Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[CH:59][C:58]=1[NH:67][C:68](=[O:86])[CH2:69][N:70](C(OC(C)(C)C)=O)[CH2:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[CH:59][C:58]=1[NH:67][C:68](=[O:86])[CH2:69][N:70]([C:21](=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)CC(=O)Nc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCc1ccccc1)CC(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution (0° C.) of Nα,Nδ-bis-Boc-D-ornithine (130 mg, 0.39 mmol), diisopropylethylamine (1.6 mmol) and methylene chloride (10 mL) was treated with PyBroP (275 mg, 0.59 mmol) and kept at 0° C. for 30 min. In another reaction, a solution of Boc-N-(phenethyl)glycine 2-naphthylamide (240 mg, 0.59 mmol) (made by coupling of N-Boc-N-(phenethyl)glycine and 2-naphthylamine) and trifluoroacetic acid (3 mL) was stored at 24° C. for 1 hr and then concentrated in vacuo. The residue was coevaporated twice with methylene chloride and the resultant solid resuspended in methylene chloride (10 mL) and treated with diisopropylethylamine (1.2 mmol). The two solutions were mixed and stirred at 25° C. for 1 hr at which time the mixture was washed with 1M hydrochloric acid (2×25 mL), sat. sodium bicarbonate (25 mL), and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate and adsorbed onto silica gel (500 mg) and applied to a column prepacked with silica gel. The column was eluted with ethyl acetate:hexane (50:50, v:v) to afford the titled compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:37][O:38][S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:49]1[C:64]2[N:63]=[C:56]([NH:57][C:58](=[O:62])[CH:59]([CH3:61])[CH3:60])[NH:55][C:53](=[O:54])[C:52]=2[N:51]=[CH:50]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@:8]([CH2:37][O:38][S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)(=[O:40])=[O:41])([CH2:18][O:19][Si:20]([C:33]([CH3:34])([CH3:36])[CH3:35])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:7][C@@H:6]([N:49]2[C:64]3[N:63]=[C:56]([NH:57][C:58](=[O:62])[CH:59]([CH3:60])[CH3:61])[NH:55][C:53](=[O:54])[C:52]=3[N:51]=[CH:50]2)[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O[C@H]1[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(COS(=O)(=O)c2ccc(C)cc2)[C@H]1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)[C@H](O)[C@@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.2 %

Procedure:
To a methyl alcohol solution (3.0 ml) of Compound 44 (137.0 mg, 0.151 mmol), potassium carbonate (15.8 mg, 0.113 mmol) was added at room temperature, and the mixture was stirred for 45 minutes at room temperature. Concentrated hydrochloric acid was added to the reaction mixture to neutralize it, whereafter the system was extracted 3 times with methylene chloride. The organic phase was washed with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvents were distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (CHCl3-MeOH, 30:1) to obtain a white powder, Compound 45 (83.4 mg, 0.097 mmol, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]2[CH3:29])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc(Cc2c(-c3ccccc3)n(C)c3cc(OC)ccc23)n1
Temperature: 25 °C
Reaction time: 67 h
Yield: 97.9 %

Procedure:
To a solution of methyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (500 mg) in N,N-dimethylformamide (5.4 mL) were added cesium carbonate (1.09 g) and methyl iodide (0.168 mL), and this mixture was stirred at room temperature for 67 hours. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (508 mg). 1H-NMR (CDCl3) δ ppm: 3.61 (3H, s), 3.89 (3H, s), 4.02 (3H, s), 4.35 (2H, s), 6.74 (1H, dd, J=2.3, 8.5 Hz), 6.84 (1H, d, J=2.3 Hz), 7.12-7.18 (1H, m), 7.28 (1H, d, J=8.5 Hz), 7.33-7.49 (5H, m), 7.59 (1H, t, J=7.8 Hz), 7.88-7.94 (1H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[S:8][N:7]=2)=[CH:2]1.Cl.CCCCCC>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]=[C:9]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[S:8][N:7]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccoc3)ns2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1cc(-c2nsc(N3CCNCC3)n2)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-[3-(3-furyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxylate (3.30 g, 9.81 mmol) was dissolved in ethyl acetate (50 ml), and a solution of 4 N hydrogen chloride in ethyl acetate (25 ml) was added thereto, followed by stirring at room temperature for 18 hours. Hexane (120 ml) was poured to the reaction mixture, and a solid was separated by filtration. The obtained solid was dissolved in an aqueous saturated sodium hydrogen carbonate solution, followed by stirring at room temperature for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with a mixed solution of ethyl acetate/tetrahydrofuran (1:1). The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and 1.30 g (56.0%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1Cc2ccc(F)cc2N1

Procedure:
With addition of 20 g of palladium on activated carbon (10%), 119 g of 4-fluoro-2-nitrophenylacetic acid (starting material III) are hydrogenated in 600 ml of acetic acid under a hydrogen pressure of 50 psi. The catalyst is filtered off with suction and the solvent is distilled off. The crude product is triturated with 500 ml of petroleum ether, filtered off with suction, washed with water and dried.
Reaction SMILES: OO.[C:3]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([O-:23])(=[O:22])=[O:21])(=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+:24].[B-:25]1([OH:34])([OH:33])[O:30][O:29][B-:28]([OH:32])([OH:31])[O:27][O:26]1.C([O:38][OH:39])(O)=O>>[C:3]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([O-:23])(=[O:21])=[O:22])(=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+:24].[B-:25]1([OH:34])([OH:33])[O:30][O:29][B-:28]([OH:32])([OH:31])[O:27][O:26]1.[O:38]=[O:39]
Reactant: O=C(O)OO
Agent: CCCCCCCCC(=O)Oc1ccccc1S(=O)(=O)[O-]
Agent: OO
Agent: O[B-]1(O)OO[B-](O)(O)OO1
Product: O=O

Procedure:
It can be seen that bleaching from these peroxycarbonic acid bleaches is excellent, giving substantial stain removal on a variety of stains. As evidenced from Table, the SPCC system has been studied most extensively. A number of observations may be gleaned from the Table with respect to SPCC. At a theoretical percarbonic acid yield of 15 ppm active oxygen (9.4×10-4M), outstanding bleaching is obtained at 40° in 15 minutes on hydrophilic stains such as tea, red wine and blackberry. Bleaching remains outstanding at hydrogen peroxide/precursor ratios as low at 2:1. Even at 1:1, bleaching is very good compared to state-of-the-art systems such as sodium nonanoyloxybenzene sulfonate with perborate. At a theoretical percarbonic acid yield of 5 ppm active oxygen (3.1×10-4M), bleaching of hydrophilic stains is comparable to that obtained with sodium nonanoyloxybenzene sulfonate with perborate at 10 ppm active oxygen theoretical peracid. Levels of 15 ppm active oxygen give very good bleaching at 20° C. and perceivable bleaching even as low as 10° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][N:5]([CH2:27][C@@H:28]2[C@H:31]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30](=[O:43])[N:29]2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[N:4]=1.[N+:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[S:64](Cl)(=[O:66])=[O:65])([O-:57])=[O:56]>C(Cl)Cl>[Si:10]([O:9][CH2:8][C:7]1[C:3]([CH2:2][NH:1][S:64]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[N+:55]([O-:57])=[O:56])(=[O:65])=[O:66])=[N:4][N:5]([CH2:27][C@@H:28]2[C@H:31]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30](=[O:43])[N:29]2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[N:6]=1)([C:23]([CH3:24])([CH3:25])[CH3:26])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CN)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 2.2 h
Yield: 86.5 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(aminomethyl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (234 mg, 0.312 mmol) in DCM (3.1 mL) at 0° C. was added 2-nitrobenzene-1-sulfonyl chloride (77.2 mg, 0.338 mmol) followed by TEA (87 μL, 0.62 mmol). After 2.2 h of stirring at rt, it was diluted with DCM and washed with KHSO4 (2%, aq). The aqueous layer was extracted with DCM (3×) and the combined organic layers were washed with brine, dried over Na2SO4 and concd in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-60%), affording the title compound (252 mg, 87%) as an off-white solid. Rt=1.24 min, m/z=934.4 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[N:9]1[S:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[CH:14][C:13]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(N(CC)CC)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[C:18]([C:16]1[CH:15]=[CH:14][C:13]2=[N:9][S:10][N:11]=[C:12]2[CH:17]=1)=[O:19]
Reactant: O=C(O)c1ccc2nsnc2c1
Reactant: CNC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc2nsnc2c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Methyltetrahydro-2H-pyran-4-amine (0.4 g, 3.4 mmol), [2,1,3]-benzothiadiazole-5-carboxylic acid (0.23 g, 1.4 mmol), DMAP (0.2 g: 1.6 mmol), HOBT (0.2 g, 1.5 mmol), triethylamine (1.0 ml) and EDCI (1 g, 6.4 mmol) were dissolved in DMF (30 ml). The mixture was stirred at room temperature for 18 h and then concentrated under vacuum. Chloroform (100 ml) was added and the mixture washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml). The aqueous was extracted with chloroform (100 ml) and the combined organics were dried (MgSO4), concentrated under vacuum, and the crude product was purified on a silica gel column eluting with chloroform/THF (90:10), to give the product as an oil which crystallized on standing. Mp=106-108° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 8.06 (d, J=9.0 Hz, 1H); 8.01 (s, 1H); 7.60 (d, J=9.0 Hz, 1H); 4.92-4.75 and 4.15-3.10 (m, 5H); 3.10-2.80 (m, 3H) and 2.05-1.50 ppm (s, 4H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(C1C=C(B(O)O)C=CC=1)#N.[C:18]([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1)#[N:19].C1C(=O)N([Br:46])C(=O)C1>C1(C)C=CC=CC=1.CO.C(Cl)(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[C:30]([CH2:32][Br:46])[CH:29]=[C:28]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1)#[N:19]
Reactant: COC(=O)COc1cc(C)cc(-c2cccc(C#N)c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)COc1cc(CBr)cc(-c2cccc(C#N)c2)c1
Yield: 99.5 %

Procedure:
A solution of 7.0 g of 3-bromo-5-methylphenol and 5.97 g of methyl bromoacetate and also 13 g of caesium carbonate in 100 ml of acetonitrile is stirred overnight at room temperature. After customary working up, 9.70 g of methyl 3-bromo-5-methylphenoxyacetate (“AB”) are obtained. A suspension of 2.0 g of “AB”, 100 mg of tetrakis(triphenylphosphine)palladium and 0.85 g of sodium carbonate in 50 ml of toluene is heated to boiling. A solution of 2.94 g of 3-cyanophenylboronic acid in 30 ml of methanol is then added dropwise and the mixture is heated under reflux for 14 hours. It is worked up in the customary manner and 2.17 g of methyl 3′-cyano-5-methylbiphenyl-3-yloxyacetate (“AC”) are obtained. A solution of 1.2 g of “AC” and 0.765 g of NBS in 50 ml of carbon tetrachloride is irradiated with UV light at room temperature. After customary working up, 1.54 g of methyl 3′-cyano-5-bromomethylbiphenyl-3-yloxyacetate (“AD”) are obtained. A solution of 185 mg of “AD”, 63.1 mg of 4-hydroxybenzonitrile and 172.7 mg of caesium carbonate in 10 ml of acetonitrile is stirred at room temperature for 4 days. After customary working up, methyl 3′-cyano-5-(4-cyanophenoxymethyl)biphenyl-3-yloxyacetate (“AE”) is obtained. A solution of 60 mg of “AE”, 69.5 mg of hydroxylammonium chloride and 101 mg of triethylamine in 10 ml of methanol is heated under reflux for 14 hours. After removal of the solvent, the residue is taken up in water. The solid is separated off and 70 mg of methyl 3′-N-hydroxyamidino-5-(4-N-hydroxyamidinophenoxymethyl)biphenyl-3-yloxyacetate (“AF”) are obtained. By reduction with H2/Raney nickel, methyl 3′-amidino-5-(4-amidinophenoxymethyl)biphenyl-3-yloxyacetate, FAB 433
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([CH2:22]O)[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])[CH3:2].P(Br)(Br)[Br:25]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([CH2:22][Br:25])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)C(CO)CCC3
Solvent: ClCCl
Product: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)C(CBr)CCC3

Procedure:
From 5,6,7,8-tetrahydro-5-hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester (example 2) by reaction with phosphorus tribromide in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][N:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(Cl)cnnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cnnc2cc(CBr)ccc12
Temperature: 80 °C
Yield: 35.6 %

Procedure:
A solution of 4-chloro-7-methylcinnoline (0.6 g, 3.37 mmol) in carbon tetrachloride (30 mL) is treated with N-bromosuccinimide (0.64 g, 3.4 mmol) and a catalytic amount of 70% benzoyl peroxide (0.22 g, 0.63 mmol). The solution is heated to 80° C. overnight, then filtered. The filtrate is concentrated in vacuo and the resulting residue is chromatographed (20% ethyl acetate/methyl chloride) to give the title compound (0.3 g, 1.2 mmol) and some unreacted starting material (0.1 g, 0.56 mmol). MS m/z: [M+H]+=257; 1H NMR (CDCl3, 300 MHz) δ9.35 (s, 1H), 8.55 (s, 1H), 8.2 (d, 1H), 8.85 (d, 1H), 4.75 (s, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:5][C@H:6]1[NH:11][C:10](=[O:12])[CH2:9][O:8][CH2:7]1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.[Cu]Cl>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:4]([CH2:5][C@H:6]2[NH:11][C:10](=[O:12])[CH2:9][O:8][CH2:7]2)=[CH:3][C:2]=1[N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: COc1ccc(C[C@@H]2COCC(=O)N2)cc1I
Reactant: c1cn[nH]c1
Agent: Cl[Cu]
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H]2COCC(=O)N2)cc1-n1cccn1
Temperature: 25 °C

Procedure:
A mixture of (R)-5-(3-iodo-4-methoxy-benzyl)-morpholin-3-one C-7 (60 mg, 0.17 mmol), pyrazole (18 mg, 0.30 mmol), K2CO3 (48 mg, 0.35 mmol), copper(I) chloride (1.7 mg, 0.02 mmol) and L-proline (4 mg, 0.04 mmol) in DMF (1 mL) was heated under argon to 110° C. for 168 h. The reaction mixture was cooled to RT and partitioned between water and DCM before being filtered through a celite plug. The layers were separated and the aqueous phase was re-extracted with DCM (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (Biotage SP1, 10 g SNAP-cartridge eluting with 95:5 DCM:MeOH) to give the title compound as a brown oil. LC-MS B: tR=0.53 min; [M+H]+=288.16.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][C@@H:16]([CH2:43][OH:44])[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[N:41]=[C:29]([NH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]([CH:40]=4)[CH2:36][CH2:37][C:38]=1[CH:39]=2)[N:28]=[CH:27][C:26]=3[Cl:42])=[O:18].[C:45]1([N:51]=[C:52]=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:51]([C:52]([NH:15][C@@H:16]([CH2:43][OH:44])[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[N:41]=[C:29]([NH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]([CH:40]=4)[CH2:36][CH2:37][C:38]=1[CH:39]=2)[N:28]=[CH:27][C:26]=3[Cl:42])=[O:18])=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: N[C@@H](CO)C(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)N[C@@H](CO)C(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using (2S)-2-amino-N-[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-12-yl]-3-hydroxypropanamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 36% yield. LCMS for C28H27ClN7O3 (M+H)+: m/z=544.2.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[NH:7][C:8](=[O:11])[CH2:9][Cl:10].S(Cl)([Cl:16])(=O)=O>C(Cl)Cl>[Cl:16][C:4]1[S:3][C:2]([CH3:1])=[C:6]([NH:7][C:8](=[O:11])[CH2:9][Cl:10])[C:5]=1[CH3:12]
Reactant: Cc1csc(C)c1NC(=O)CCl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cc1sc(Cl)c(C)c1NC(=O)CCl

Procedure:
To the stirred solution of 5.0 g (0.0245 mol) of N-(2,4-dimethylthien-3-yl)-chloroacetamide in 50 ml of dry CH2Cl2 are added dropwise at 0° 3.3 g (0.0245 mol) of sulfuryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2.[C:22]1(=[O:28])[NH:26][C:25](=[O:27])[CH:24]=[CH:23]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:24]2[C:25](=[O:27])[NH:26][C:22](=[O:28])[CH:23]2[C:18]2[C:17]3[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH2:9]1
Reactant: O=C1C=CC(=O)N1
Reactant: O=[N+]([O-])c1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1
Product: O=C1NC(=O)C2C(c3ccccc3Cl)Cc3[nH]c4ccc([N+](=O)[O-])cc4c3C12
Yield: 74 %

Procedure:
Reaction of the diene (905) prepared as described in example 455 with maleimide using the procedure described in example 68 gave the adduct (917) (74%) as a dark solid which was immediately aromatised.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][OH:13]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:13][CH3:12])[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: CO
Product: COc1cc(Cl)ccc1C(=O)O
Temperature: 80 °C
Yield: 86.3 %

Procedure:
Except for using 2.8 g of 2,4-dichlorobenzoic acid (14.6 mM), 0.75 g of cuprous chloride (7.5 mM) and 100 ml of methanol containing 20% dimethylamine (77 g), the same apparatus, reagents and procedures were employed for reaction as in Example 1. The reaction was followed by reversed-phase HPLC as in Example 1, and as a result, completion of the methanol reaction within two hours was confirmed. After the methanol was removed, 50 ml of water was added and heated in a bath temperature of 80° C., to turn the solution into a uniform mixture solution of green. The green solution was cooled in ice-water to a room temperature. Then, 1.2 ml of conc. HCl was added to consequently deposit needle-liuke crystal. Effecting separation, washing and drying processes in the same manner as in Example 1, about 2.3 g of 4-chloro-2-methoxybenzoic acid was obtained in crystal at a yield of 86.3%. Concerning 1H-NMR, IR(KBr), GC-MSE1 and melting point, the product was confirmed to show the data agreeable with the reference standard data.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12].C(N(CC)CC)C.[CH2:20]([N:24]=[C:25]=[O:26])[CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:20]([NH:24][C:25](=[O:26])[NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN=C=O
Reactant: N#Cc1c(N)sc2c1CCCC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCNC(=O)Nc1sc2c(c1C#N)CCCC2
Temperature: 80 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
A mixture of 5.35 g (30 mmol) of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (prepared according to Intermediate 1e), 2.0 ml (45 mmol) of triethylamine, 10 ml (90 mmol) of n-butyl isocyanate and 100 ml of toluene was stirred for 16 hours at 80° C. The solid formed was then isolated and was recrystallized from ethanol. Yield: 18%; mp.: 170°-171° C.