Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12](=[S:13])[NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]4[CH2:30][CH2:31][CH:32]([N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)[CH2:33][CH2:34]4)=[O:28])[CH:21]=3)=[CH:42][CH:43]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)CC1
Reaction time: 3 h
Yield: 40 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (149 mg) and (+)-10-camphorsulfonic acid (152 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 97:3) to provide the title compound (88.2 mg, 40%) as white powder.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:9][CH2:10][N:11]1[CH2:30][CH2:29][C:14]2([NH:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[C:15]2=[O:28])[CH2:13][CH2:12]1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.[OH-].[Na+]>>[NH2:7][C@H:8]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][C:14]2([NH:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[C:15]2=[O:28])[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN1CCC2(CC1)NC(=O)N(Cc1ccc(Br)cc1)C2=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCN1CCC2(CC1)NC(=O)N(Cc1ccc(Br)cc1)C2=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To 116 mg (0.2 mmol) of {3-[3-(4-bromobenzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-yl]-1-(S)-phenylpropyl}-carbamic acid tert-butyl ester were added 2 mL of a solution DCM/TFA 20%. The reaction mixture was agitated one hour at room temperature before neutralizing with 1.8 mL of a 10% aqueous solution of sodium hydroxide. Then the solution was extracted with DCM, dried over sodium sulfate, filtered and evaporated in vacuo yielding Compound 5 as a white solid (97 mg, 100%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)(C)C(N)=NO
Product: CC(C)(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 26 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 68 mg (70% of theory)
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]=[N:13]1)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]=[N:13]1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Yield: 64 %

Procedure:
1-(7-Methoxycarbonylheptyl)-4,5-diphenyltriazole (1g) was treated with 2N sodium hydroxide in aqueous ethanol at reflux temperature for 2.5 hours. The ethanol was removed in vaCuo and the residual mixture acidified with 2N aq HCl. The aqueous solution was extracted with ethyl acetate and the organic extracts combined, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from ethanol and water gave 1-(7-carboxyheptyl)-4,5-diphenyltriazole (0.61 g, 64%) as a white solid, m.p. 103°-104° C. Found: C, 72.66; H, 6.92; N, 11.44%
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[S:10][C:6]=2[CH:5]=1)([O-])=O.CN(C)C=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[S:10][C:6]=2[CH:5]=1
Reactant: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)c1ccncc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc2nc(NC(=O)c3ccncc3)sc2c1
Yield: 79.6 %

Procedure:
N-(6-Nitrobenzothiazol-2-yl)isonicotinamide (2.42 g, 8.04 mmol) was suspended in ethyl acetate (150 mL), and dimethylformamide was added until dissolution occured. After addition of palladium on charcoal (4.25 g, 10% Pd, 4 mmol Pd) the mixtue was hydrogenated (1 bar) at 60° C. until completion of the reaction. The palladium was removed by filtration through a pad of celite and the solvent was evaporated. The residue was taken up in little methanol and precipitated by addition of water to obtain N-(6-aminobenzothiazol-2-yl)isonicotinamide (1.73 g, 6.4 mmol, 80%). LC/ESI-MS: m/z=271 [M+H]+; m/z=269 [M−H]−; Rt=1.43 min.
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH3:22][C:23]12[CH2:29][C:28](=O)[CH:27]1[CH:26]=[CH:25][CH2:24]2>O>[CH3:22][C@:23]12[CH2:29][C:28](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:27]1[CH:26]=[CH:25][CH2:24]2
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CC12CC=CC1C(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1C[C@]2(C)CC=C[C@@H]12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.29 g, 14.7 mmol) was added dropwise at 0° C. over 5 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.59 g, 63%, 15.5 mmol), and the mixture was stirred at 0° C. for 15 minutes. To this solution, a tetrahydrofuran (15 mL) solution of 1-methylbicyclo[3.2.0]hept-3-en-6-one (1.60 g, 13.1 mmol) was added dropwise at 0° C. over 10 minutes, and the mixture was stirred at room temperature for 4 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (1.80 g, 62%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](O)([CH3:21])[CH2:13][C:12]2([CH3:24])[CH3:23])[CH:8]=[N:9][CH:10]=1)=[O:5]>CO>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][C:12]2([CH3:24])[CH3:23])[CH:8]=[N:9][CH:10]=1)=[O:5]
Reactant: COC(=O)c1cncn1C1c2ccccc2C(C)(O)CC1(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cncn1C1c2ccccc2C(C)=CC1(C)C
Temperature: 50 °C

Procedure:
To a 1.25 M anhydrous methanol solution of HCl (3 mL) is added 3-(4-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester, which can be prepared as described in Example 38, (85 mg, 0.27 mmol). The reaction is then heated to 50° C., and is then concentrated to dryness. The resulting residue is purified by silica gel flash chromatography (diethylamine-methanol-dichloromethane, 0.5:1:98.5) to provide 3-(2,2,4-trimethyl-1,2-dihydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 297.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.86 (s, 3 H), 1.13 (s, 3 H), 2.15 (d, J=1.3 Hz, 3 H), 3.91 (s, 3 H), 5.56 (s, 1 H), 6.31 (s, 1 H), 7.16-7.26 (m, 2 H), 7.31-7.41 (m, 2 H), 7.43 (s, 1 H), 7.70 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to afford the HCl salt of 3-(2,2,4-trimethyl-1,2-dihydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: ClCCl
Solvent: CCO
Product: Ic1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 1.1 c. from 4-iodobenzyl bromide and piperidine. Yield: 0.85 g (67% of theory); C12H16IN (M=301.17); calc.: molecular ion peak (M+H)+: 322; found: molecular ion peak (M+H)+: 302; Rf value: 0.55 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][NH2:10])[CH:2]=1.[CH2:11](Cl)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:11]([NH:10][CH2:9][CH2:8][NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCNc1cccnc1
Reactant: ClCC=Cc1ccccc1
Product: C(=C/c1ccccc1)\CNCCNc1cccnc1
Yield: 39 %

Procedure:
By treating 10 g of N-(3-pyridyl)ethylenediamine and 4.5 g of cinnamyl chloride (trans-form) in the same manner as in Example 106-(1), 2.91 g of (E)-N-cinnamyl-N'-(3-pyridyl)ethylenediamine was obtained as an oily substance.
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[S:7](=[O:11])(=[O:10])([OH:9])[OH:8]>>[S:7]([OH:11])([OH:10])(=[O:9])=[O:8].[C:3]([NH2:4])(=[O:8])[C:2]([CH3:6])=[CH2:1]
Reactant: CC(C)(O)C#N
Agent: O=S(=O)(O)O
Product: C=C(C)C(N)=O

Procedure:
Methacrylates have been commercially prepared by reacting acetone cyanohydrin and sulfuric acid to form methacrylamide sulfate and then adding water and an alcohol to effect hydrolysis and esterification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: BrCc1ccccc1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccccc2)c(=O)[nH]c1=O
Yield: 79.8 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (289 mg, yield: 79.8%).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>>[NH2:36][C:34]([C:23]1[CH:24]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[C:27]2[C:22]=1[NH:21][CH:20]=[C:19]2[CH:16]1[CH2:17][CH2:18][N:13]([S:10]([CH2:9][CH2:8][CH2:7][NH:37][CH:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: CC(C)(C)OC(=O)N1CCC(NCCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)CC1
Yield: 25.5 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (50 mg, 0.0.109 mmol) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (108.8 mg, 0.543 mmol) were allowed to react in the presence of K2CO3 (60 mg, 0.435 mmol) and sodium iodide (2 mg). The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (17.3 mg, 26%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:11]1[CH:16]=[CH:15][C:14]([C:17](O)=O)=[CH:13][N:12]=1.N>>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:13][N:12]=1
Reactant: O=C(O)c1ccnnc1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccnnc3)n2)c1

Procedure:
The titled compound was prepared according to the procedure of Method C using N′-hydroxynicotinimidamide (Aldrich) and pyridazine-4-carboxylic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.67 (ddd, J=8.1, 5.0, 0.8 Hz, 1 H), 8.45 (dd, J=5.4, 2.4 Hz, 1 H), 8.60 (dt, J=8.1, 1.9 Hz, 1 H), 8.78 (dd, J=5.1, 1.7 Hz, 1 H), 9.34 (dd, J=2.2, 0.8 Hz, 1 H), 9.55 (dd, J=5.4, 1.4 Hz, 1 H), 9.94 (dd, J=2.2, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z=226 (M+H)+.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29](ON3C(=O)CCC3=O)=[O:30])C3C(=CC=CC=3)C=2C=CC=1.[ClH:40].[NH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[C:44](=[O:65])[N:45]([C:52]1([CH2:60][CH2:61][CH2:62][CH2:63][NH2:64])[CH2:57][CH2:56][C:55](=[O:58])[NH:54][C:53]1=[O:59])[C:46]2=[O:51].C(N(CC)CC)C>CS(C)=O>[NH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[C:44](=[O:65])[N:45]([C:52]1([CH2:60][CH2:61][CH2:62][CH2:63][NH:64][C:29](=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][NH2:17])[CH2:57][CH2:56][C:55](=[O:58])[NH:54][C:53]1=[O:59])[C:46]2=[O:51].[ClH:40].[NH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[C:44](=[O:65])[N:45]([C:52]1([CH2:60][CH2:61][CH2:62][CH2:63][NH2:64])[CH2:57][CH2:56][C:55](=[O:58])[NH:54][C:53]1=[O:59])[C:46]2=[O:51]
Reactant: O=C(CCOCCOCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: NCCCCC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: NCCOCCOCCOCCC(=O)NCCCCC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 23 (0.012 g, 0.022 mmol) in DMSO (2 mL) were added 7 (0.011 g, 0.0289 mmol) and triethylamine (0.01 mL, 0.071 mmol) under an atmosphere of argon, and the mixture was stirred at room temperature. After 16 h, the crude mixture was directly purified by preparative HPLC to afford 25 (0.005 g, 42%), 24 (0.0014 g, 8.2%) and unreacted 7 (0.0037 g, 48%). 1H NMR (400 MHz, DMSO) δ 8.39 (s, 2H), 7.86 (s, 1H), 7.49-7.37 (m, 1H), 7.04-6.82 (m, 2H), 6.53 (s, 2H), 3.59-3.36 (m, 11H), 3.03-2.93 (m, 2H), 2.84-2.76 (m, 2H), 2.33-2.16 (m, 5H), 2.05-1.96 (m, 2H), 1.44-1.31 (m, 3H), 1.25-1.16 (m, 3H). MS (ESI) m/z calcd for C26H38N5O8 [M+H]+ 548.6, found 548.5.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([NH:15][C:16]1[N:21]=[C:20]([C:22]2[N:26]3[CH:27]=[CH:28][N:29]=[C:30]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[C:25]3=[N:24][CH:23]=2)[CH:19]=[CH:18][N:17]=1)[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)(C)(C)C.Cl>C(O)C>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([C:30]2[C:25]3[N:26]([C:22]([C:20]4[CH:19]=[CH:18][N:17]=[C:16]([NH:15][CH:9]([C:10]5[CH:14]=[CH:13][S:12][CH:11]=5)[CH2:8][NH2:7])[N:21]=4)=[CH:23][N:24]=3)[CH:27]=[CH:28][N:29]=2)[CH2:36][CH2:35]1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(NC(CNC(=O)OC(C)(C)C)c5ccsc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CN)c5ccsc5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude (2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester (150 mg, 0.280 mmol) in ethanol (5 mL) was added concentrated hydrochloric acid (5 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford N1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-ethane-1,2-diamine; hydrochloride. (Yield 13 mg, 5.57%). 1H NMR (300 MHz, CD3OD): δ 8.81 (brs, 1H), 8.63 (s, 1H), 8.29 (d, 1H, J=6.0 Hz), 7.61-7.52 (m, 3H), 7.46-7.43 (m, 1H), 7.23 (d, 1H, J=5.1 Hz), 5.72 (brs, 1H), 5.47-5.43 (m, 2H), 3.63-3.60 (m, 4H), 3.50-3.48 (m, 2H), 3.29-3.26 (m, 2H), 2.89 (s, 3H). LC-MS: [M+H]+ 436.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8].Cl.[C:18](=N)(OC)[CH3:19]>C(OCC)C>[CH3:18][C:19]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=2[N:3]=1
Reactant: COC(C)=N
Reactant: CCCNc1ccc(C(=O)O)cc1N
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCCn1c(C)nc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 116.5 %

Procedure:
To a methanol (17 mL) solution of 3-amino-4-n-propylaminobenzoic acid (see Working Example 82-2) (1.68 g, 8.65 mmol) was added methyl acetimidate hydrochloride (1.14 g, 10.4 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, diethyl ether was added, and this was allowed to stand at room temperature for 10 minutes. The crystals obtained were filtered, and after being washed with diethyl ether, they were dried to yield the title compound (2.20 g, quant.).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Cl)(=[O:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+].ClCCl.CCCCCC>C(N)=O.C(OCC)(=O)C>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[N:25]=[N+:26]=[N-:27])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 46 (950 mg) was added to a precooled solution of 1 g of sodium azide in 10 mL formamide. The mixture was stirred at room temperature for 24 hr. The reaction mixture was poured into a mixture of 50 mL of dichloromethane and 50 g of ice. The dichloromethane layer was collected and dried and the solvent was removed to give a gum. The gum was dissolved in 2 mL ethyl acetate and added dropwise to 100 mL hexane. Crystals of 2-acetamido-3,4,6-tri-O-acetyl-1-azido-1,2-dideoxy-a-D-galactopyranose 47, formed immediately and were collected by filtration (1.0 g).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:14])([F:13])[C:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[NH2:15][C:16]1[S:17][C:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[C:24]1([S:21]([C:18]2[S:17][C:16]([NH:15][C:8](=[O:9])[C:7]([OH:12])([CH3:11])[C:6]([F:14])([F:13])[F:5])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)s1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)s1)C(F)(F)F
Reaction time: 1 h

Procedure:
Thionyl chloride (80 μl, 1.1 mmol) is added to 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (170 mg, 1.08 mmol) in 5 ml of N,N-dimethylacetamide at -15°/-10° C. and the mixture is stirred at this temperature for one hour. After adding 2-amino-5-(phenylsulfonyl)thiophene (170 mg, 0.710 mmol) and equilibration to room temperature and after the reaction has ended, the reaction mixture is poured into 200 ml of water and subjected to extraction with 3×100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and filtered and the solvent is distilled off. The orange-colored oil which remains is purified by flash chromatography (eluent: 50% v/v ethyl acetate in petroleum ether (40/60)).
Reaction SMILES: [C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][N:16]([C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+]>CO>[C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][N:16]([C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CN(C(=O)CCCCC)c2cccc(C(=O)OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCCCC)c2cccc(C(=O)O)c2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl 3-[(4-dec-1-yn-1-ylbenzyl)(hexanoyl)amino]benzoate and NaOH 5N aq in the presence of MeOH as a pale yellow oil (89%). 1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J=7.5 Hz, 1H), 7.82 (s, 1H), 7.43 (m, 1H), 7.31 (d, J=8.3 Hz, 2H), 7.12 (m, 3H), 4.91 (s, 2H), 2.39 (t. J=7.0 Hz, 2H), 2.07 (m, 2H), 1.60 (m, 4H), 1.44 (m, 2H), 1.35-1.17 (m, 12H), 0.86 (m, 6H). M− (ESI): 460.6; M+ (ESI): 462.5. HPLC, Rt: 5.65 min (Purity: 99.5%).
Reaction SMILES: [NH2:1][C:2](=[C:7]1C(=O)O[C:10](C)([CH3:14])[O:9][C:8]1=[O:16])[CH2:3][CH:4]1[CH2:6][CH2:5]1.[Na]>C(O)C.ClCCl>[CH2:10]([O:9][C:8](=[O:16])[CH:7]=[C:2]([NH2:1])[CH2:3][CH:4]1[CH2:5][CH2:6]1)[CH3:14]
Reactant: CC1(C)OC(=O)C(=C(N)CC2CC2)C(=O)O1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C=C(N)CC1CC1
Yield: 70 %

Procedure:
397 mg (2 mmol) 5-(1-Amino-2-cyclopropyl-ethylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione were added to a solution of 45 mg (2 mmol) sodium in 3 ml ethanol. The reaction mixture was heated under reflux for 14 h, diluted with dichloromethane and poured onto ice water/brine 1/1. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to give 231 mg (1.4 mmol, 77%) of the title compound as orange oil.