Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:27]([C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2ccccc2c1
Product: CC(C)N1C(=O)NC(c2ccc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 60 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (226 mg) and 2-naphthaldehyde (152 mg) by the procedure described in example 10 in 60% yield, mp: 186-178° C. 1H NMR (CDCl3): 7.86-7.75 (m, 4H), 7.52-7.42 (m, 3H), 6.70 (s, 1H), 6.32 (s, 1H), 5.91 (d, J=1.3, 1H), 5.88 (d, J=1.3, 1H), 5.47 (s, 1H), 5.16 (br s, 1H), 4.45 (m, 1H), 1.58 (m, 6H). Anal. calcd. for C22H20N2O3: C. 73.32; H, 5.59; N, 7.77. Found: C, 73.10; H, 5.49; N, 7.62.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[C:27]([F:32])[C:28]([F:31])=[N:29][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[F:31][C:28]1[C:27]([F:32])=[CH:26][C:25]([C:13]2[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:14]=2)=[CH:30][N:29]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cc(-c2cnn(CCOC3CCCCO3)c2)cnc1F
Temperature: 100 °C
Yield: 60.5 %

Procedure:
A 48 mL tube was charged with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.4 g, 19.9 mmol), 5-chloro-2,3-difluoropyridine (1.7 mL, 16.6 mmol), X-Phos (1.6 g, 3.3 mmol), Potassium phosphate (3.5 g, 16.6 mmol), PdOAc2 (0.4 g, 1.7 mmol), 1,4-dioxane (50 mL), and water (5.0 mL), flushed with argon, sealed, then heated at 100° C. for 3 hours. The mixture was concentrated and purified by MPLC, eluting with 2.5% MeOH/DCM over 40 minutes to afford 2,3-difluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine as a clear oil which solidified upon standing at room temperature (3.1 g, 60.5% yield). LC/MS shows the product as the free alcohol. However, the structure of the product is as drawn above. MS m/z=226.2 [M+1]+. Calc'd for C15H17F2N3O2: 309.3
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(N(CCCC)CCCC)CCC.C(O)C.[CH3:29][C:30]1[C:35]2[C:36]([NH2:41])=[N:37][C:38]([NH2:40])=[N:39][C:34]=2[CH:33]=[CH:32][C:31]=1[CH2:42][NH:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=1.FC(F)(F)C([O-])=O>CC(O)C>[CH3:29][C:30]1[C:35]2[C:36]([NH2:41])=[N:37][C:38]([NH2:40])=[N:39][C:34]=2[CH:33]=[CH:32][C:31]=1[CH2:42][NH:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=1.[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
Agent: O=C([O-])C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(C)O
Solvent: CCO
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
This part of the preparation was carried out, as far as possible, under a nitrogen atmosphere. Equivalent quantities of ascorbic acid (0.463 g) and tributylamine (0.487 g) were heated in 20 ml of 200 proof ethanol at 60° C. to give a clear solution. This was cooled to room temperature and a half-equivalent of trimetrexate trifluoroacetate (0.635 g; assumed unsolvated) added and the mixture heated to near reflux to give a clear yellow solution. To the hot solution was added 50 ml of 2-propanol. A light-colored flocculent solid was immediately precipitated. The mixture was heated at 50° C. for 3 minutes, and then allowed to stand in air for about 1.5 hours. The solid was collected, washed with 2:1 2-propanol/ethanol at room temperature, and immediately transferred to a desiccator and dried (diaphragm pump vacuum) over P2O5 to give 0.425 g of the salt as a very pale yellow-green powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:8]([NH2:11])=[N:9][CH:10]=1.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1>>[NH2:27][C:25]1[N:26]=[C:21]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:8]([NH2:11])=[N:9][CH:10]=2)[CH:22]=[CH:23][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: NCCNc1cnc(N)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: Nc1nc(NCCNc2cnc(N)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
The compound was prepared from N5-(2-aminoethyl)-3-(2,4-dichlorophenyl)pyrazine-2,5-diamine and 6-chloro-3-nitro-2-pyridylamine in accordance to the procedure described for Example 6.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:21]([OH:22])[C@H:20]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:19]([CH2:32][OH:33])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@H]1(O[C@H]2[C@H](O)[C@@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)O[C@H](OCCN)[C@H]2O)O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O.[C:71](Cl)([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:9][C@H:10]1[C@@H:21]([OH:22])[C@H:20]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:19]([CH2:32][O:33][C:71]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)[C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)[O:18][C@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](O)[C@@H]1OC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Solvent: c1ccncc1
Product: [N-]=[N+]=NCCO[C@@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](O)[C@@H]1OC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
In a 250 ml round bottom flask, 2-azidoethyl 2,4-di-O-benzoyl-α-D-mannopyranoside (1.0 g, 2.186 mmol; See WO 2010/088294 A1, incorporated herein by reference) was dissolved in pyridine (50 mL). To the above solution was added DMAP (13 mg, 0.109 mmol) followed by trityl chloride (762 mg, 2.73 mmol). After stirring at 80° C. for 18 hr, the reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel (40 g), eluting with 0-50% EtOAc in hexanes to give the title compound. UPLC Method C: m/e=722.2955, [M+Na]; Rt=4.50. 1H NMR (CDCl3) δ 7.0-8.3 (m, 25H), 5.8 (t, 1H), 5.5(m, 1H), 5.2 (s, 1H), 4.3 (m, 1H), 4.1 (m, 2H), 4.0 (m, 1H), 3.5 (m, 1H), 3.4 (m, 2H), 3.2 (dd, 1H), 2.7 (d, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10]C(C)(C)C)=O)[CH2:3]1.CC1C=CC(S(O[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:28]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:52]=[C:53]([N:58]=C=O)[CH:54]=[CH:55][C:56]=1[Cl:57]>C(#N)C.ClCCl>[Cl:50][C:51]1[CH:52]=[C:53]([NH:58][C:8]([N:4]2[CH2:5][CH2:6][N:7]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:28]3)[C@H:2]([CH3:1])[CH2:3]2)=[O:10])[CH:54]=[CH:55][C:56]=1[Cl:57]
Reactant: CCN1CCCC(COS(=O)(=O)c2ccc(C)cc2)C1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCCC(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)C[C@H]2C)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of tert-butyl (3R)-3-methylpiperazine-1-carboxylate (84 mg) and (1-ethylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (150 mg) in acetonitrile (3 mL) was added potassium carbonate (233 mg). The mixture was heated to 100° C. in the microwave for 2 hours and then evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane. To a solution of the isolated material (50 mg) in methanol (5 mL) was added 4M HCl in dioxane (0.5 mL). The mixture was stirred overnight at room temperature and then evaporated to give a colourless oil. To a mixture of this oil in dichloromethane (10 mL) was added di-iso-propylethylamine (0.11 mL) and 3,4-dichlorophenylisocyanate (35 mg). The mixture was stirred for 15 minutes and then evaporated. The residue was purified using reverse phase HPLC eluting with a mixture of 5-95% acetonitrile in water to give the title compound as a white foam (52 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15](=O)([O-])[O-].[K+].[K+].BrC[C:23]1[CH:24]=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=1>CN(C=O)C.CCOC(C)=O>[CH3:30][S:29][C:26]1[N:25]=[C:24]([CH2:15][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH:23]=[CH:28][N:27]=1
Reactant: CSc1ncc(CBr)cn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.5 g, 2.58 mmol), potassium carbonate (0.356 g, 2.58 mmol) and 5-(bromomethyl)-2-(methylthio)pyrimidine (30% in THF, 2.070 g, 2.83 mmol) in DMF (5 mL) was stirred at room temperature for 14 h. After this time, the reaction mixture was diluted with EtOAc, washed with saturated sodium bicarbonate, dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (0.6 g, 70% yield) as a light yellow solid. LCMS, [M+H]+=333.2. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=5.1 Hz, 1H), 7.87 (s, 1H), 7.81 (s, 1H), 6.49 (d, J=5.1 Hz, 1H), 5.36 (s, 2H), 2.56 (s, 3H), 1.33 (s, 12H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:10][C:9]([C:15]#[C:16][CH:17]2[CH2:19][CH2:18]2)([C:11]([F:14])([F:13])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[N:6](CC2C=CC(OC)=CC=2)[C:5]1=[O:34].O>C(#N)C>[Br:1][CH2:2][CH2:3][C@@H:4]1[O:10][C@:9]([C:15]#[C:16][CH:17]2[CH2:18][CH2:19]2)([C:11]([F:13])([F:14])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[NH:6][C:5]1=[O:34]
Reactant: COc1ccc(CN2C(=O)C(CCBr)OC(C#CC3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Solvent: O
Solvent: CC#N
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O[C@H]1CCBr
Reaction time: 0.5 h

Procedure:
To a room temperature solution of 1.13 g of 3-(2-bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 50 mL of acetonitrile was added 25 mL of water and 5.7 g of ceric ammonium nitrate. After 30 min, the reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (270 mg) was the title compound.
Reaction SMILES: CCCP(=O)=O.[CH2:7]([O:9][C:10]([C:12]1[N:13]([CH3:20])[N:14]=[CH:15][C:16]=1[C:17]([OH:19])=O)=[O:11])[CH3:8].[NH:21]1[CH2:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:7]([O:9][C:10]([C:12]1[N:13]([CH3:20])[N:14]=[CH:15][C:16]=1[C:17]([N:21]1[CH2:24][CH2:23][CH2:22]1)=[O:19])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1c(C(=O)O)cnn1C
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 111.3 %

Procedure:
Propylphosphonic anhydride solution (50% in ethyl acetate, 8.0 ml) was added to a cooled (0° C.) solution of 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 3-ethyl ester (1.00 g, 5.0 mmol), azetidine (576 mg, 10.1 mmol), and N,N-diisopropylethylamine (2.0 g) in ethyl acetate (40 ml). The mixture was stirred for 30 min at 0° C. and overnight at r.t. The reaction mixture was taken up in ethyl acetate, washed with water, dried (Na2SO4) and evaporated. The obtained title compound (1.32 g, 99%) was used in the next step without further purification. MS (m/e)=238.3 [M+H+].
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4]([Cl:7])([Cl:6])[Cl:5].[CH2:9]([O:16][NH:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[CH2:9]([O:16][N:17]([C:2]([O:3][C:4]([Cl:7])([Cl:6])[Cl:5])=[O:1])[C@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C=CCOC(=O)[C@@H]1C[C@@H](NOCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H]1C[C@@H](N(OCc2ccccc2)C(=O)OC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Diphosgene (0.1 mL, 0.804 mmol) was added slowly to a solution of 2-allyl 1-tert-butyl (2S,4R)-4-[(benzyloxy)amino]pyrrolidine-1,2-dicarboxylate (261 mg, 0.745 mmol) and triethylamine (0.13 mL, 0.933 mmol) in dichloromethane (4 mL) at 0° C. The reaction mixture was stirred at 0° C. for 4 hours then allowed to stand at room temperature overnight. The reaction mixture was chromatographed on silica gel eluted first with hexane then with 4:1 hexane:ethyl acetate to afford the title compound as a clear gum.
Reaction SMILES: C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:14][C:15](=O)[CH2:16][C:17]1([CH2:37][C:38](O)=[O:39])[S:21][C:20]2[CH:22]=[C:23]3[S:27][C:26]([CH2:32][C:33](O)=[O:34])([CH2:28][C:29](O)=[O:30])[S:25][C:24]3=[CH:36][C:19]=2[S:18]1)C.C(O)C>O>[OH:34][CH2:33][CH2:32][C:26]1([CH2:28][CH2:29][OH:30])[S:25][C:24]2[CH:36]=[C:19]3[S:18][C:17]([CH2:37][CH2:38][OH:39])([CH2:16][CH2:15][OH:14])[S:21][C:20]3=[CH:22][C:23]=2[S:27]1
Reactant: CCOC(=O)CC1(CC(=O)O)Sc2cc3c(cc2S1)SC(CC(=O)O)(CC(=O)O)S3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: OCCC1(CCO)Sc2cc3c(cc2S1)SC(CCO)(CCO)S3
Temperature: 25 °C

Procedure:
A dry flask under argon atmosphere was charged with diethyl ether (2600 ml) and LiAlH4 (21.2 g 0.56 mol) Benzo[1,2-d:4,5-d']bis(1,3)dithiole-2,2,6,6-tetraacetic acid ethyl ester (80.2 g, 0.139 mol) was added and the mixture was refluxed for 26 h. The mixture was cooled to ambient temperature and ethanol (165 ml) was carefully added followed by water (410 ml). The ether was decanted off and the white precipitate was stirred with water (3300 ml) to give a slurry. After acidification with hydrochloric acid the slurry was filtered and the crude product was washed with water and dried.
Reaction SMILES: [CH:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>C(O)C.[Pd]>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCCCCCC=Cc1cc2ccccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCc1cc2ccccc2[nH]1

Procedure:
2-Undec-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred until the hydrogen gas consumption was completely stopped. The reaction mixture was filtered through celite. The solvent was evaporated to afford the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.C(O)(=O)C.Cl>O1CCOCC1>[Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)CCn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Temperature: 90 °C

Procedure:
To a solution of ethyl 3-(3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)propanoate (75 mg, 0.148 mmol) in dioxane (492 μL) was added acetic acid (253 μL, 4.43 mmol) and conc. HCl (363 μL, 4.43 mmol). The mixture was heated at 90° C. for 1 h. The solvent was evaporated to one-third its volume, diluted with water (2 mL) and extracted with EtOAc (2×2 mL). The combined organic fractions were extracted with 1N NaOH (1 mL), the aqueous layer was acidified with 2N HCl (1 mL) and extracted with EtOAc (3×2 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated. The product was triturated with hexanes (2×2 mL) and dried under high vacuum to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([N:18]1[CH:22]=CC=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[N:30]1([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:35]CN[CH2:32][CH2:31]1>CO>[CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:32][CH2:31][N:30]([C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:35][CH2:22]1)=[N:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CC1
Yield: 50.3 %

Procedure:
Following the procedure described in Example 7, the reaction of N,N′-bis{[(2-methyl-2-propanyl)oxy]carbonyl}-1H-pyrazole-1-carboximidamide (0.25 g, 1.1 mmol), triethylamine (0.5 mL, 3.4 mmol) and benzyl piperazine-1-carboxylate (0.422 g, 1.36 mmol) in methanol (10 mL) gave the title compound (0.256 g, 50%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O:14][C:15](=[O:25])[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:17]([CH2:16][C:15]([OH:25])=[O:14])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Product: O=C(O)CN(Cc1ccccc1)c1cc(Br)ccc1[N+](=O)[O-]
Yield: 54.8 %

Procedure:
In a manner as described above, 4-bromo-2-fluoro-1-nitro-benzene (11 g, 50 mmol), and N-benzyl-glycine ethyl ester (10 g, 50 mmol) were reacted to give crude [(5-bromo-nitro-phenyl)-benzyl-amino]-acetic acid (10 g, 55%). This product was reacted with iron powder to obtain crude 4-benzyl-6-bromo-3,4-dihydroquinoxalin-2(1H)-one (5 g, 58%). A sample was recrystallized from ethyl acetate/hexane: m.p. 174-176° C. 1H-NMR (DMSO-d6) δ 3.75 (s, 2H), 4.43 (s, 2H), 6.71 (d, J=1.9 Hz, 1H), 6.81 (m, 2H), 7.32 (m, 5H), 10.57 (s, 1H).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+].[CH2:14]([O:32][CH2:33][CH:34]1O[CH2:35]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CC.Cl.[CH:38]([OH:41])(C)[CH3:39]>O>[ClH:1].[OH:41][CH:38]([CH:14]([O:32][CH2:33][CH2:34][CH2:35][NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:39]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CC(C)O
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCC(OCCCNCCCC[C@H](N)C(=O)O)C(C)O
Yield: 23.6 %

Procedure:
L-lysine hydrochloride (18.3 g, 0.1 mols) and 2.0 g (0.2 mols) of sodium hydroxide were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 32.6 g (0.1 mols) of octadecylglycidyl ether were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that octadecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 12.0 g of Nε-(2-hydroxy-3-octadecyloxy)propyl-L-lysine hydrochloride (yield 23.6%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[Na].Cl[CH2:15][C:16]1[N:20]=[C:19]([CH3:21])[O:18][N:17]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:15][C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: Cc1nc(CCl)no1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1nc(Cn2cnc3c2c(=O)[nH]c(=O)n3C)no1
Temperature: 100 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 3.76 g of (20 millimoles) of 3-methylxanthine-sodium, 100 ml of dimethyl formamide and 2.60 g (19.6 millimoles) of 3-chloromethyl-5-methyl-1,2,4-oxadiazole is stirred at 100° C. for one hour and a half. The hot reaction mixture is filtered and to the filtrate 50 ml of methanol are added. Thus 3.65 g of 3,7-dihydro-3-methyl-7-([5-methyl-1,2,4-oxadiazole-3-yl]-methyl)-1H-purine-2,6-dione are obtained, m.p.: 262°-264° C. Yield: 69%.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:7]1[C:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:9]([C:19]([O:21]CC)=[O:20])=[N:8]1)[CH2:5][CH3:6].C(O)(=O)C>CO.O>[CH2:4]([N:7]1[C:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:10][C:9]([C:19]([OH:21])=[O:20])=[N:8]1)[CH2:5][CH3:6]
Reactant: CCCn1nc(C(=O)OCC)cc1CC1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCn1nc(C(=O)O)cc1CC1CCOCC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 84.5 %

Procedure:
Lithium hydroxide monohydrate (3.8 g, 92 mmol) was added to a solution of ethyl 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxylate (6.43 g, 22.9 mmol) in methanol (30 mL) and water (10 mL). The mixture was stirred for 20 hours. Most of the volatiles were removed under reduced pressure, and water (100 mL) and acetic acid (52 mL, 910 mmol) were sequentially added. The solution was cooled to approximately 0° C. After five minutes, a white solid formed, and more water (100 mL) was added. The mixture was stirred for 30 minutes, and the solid was isolated by filtration, washed with water, and dried on the vacuum filter funnel to provide 4.88 g of 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxylic acid as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Cl[CH2:10][CH:11]=O>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[CH:11][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(I)ccn1
Reactant: O=CCCl
Solvent: CCO
Product: Ic1ccn2ccnc2c1
Temperature: 83 °C
Reaction time: 15 h
Yield: 31.6 %

Procedure:
Combine 4-iodo-pyridin-2-ylamine (4.00 g, 18.18 mmol) and chloroacetaldehyde (2.77 mL, 21.82 mmol) in ethanol (40 mL). Attach a reflux condenser, and heat the mixture to 83° C., stir overnight (15 hours), and cool to room temperature. Filter the resulting solution to yield the product as a tan solid (1.40 g, 32%). MS(ES), m/z 245 (M+1)