxybenzoylamino)ethyl]-5-sulfamoylthiophene were dissolved in 3 ml of absolute DMF together with 415 mg of K2 CO3 and 90 mg of methyl isothiocyanate, and the mixture was then stirred for 3 h at 60° C. The cooled solution was introduced into 2N HCl and the resulting precipitate was filtered off with suction. The dried residue was chromatographed on silica gel using the eluent system ethyl acetate/toluene 1:1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([SH:39])[N:3]=1.Cl[CH2:41][C:42]1[N:43]=[C:44]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)[S:45][CH:46]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:35])([CH3:36])[CH3:34])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([S:39][CH2:41][C:42]2[N:43]=[C:44]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)[S:45][CH:46]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CC(C)(C)[Si](OCCOC1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOC1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (0.32 mmol) of the compound from Example 6A (isomer mixture) are dissolved in 2.4 ml of dry DMF, 95 mg (0.39 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 109 mg of sodium bicarbonate are added and the mixture is stirred at RT for 8 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5), the cis/trans isomers being separated in the process.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1>CCOC(C)=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([C:47](=[O:48])[C:46]3[CH:50]=[CH:51][C:43]([Cl:42])=[CH:44][CH:45]=3)[CH3:24])=[CH:19][CH:18]=2)=[N:5][C:6]=1[N:13]([CH3:14])[CH3:15]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CNc1ccc(Cc2nc(Cl)c(CC(=O)OC)c(N(C)C)n2)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl {4-chloro-6-(dimethylamino)-2-[4-(methylamino)benzyl]pyrimidin-5-yl}acetate (0.080 g, 0.23 mmol), 1-hydroxybenzotriazole (0.043 g, 0.32 mmol), triethylamine (0.11 mL, 0.80 mmol), and 4-chlorobenzoic acid (0.043 g, 0.28 mmol) was treated with WSCI (0.066 g, 0.34 mmol) at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was then added and the organic layer was washed sequentially with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product methyl[4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]benzyl}-6-(dimethylamino)pyrimidin-5-yl]acetate.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:70])/[C:13](=[N:27]\[O:28][C@@H:29]([CH2:46][O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54](=[NH:69])[NH:55][CH:56]4[CH2:61][CH2:60][N:59](C(OC(C)(C)C)=O)[CH2:58][CH2:57]4)=[CH:50][CH:49]=3)[C:30]([O:32]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:71])[N:8]2[S:72]([OH:75])(=[O:74])=[O:73])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:70])/[C:13](=[N:27]\[O:28][C@@H:29]([CH2:46][O:47][C:48]3[CH:49]=[CH:50][C:51]([C:54](=[NH:69])[NH:55][CH:56]4[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)=[CH:52][CH:53]=3)[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:71])[N:8]2[S:72]([OH:75])(=[O:74])=[O:73])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(NC1CCNCC1)c1ccc(OC[C@H](O/N=C(\C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)c2csc(N)n2)C(=O)O)cc1
Yield: 20 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((((S)-1-(benzhydryloxy)-3-(4-(N-(1-(tert-butoxycarbonyl)piperidin-4-yl)carbamimidoyl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (0.085 mmol), DCM (850 μL) and TFA (327 μL, 4.25 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (12 mg, 17%) as a white powder. LCMS: Rt=0.41 min, m/z=706.2 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=7.4 Hz, 1H) 9.40 (br s, 1H) 9.01 (br s, 1H) 8.53-8.71 (m, 1H) 8.41 (s, 1H) 7.92 (s, 1H) 7.67 (d, J=9.0 Hz, 2H) 7.21 (br s, 2H) 7.03 (d, J=7.8 Hz, 1H) 6.76 (s, 1H) 5.17-5.24 (m, 1H) 4.94 (d, J=3.9 Hz, 1H) 4.46-4.53 (m, 2H) 4.37-4.45 (m, 1H) 4.25-4.32 (m, 1H) 3.88 (br s, 1H) 3.39 (br s, 4H) 2.92 (t, J=11.5 Hz, 2H) 2.05-2.14 (m, 2H) 1.79 (d, J=11.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH3:37][O:38][NH2:39]>C1COCC1>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:25]([NH:39][O:38][CH3:37])=[O:27])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: CON
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CONC(=O)NC1(c2ccc(C(C)C)cc2OC)C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.61 mmol) in anhydrous THF (20 ml) was added triphosgene (0.528 g, 1.77 mmol) and stirred for 15 min. The reaction mixture was concentrated and was dissolved in anhydrous THF (20 ml) and was added O-methyl-hydroxylamine hydrochloride (0.28 g, 4.04 mmol) was stirred for 2 hrs at room temperature. The reaction mixture was oncentrated and was purified using silica gel column chromatography (1:1=ethylacetate:hexane) to afford the title compound (420 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[CH2:16](Br)[C:17]#[CH:18]>ClCCl>[CH2:18]([S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)[C:17]#[CH:16]
Reactant: S=c1ncc(Cl)c[nH]1
Reactant: C#CCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCSc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (5 mmol) and triethylamine (5 mmol) was stirred together in dichloromethane (40 ml) for 5 min before propargyl bromide (6 mmol) was added. The mixture was stirred at room temperature for 1 h before the solvent was evaporated. The residue was triturated with water (20 ml), and the solid recrystallized from methanol; yield 87%, m.p. 66° C. 1H NMR (CDCl3): δ2.16 (HC≡, t, J 2 Hz), 3.88 (CH2, d, J 2 Hz), 8.80 (H-4, H-6). IR (KBr): 3300 Cm-1 (HC≡).
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11].COC(OC)OC.[CH2:21](O)[CH2:22][OH:23]>>[CH3:3][O:4][C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:11])[O:23][CH2:22][CH2:21][O:12]1
Reactant: COC(=O)CCCCC(C)=O
Reactant: OCCO
Agent: N#N
Solvent: COC(OC)OC
Product: COC(=O)CCCCC1(C)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 6-oxo-heptanoic acid methyl ester (7.96 g, 50.32 mmol) in ethylene glycol (55.0 mL) was treated with trimethylorthoformate (10.65 mL, 110.14 mmol) followed by LiBF4 (963 mg, 10.06 mmol). The reaction mixture was heated at 95° C. for 14 h. The reaction mixture was cooled to rt and partitioned between EA and sat. aq. NaHCO3 The layers were separated and the aq. layer extracted with EA. The combined org. extracts were washed with sat. aq. NaHCO3, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (50:1→2:1 hept-EA) gave the title compound as a dark yellow oil. TLC: rf (3:1 hept-EA)=0.30.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([O:13][CH2:14][CH:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH2:6]([O:13][CH2:14][CH:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:16][N:17]([C:3](=[O:4])[CH2:2][Br:1])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC(CNCc1ccc(F)cc1)COCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1)CN(Cc1ccc(F)cc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Bromoacetyl bromide (588 μL, 6.75 mmol) was added slowly to a stirred solution of tert-butyl 2-(benzyloxy)-1-{[(4-fluorobenzyl)amino]-methyl}ethylcarbamate (2.39 g, 6.14 mmol) and triethylamine (941 μL, 6.75 mmol) in anhydrous THF (12 mL) at 0° C. under inert atmosphere. After stirring for 20 min, the reaction was poured into ice water and extracted twice with diethyl ether. The combined organic layers were washed twice with brine, dried over Na2SO4, and concentrated in vacuo. The resulting orange/brown oil was purified by silica gel chromatography (10% to 40% EtOAc/hexanes) to afford the title compound as a red-orange oil. 1H NMR (500 MHz, CDCl3) δ 7.40-7.21 (m, 6H), 7.16-6.96 (m, 3H), 5.20 (d, J=8.0 Hz, 1H), 5.01 (d, J=9.0 Hz, 1H), 4.75-4.66 (m, 1H), 4.59-4.48 (m, 2H), 4.39 (d, J=15.0 Hz, 1H), 4.04-3.92 (m, 2H), 3.87-3.28 (m, 4H), 1.43 (s, 9H). ES MS (M+1−100, for loss of BOC group)=409.4.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[N:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:27][C:17]([F:16])([F:26])[C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[N:22][CH:23]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C(F)(F)F)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C(F)(F)F)cn2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyrazine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O>>[CH:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:26]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: OB(O)c1ccc2ccccc2c1
Product: CC1(C)CC(Nc2nccc(-c3ccc4ccccc4c3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-naphthylboronic acid according to Method C (Example 178). Yield: 142 mg (70%)
Reaction SMILES: CC(N)C1C=CC=CC=1.C(OC([NH:20][CH:21]([PH:26](=[O:28])[OH:27])[C:22]([SH:25])([CH3:24])[CH3:23])=O)C1C=CC=CC=1>>[NH2:20][CH:21]([PH:26](=[O:27])[OH:28])[C:22]([SH:25])([CH3:24])[CH3:23]
Reactant: CC(C)(S)C(NC(=O)OCc1ccccc1)[PH](=O)O
Agent: CC(N)c1ccccc1
Product: CC(C)(S)C(N)[PH](=O)O

Procedure:
The (-)-α-methylbenzylamine salt of (+)-(1-benzyloxycarbonylamino-2-mercapto-2-methylpropyl)phosphinic acid [paragraph (b)] was treated in an analogous manner to that described in paragraph (d) to give (+)-(1-amino-2-mercapto-2-methylpropyl)phosphinic acid of melting point 215° C. (decomposition); [α]D25 =+4.0° (c=1.5% in water).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:12]([C:15]([OH:17])=[O:16])#[C:13]C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]1[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[N:7]=[N:6]1
Reactant: [N-]=[N+]=NCc1ccccc1F
Reactant: CC#CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)c1cn(Cc2ccccc2F)nn1
Temperature: 25 °C

Procedure:
The starting material may be prepared as follows: A solution of 50 g (0.33 mole) of o-fluorobenzyl azide, 23.1 g (0.33 mole) of propinecarboxylic acid and 400 ml of toluene is stirred for 24 hours at 70° C. After the reaction mixture has cooled to room temperature, the precipitated product is filtered with suction and washed first with toluene and then with diethyl ether, affording 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 151° C. (dec.).
Reaction SMILES: [CH2:1]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)[CH2:2][C:3]#[CH:4].CC1CCCO1.[CH3:29][C:30]1([CH3:37])[C:34]([CH3:36])([CH3:35])[O:33][BH:32][O:31]1>[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].C(N(CC)CC)C.ClCCl>[CH3:29][C:30]1([CH3:37])[C:34]([CH3:36])([CH3:35])[O:33][B:32](/[CH:4]=[CH:3]/[CH2:2][CH2:1][N:5]2[CH2:6][C:7]3([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]3)[CH2:20][CH2:21][CH2:22]2)[O:31]1
Reactant: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CC1(C)OBOC1(C)C
Agent: [Zr+2]
Agent: [Cl-]
Agent: c1cc[cH-]c1
Solvent: CC1CCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(CC/C=C/B3OC(C)(C)C(C)(C)O3)C2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a mixture of tert-butyl 8-but-3-ynyl-3,8-diazaspiro[5.5]undecane-3-carboxylate (2.41 moles; 750.86 g), zirconocene chloride (240.73 mmoles; 62.08 g), triethylamine (240.73 mmoles; 33.55 mL; 24.36 g), and 2-methyltetrahydrofuran (738 mL), add 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.53 moles; 323.49 g). Heat the mixture to 60° C. and stir overnight. Cool the mixture and pass through a plug of silica eluting with dichloromethane. Concentrate the filtrate under reduced pressure to give the final title compound, tert-butyl 4-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (1072 g, about 94% purity, 96% yield).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[C:18]2CC3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.BrCC.Cl>C1COCC1.O>[CH2:3]([CH:2]1[C:1]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:9]1=[CH:8][CH:7]=[CH:6][CH:18]=2)[CH3:4]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC1c2ccccc2-c2ccccc21
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium (79.52 cm3, 0.2168 mol, 2.5M in hexane) was added slowly to a solution of fluorene (30.00 g, 0.1807 mol) in THF (300 cm3) at −70° C. The solution was stirred for 1 hour at −75° C. and 1-bromoethane (17.59 cm3, 0.2349 mol) was added slowly. The solution was allowed to warm to room temperature and then stirred overnight. Dilute hydrochloric acid (200 ml, 20%) was added to the reaction mixture and stirred for a further 10 minutes. Water (250 cm3) was added and the product extracted into diethyl ether (3×300 cm3). The combined organic extracts were dried (MgSO4) and the solvent removed on a rotary evaporator. The resulting oil was purified by distillation to yield a pale yellow oil (25.00 g, 71%, b.pt.—150° C. @ 1 mbar Hg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c[nH]c23)cc1F

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.