Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N+]1(C)CCCC1)C=C.[NH2:10][C:11]1[S:15][N:14]=[C:13](/[C:16](=[N:20]/[O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)/[C:17]([O-:19])=O)[N:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:58][C@@H:59]1[C:66](=[O:67])[N:65]2[C@@H:60]1[S:61][CH2:62][C:63](/[CH:71]=[C:72]1/[C:73](=[O:96])[N:74]([CH2:77][C:78]3[CH:83]=[CH:82][N+:81]([CH2:84][C:85](=[O:95])[NH:86][C:87]4[CH:92]=[CH:91][C:90]([OH:93])=[C:89]([F:94])[CH:88]=4)=[CH:80][CH:79]=3)[CH2:75][CH2:76]/1)=[C:64]2[C:68]([O-:70])=[O:69]>CN(C=O)C>[NH2:10][C:11]1[S:15][N:14]=[C:13](/[C:16](=[N:20]/[O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)/[C:17]([NH:58][C@@H:59]2[C:66](=[O:67])[N:65]3[C@@H:60]2[S:61][CH2:62][C:63](/[CH:71]=[C:72]2/[C:73](=[O:96])[N:74]([CH2:77][C:78]4[CH:79]=[CH:80][N+:81]([CH2:84][C:85](=[O:95])[NH:86][C:87]5[CH:92]=[CH:91][C:90]([OH:93])=[C:89]([F:94])[CH:88]=5)=[CH:82][CH:83]=4)[CH2:75][CH2:76]/2)=[C:64]3[C:68]([O-:70])=[O:69])=[O:19])[N:12]=1
Reactant: Nc1nc(/C(=N/OC2CCCC2)C(=O)[O-])ns1
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Agent: C=CC[N+]1(C)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OC2CCCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C4\CCN(Cc5cc[n+](CC(=O)Nc6ccc(O)c(F)c6)cc5)C4=O)CS[C@H]23)ns1
Reaction time: 78 h

Procedure:
A solution of (Z)-(5-amino-[1,2,4]thiadiazol-3-yl)-cyclopentyloxyimino-acetate 1-allyl-1-methyl-pyrrolidinium salt in 10 ml DMF was treated with HBTU (170 mg, 0.45 mmol) for 1.5 h at room temperature. (E)-(6R,7R)-7-Amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetic acid salt (300 mg, 0.45 mmol) was added and the mixture was stirred for 78 h before it was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with water. The organic phase was evaporated and the residue triturated with diethylether. The product was purified by gel chromatography (MCI-gel, using a gradient of water with increasing concentrations of acetonitrile). Yield: 40 mg (11%).
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.Cl.[N:16]1[C:25]2[C:20](=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[C:7]([C:4]1[C:3]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[C:2]([NH:1][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][CH:17]=[N:16]3)[S:6][CH:5]=1)#[N:8]
Reactant: N#Cc1csc(N)c1-c1cnccn1
Reactant: O=C(O)Cc1cccc2ncccc12
Agent: Cl
Product: N#Cc1csc(NC(=O)Cc2cccc3ncccc23)c1-c1cnccn1

Procedure:
The title compound was synthesized from 5-amino-4-(pyrazin-2-yl)thiophene-3-carbonitrile (30.5 mg, 0.15 mmol) and 2-(quinolin-5-yl)acetic acid hydrochloride (36 mg, 0.16 mmol) according to protocol A. The product was purified by HPLC method [4], retention time=1.393 min; MS(ESI) 372.1 (MH+); 1H NMR (300 MHz, CD3OD) δ 9.30 (d, J=1.5 Hz, 1H), 9.06 (dd, J=4.8, 1.3 Hz, 1H), 8.99 (d, J=8.5 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.29 (t, J=1.9 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.09 (dd, J=8.6, 7.1 Hz, 1H), 7.95 (s, 1H), 7.93 (d, J=6.7 Hz, 1H), 7.86 (dd, J=8.6, 4.9 Hz, 1H), 4.55 (s, 2H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[N:11]=[CH:10]1)=O.CSC.B>O1CCCC1>[N+:14]([C:12]1[N:11]=[CH:10][N:9]([CH:6]2[CH2:7][CH2:8][CH:5]2[CH2:3][OH:2])[CH:13]=1)([O-:16])=[O:15]
Reactant: COC(=O)C1CCC1n1cnc([N+](=O)[O-])c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn(C2CCC2CO)cn1
Yield: 37.9 %

Procedure:
A mixture of the 2-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl ester (2.640 g, 0.01105 mol), borane-dimethyl sulfide complex (1M in tetrahydrofuran) (33.2 mL, 0.0332 mol) and tetrahydrofuran (10 mL) was heated at reflux for 17 hours. The reaction was quenched by water. The volatile solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was then evaporated under reduced pressure to yield [2-(4-Nitro-imidazol-1-yl)-cyclobutyl]-methanol (0.825 g, 0.00419 mol) as a white solid. M+1=198.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[O:14]=[C:12]1[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)CCC1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 114.4 %

Procedure:
1-(tert-Butoxycarbonyl)-5-oxopiperidine-2-carboxylic acid (2.0 g, 8.22 mmol) was dissolved in DMF (20 mL) under nitrogen and potassium carbonate (1.7 g, 12.33 mmol) was added, followed by iodomethane (620 μL, 9.95 mmol). The reaction mixture was stirred at room temperature under nitrogen for 23 h. Additional methyl iodide (256 μL, 4.11 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×25 mL) and brine (2×25 mL), then dried over sodium sulfate and concentrated to dryness. The crude residue was purified by flash column chromatography (Biotage), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (2.42 g, 53%) as a pale yellow oil. δH (250 MHz, CDCl3) 4.70 (dt, J 59.4, 6.3 Hz, 1H), 4.35 (dd, J 27.3, 19.0 Hz, 1H), 3.90 (dd, J 19.0, 12.4 Hz, 1H), 3.77 (s, 3H), 2.56-1.95 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.Cl.[C:38]1([CH2:44][O:45][NH2:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:46][O:45][CH2:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:12]([N:14]2[C@H:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NOCc1ccccc1
Reactant: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)O)CC2CCCC2)n1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (314 mg, 0.79 mmol) in dichloromethane (DCM) (10 mL) was added N-methylmorpholine (0.22 mL, 2.04 mmol), O-(phenylmethyl)hydroxylamine hydrochloride (188 mg, 1.18 mmol), EDC (181 mg, 0.94 mmol) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (107 mg, 0.79 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then washed with water (5 mL) and NaHCO3 solution (5 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (157 mg, 39% yield). MS: 506 ([M+H]+).
Reaction SMILES: C[CH:2]([CH3:4])[O-:3].[Al+3].C[CH:7]([CH3:9])[O-:8].CC(C)[O-].C(O)(=O)CCCCCCCC.[C:25]([O-:44])(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]CCCCCCC.[K+]>>[C:2]1(=[O:3])[O:8][CH2:7][CH2:9][O:44][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:4]1
Reactant: CC(C)[O-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCCC(=O)O
Agent: [Al+3]
Agent: [K+]
Product: O=C1CCCCCCCCCCCC(=O)OCCO1
Yield: 89.3 %

Procedure:
Aluminum tripelargonate, obtained by reacting 0.5 mole aluminum isopropoxide and 1.5 mole pelargonic acid at 120° C., was combined with an equimolar amount, based on aluminum, of potassium stearate and the resulting mixed metal catalyst (1.7 weight percent) charged to a reactor with 76 grams poly(ethylene brassylate). The depolymerization was conducted in the usual manner. Ethylene brassylate was obtained at a rate of 42 mls/hour and yield of 89.3 percent.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[N+]([CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O-])=O>>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:19]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27]1
Reactant: NCc1ccccc1Cl
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Clc1ccccc1Cn1cc(-c2ccccc2)c2c1CCNC2

Procedure:
The title compound (113.8 mg) was prepared from 0.55 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 334 μL of 2-chlorobenzylamine, 0.40 g of (2-nitro-vinyl)-benzene, and without SiO2. MS (ESI): exact mass calculated for C20H19ClN2, 322.12; found, m/z 323.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.46 (m, 1H), 7.37-7.26 (m, 6H), 7.22-7.19 (m, 1H), 7.07 (s, 1H), 6.85-6.82 (m, 1H), 5.25 (s, 2H), 4.39 (s, 2H), 3.54 (t, J=6.3 Hz, 2H), 2.88 (t, J=6.3 Hz, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]([F:34])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:20]([OH:22])=O)[CH3:15].[CH3:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:34][CH:11]([F:10])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:20]([NH:41][C:38]1[CH:39]=[CH:40][N:36]([CH3:35])[N:37]=1)=[O:22])[CH3:15]
Reactant: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1

Procedure:
DIPEA (0.198 mL, 1.14 mmol) was added to a mixture of 3-[(2S)-1-(difluoromethoxy) propan-2-yl]oxy-5-phenylmethoxy-benzoic acid (0.10 g, 0.28 mmol), 1-methylpyrazol-3-amine (CAS no. 1904-31-0) (39 mg, 0.4 mmol) and HATU (0.227 g, 0.6 mmol) in DMF (3 mL) and stirred at RT for 20 hours. Ethyl acetate (30 mL) was added and the mixture washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and reduced in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (0.1 g).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13]([C@@:16]1([CH3:44])[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C@@H:19]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([F:36])[CH:30]=2)[N:18]([C@@H:37]([CH:40]2[CH2:42][CH2:41]2)[CH2:38][OH:39])[C:17]1=O)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH2:13]([C@@:16]1([CH3:44])[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C@@H:19]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([F:36])[CH:30]=2)[N+:18]2[C@@H:37]([CH:40]3[CH2:42][CH2:41]3)[CH2:38][O:39][C:17]1=2)[CH:14]=[CH2:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)c(F)c2)N([C@H](CO)C2CC2)C1=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)c(F)c2)[N+]2=C1OC[C@@H]2C1CC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 4 h

Procedure:
p-Toluenesulfonic acid monohydrate (30.3 g, 159 mmol, Aldrich, St. Louis, Mo.) was added to a solution of (3S,5R,6S)-3-allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (73.6 g, 154 mmol) in toluene (386 mL). The reaction mixture was heated at reflux using a Dean-Stark apparatus. After 4 hours, the reaction was cooled and concentrated under reduced pressure to provide the title compound as a pale yellow syrup. The crude product was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CNCCN(C)C
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc(C(=O)N(C)CCN(C)C)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and N,N,N′-trimethylethylenediamine (Aldrich, Cat. No. 127124). LCMS (M+H)+: m/z=544.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]#[N:6]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N2CCNCC2)c(Cl)c1

Procedure:
A solution of 3-chloro-4-fluoro-benzonitrile (236 mg, 1.52 mmoles), piperazine (784 mg, 9.1 mmoles) and potassium carbonate (276 mg, 2 mmoles) in acetonitrile (5 mL) was heated to 100° C. overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. MS(APCI+) m/z 222 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2C=CN=[C:8]([CH3:12])[CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Br:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[CH:18]=[N+:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.BrC1C=C(C=CC=1)C=O.[NH:36]1CC[CH2:38][CH2:37]1>>[Br:14][C:15]1[CH:16]=[C:17]([CH:18]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:5]2[N:1]([CH2:6][C:7]3[CH:8]=[CH:12][CH:38]=[CH:37][N:36]=3)[CH:2]=[CH:3][CH:4]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: C1CCNC1
Reactant: Brc1cccc(C=[N+]2CCCC2)c1
Reactant: Cc1cc(-n2cccc2)ccn1
Agent: O=Cc1cccc(Br)c1
Agent: [Cl-]
Product: Brc1cccc(C(c2cccn2Cc2ccccn2)N2CCCC2)c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-pyrrol-1-yl-methyl-pyridine and 1-(3-bromo-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 3-bromobenzaldehyde and pyrrolidine.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:16].O>CN(C)C(=O)C>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:19][C:18]=1[S:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)#[N:16]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: N#Cc1ccc(N)cc1Sc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(C#N)c(Sc2ccccc2)c1)C(F)(F)F
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.62 g 10.2 mmol) in N,N-dimethylacetamide (15 mL) was rapidly added thionyl chloride (1.30 g, 10.9 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -20° C. to -5° C. for 1 hour. 4-Cyano-3-phenylthiobenzenamine (1.55 g, 6.85 mmol) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into water, extracted with ethyl ether (2×100 mL); the etheral extracts dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on 315 g of silica gel using a ethyl ether (0%, 10%, and 20%) in methylene chloride gradient. The proper fractions were combined, the solvent removed in vacuo and the residue dissolved in a mixture of 100 mL hexane and 150 mL methylene chloride. Most of the methylene chloride was distilled off as the solution was scratched to induce crystal growth. After cooling the solid was collected and dried at 85° C. /0.1 mm to yield the title propanamide (2.38 g, 91%); mp 111°-113° C. 1H--NMR (250 MHz, CDCl3): 1.67 (s, 3H, CH 3), 3.68 (s, 1H, OH), 7.27 (d, 1H, J=1.9 Hz, aromatic), 7.40-7.51 (m, 5H, aromatic), 7.59-7.69 (m, 2H, aromatic), 8.51 (s, 1H, NH). MS (CI, CH4): 367(M+1).
Reaction SMILES: [OH-:1].[K+].F[C:4](F)(F)[C:5]([OH:7])=O>>[O:1]=[CH:4][C@@H:5]([C@H:4]([C@H:5]([C@@H:4]([CH2:5][OH:7])[OH:1])[OH:7])[OH:1])[OH:7].[O:1]=[CH:4][C@@H:5]([C@H:4]([C@@H:5]([C@@H:4]([CH2:5][OH:7])[OH:1])[OH:7])[OH:1])[OH:7]
Reactant: O=C(O)C(F)(F)F
Reactant: [OH-]
Agent: [K+]
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The polysaccharide of the present invention deacetylated by a dilute alkali (0.01M KOH) treatment was subjected to acid hydrolysis using 2M trifluoroacetic acid (TFA) at 100° C. for 6 hours and then derived to alditol acetate. Each of the obtained derivatives was analyzed by gas chromatography using ECNSS-Mcoated column "Gaschrom Q" (mfd. by Wako Pure Chemical Co., Ltd.). Consequently, there were detected the same compounds to that obtained from D-galactose and D-glucose as starting materials.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCc1cccnc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCc1cccnc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 3-(aminomethyl)pyridine (31 mg) according to Method B to give the title compound (14 mg). HRMS m/z 620.2471 (calc. of monoisotopic mass for C32H36N4O9 gives 620.2482).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH3:25])=[C:12]2[CH2:26][C:27]([NH:29][NH2:30])=[O:28])C.[OH-].[Na+].Cl>CCO.C1COCC1.O>[NH:29]([C:27](=[O:28])[CH2:26][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH3:25])[NH2:30]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)NN)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Yield: 18.5 %

Procedure:
A solution of 310 mg (1 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide (Example 62) in 25 mL of DMSO was treated with 45 mg (1.1 mmol) of 60% NaH/mineral oil and after 0.25 hours, 0.16 mL (1.1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 4 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with CH2Cl2 →4% MeOH/CH2C2, to give 290 mg (68% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (0.685 mmol) and 2 mL of 2N NaOH in 25 mL of EtOH and 5 mL of THF was stirred for 22.5 hours. The mixture was diluted with water, made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (Na2SO4), and concentrated at reduced pressure. The residue was dissolved in EtOH and precipitated with ether to give 50 mg (47% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid, mp, 160° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=CC=CC=2)[NH:6]C=1.C1C=CC2N([OH:22])N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CN([CH:41]=[O:42])C>>[NH2:1][C@H:2]([C:41]([OH:42])=[O:22])[CH2:3][CH2:4][CH2:12][CH2:7][NH2:6]
Reactant: CN(C)C=O
Reactant: NCCc1c[nH]c2ccccc12
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: NCCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
10 mmol of a methoxycarbonyl derivative of a basic amino acid with the L-configuration is dissolved in 30 ml of DMF, 3.2 g (20 mmol) of tryptamine, 1.54 g of HOBt (10 mmol, monohydrate) and 2.1 g of DCC (10.17 mmol) is added, and the mixture is stirred at the room temperature for 24 h. A DCU precipitate is then filtered off and the solvent evaporated. The oily residue is dissolved in 150 ml of ethyl acetate and washed with 150 ml of 10% aqueous Na2CO3, water, 1% citric acid (three times) and brine. The organic layer is dried (MgSO4), filtered and evaporated to dryness. The residue is purified by column chromatography (SiO2) with O:H phase 7:3+3% MeOH, to yield amide of tetrakis(methoxycarbonyl) derivative of lysine as a dark orange oil.