Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:75]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([CH2:88][B-](F)(F)F)[C@H:84]([CH3:93])[CH2:83]1)=[O:81])([CH3:78])([CH3:77])[CH3:76].[K+].C(N1CCN[C@H](C)C1)(OC(C)(C)C)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]3[CH:3]=[C:2]([CH2:88][N:85]4[CH2:86][CH2:87][N:82]([C:80]([O:79][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:81])[CH2:83][C@H:84]4[CH3:93])[CH:7]=[N:6][C:5]=3[F:8])[N:10]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3F)n2)cc1
Temperature: 85 °C
Yield: 73.7 %

Procedure:
In a 5 mL microwave tube was weighed 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.00 g, 2.084 mmol; Example 313, Step 1), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (0.099 g, 0.208 mmol), cesium carbonate (2.037 g, 6.25 mmol), potassium (R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate (prepared similarly according to Example 270, Stepl, from (R)-4-N-boc-2-methyl-piperazine (Sigma Adrich, Inc.), 0.701 g, 2.188 mmol,), palladium acetate (0.023 g, 0.104 mmol) followed by purging with argon. The solids were then treated with THF (10.00 mL), water (1.0 mL) and heated under a microwave irradiation at 85° C. overnight. The mixture was filtered through a short path of Celite® (diatomaceous earth), washed with ethyl acetate (3×), and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (100% DCM to 5% MeOH in DCM) to obtain the desired product (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (1.01 g, 1.535 mmol, 73.7% yield) as a yellow foam. m/z (ESI, +ve ion) 658 (M+H)+.
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[NH:5][C:6]([NH:8][C:9]1[S:10][C:11](=[S:14])[NH:12][N:13]=1)=[O:7].[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[S:14]=[C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C@@H:4]([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:3]([NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:7])=[N:13][NH:12]1
Reactant: NCCc1ccccc1
Reactant: COC(=O)[C@H](CC1CCCCC1)NC(=O)Nc1n[nH]c(=S)s1
Product: O=C(Nc1n[nH]c(=S)s1)N[C@@H](CC1CCCCC1)C(=O)NCCc1ccccc1

Procedure:
Following the general procedure outlined in EXAMPLE 5, and making non-critical variations but starting with N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-β-cyclohexyl-L-alanine methyl ester (prepared similarly to that described in EXAMPLE 1) and phenethylamine, the title compound is obtained (mp 199°-200° C.).
Reaction SMILES: [C:1]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19].C1COCC1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:57]1[C:62](=[O:63])[CH2:61][CH2:60][C:58]1=[O:59])=[N+](C)C)C>CN(C=O)C>[C:18]([O:20][N:57]1[C:62](=[O:63])[CH2:61][CH2:60][C:58]1=[O:59])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C([O-])CCCCCCCCCCCCCCCCC(=O)OCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Mono-benzyl octadecandioate was dissolved in DMF (3.5 mL) and THF (7 mL) and cooled with ice bath. DIEA (0.103 mL) and TSTU were added and the mixture was stirred 1 h at ice bath and at RT overnight. The solvent was evaporated in vacuo and the residue was dissolved in AcOEt and washed twice with 0.2 N HCl, saturated NaHCO3, dried, filtered and evaporated to dryness to give succinimidyl mono-benzyl octadecandioate (0.25 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57].O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:28]=[CH:27][C:25]([NH:26][S:56]([CH3:55])(=[O:58])=[O:57])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:29]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Nc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
While 7 mL solution of 68 mg 4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}aniline obtained in Example 19 and 34 mg triethylamine in dichloromethane was stirred in a stream of nitrogen, 20 μL methylsulfonyl chloride was added thereto. Then, the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the concentrated residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 52 mg of the title compound as a pale yellow amorphous.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]1[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH:8]([C:19]([NH2:21])=[O:20])[NH:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][S:2]([N:7]1[CH:8]([C:19]([NH2:21])=[O:20])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:6]1)(=[O:4])=[O:3]
Reactant: NC(=O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1Cc2[nH]c3ccccc3c2CC1C(N)=O
Reaction time: 8 h

Procedure:
Methane sulphonyl chloride (0.18 ml, 2.4 mmol) was added to a stirred solution of dl 1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indole-3-amide (0.430 gm, 2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry DMF (8 ml) during 15 min at room temperature 30° C. The reaction mixture was allowed to stirr for 8 hrs. at room temperature. Water (20 ml) was added to the reaction mixture and extracted with chloroform (3×15 ml). The extract was dried over Na2SO4 and concentrated over reduced pressure to give 2-[methanesulphonyl]-1,2,3,4, -tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide which was purified by column chromatography over silica gel using 2% methanol chloroform as eluent. Yield=0.150 gm (25.60%). m.p.=234° C. Mass (FAB) m/z=294 (M+). IR (KBr cm−1): 3483, 3361, 1685, 1610, 1446, 1325, 1148, 756. H1NMR (200 MHz, CDCl3) δ 3.04 (s, 3H), δ3.20-3.63 (m, 2H), δ4.69-4.84 (m, 3H), δ6.96-7.15 (m, 3H), δ7.32-7.53 (m, 3H), δ10.89 (s, 1H). Molecular Formula=C13H15N3O3S.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([NH2:7])=[O:6].[C:8]1([C:14]([C:16]2[NH:24][C:19]3=[CH:20][N:21]=[CH:22][CH:23]=[C:18]3[CH:17]=2)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCO>[C:8]1([C:14](=[N:2][O:3][CH2:4][C:5]([NH2:7])=[O:6])[C:16]2[NH:24][C:19]3=[CH:20][N:21]=[CH:22][CH:23]=[C:18]3[CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NOCC(N)=O
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Solvent: CCO
Product: NC(=O)CON=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 25 °C
Yield: 37 %

Procedure:
1 N HCl (0.67 mL, 0.67 mmol) was added to a solution of 2-(aminooxy)acetamide (Reference Example 18) (90.5 mg, 1.04 mmol) in EtOH (6.7 mL) followed by addition of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (150 mg, 0.67 mmol). The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was free based using an SCX-2 and purified by Biotage chromatography to isolate 2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]acetamide (72.9 mg, 37%) as a white solid (single isomer, geometry of the oxime double bond undefined): Rf 0.13 (90:10 methylene chloride/methanol); 1H NMR (500 MHz, DMSO-d6) δ4.65 (2H, s), 6.65 (1H, s), 7.41-7.58 (8H, m), 8.14-8.15 (1H, d, J=5.5 Hz), 8.89 (1H, s), 12.01 (1H, br s); ESI MS m/z 295 [C16H14N4O2+H]+; HPLC (Method A) 98.9% (AUC), tR=14.8 min.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:10][CH3:11])[C:8]=1[CH3:9].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([N:7]1[C:8]([CH3:9])=[C:4]([CH2:3][S:19][C:17]2[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=2)[N:5]=[CH:6]1)[CH3:11]
Reactant: CCn1cnc(CCl)c1C
Reactant: Cc1cc(O)nc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1cnc(CSc2nc(C)cc(O)n2)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.3 %

Procedure:
A mixture of 4-(chloromethyl)-1-ethyl-5-methyl-1H-imidazole hydrochloride (450 mg, 2.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (215 mg, 1.5 mmol), and potassium carbonate (720 mg, 5.2 mmol) in acetone (15 mL) was stirred at room temperature for 3 days. The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-6% MeOH/DCM), affording 2-{[(1-ethyl-5-methyl-1H-imidazol-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (128 mg, 32% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.26 (t, 3H, J=6.7 Hz), 2.18 (m, 6H), 3.86 (m, 2H), 4.26 (s, 2H), 5.95 (s, 1H), 7.55 (s, 1H); M+266. The product was used without further purification.
Reaction SMILES: [C@@H]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14](N)[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H]1(N2C3N=CN=C(O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.C([O-])(=O)C.[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[N:16]1[CH:14]=[C:13]2[C:19]([N:10]=[CH:11][NH:12]2)=[N:18][CH:17]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Product: c1ncc2[nH]cnc2n1
Reaction time: 0.33 h

Procedure:
The optimum temperature was determined by high-performance liquid chromatography with adenosine, guanosine and inosine substrates. The reaction solution (200 μl) contained 0.5 mM of adenosine or inosine or 0.25 mM of guanosine as the substrate, 50 mM of sodium acetate buffer solution (pH 4.5) or 50 mM of potassium phosphate buffer solution (pH 5.5) and a sufficient amount of enzyme, and the reaction was conducted at different temperatures for 20 minutes. The results are shown in FIGS. 5 and 6. The optimum temperature at pH 4.5 was 50° C. for adenosine, guanosine and inosine. The optimum temperature at pH 5.5 was 60° C. for adenosine and inosine and 50° C. for guanosine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].[Cl-].[NH4+]>CC(C)P([O-])(=O)[O-].O.[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: CC(C)P(=O)([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Clc1cc(Cl)c(Cl)nc1Cl
Reaction time: 0.67 h
Yield: 92.2 %

Procedure:
12.76 g (0.05 mol) of pentachloropyridine is dissolved, by heating at 90° C., in 80 ml of dimethylmethanephosphonate. After the addition of 4.1 g (0.063 gram atom) of zinc dust, there is added dropwise to the clear solution in the course of 20 minutes, with vigorous stirring, a solution of 4.26 g (0.08 mol) of ammonium chloride in 15 ml of water. After the addition of the ammonium chloride solution has been completed, stirring is continued for 40 minutes. The reaction mixture obtained is then filtered hot, and the filter residue is washed with 10 ml of dimethylmethanephosphonate. The filtrate is poured into 500 ml of ice water; there is then added 12.5 ml of concentrated hydrochloric acid and the mixture is stirred for 2 hours. The 2,3,5,6-tetrachloropyridine, which has precipitated in the form of white crystals, is subsequently washed with 150 ml of water and dried. In this manner is obtained 10.0 g (90.8% of theory) of 2,3,5,6 -tetrachloropyridine having a melting point of 89° to 90° C. According to gas-chromatographical analysis, the product contains 97.0% of 2,3,5,6-tetrachloropyridine, 0.5% of 2,3,5-trichloropyridine, 0.6% of 2,3,6-trichloropyridine and 1.6% of pentachloropyridine.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[O:36])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2c1OCC2
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](NC(=O)C4CCOCC4)CC3)CC2)c2c1OCC2

Procedure:
The title compound, white solid (60 mg, 88%), MS (ISP) m/z=457.5 [(M+H)+], mp 223.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]I)=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][O:21][C:14]3[C:15]([Cl:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[Cl:12])=[CH:26][CH:27]=2)[C:9]#[N:10])=[C:4]([Cl:11])[CH:3]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Reactant: N#CCc1ccc(Br)cc1Cl
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3Cl)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 4 using (4-bromo-2-chlorophenyl)acetonitrile (III.3) and 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1) as starting materials. Purification by column chromatography on silica gel, eluting with Hex/Tol (50 to 75%), afforded the desired compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=4)[N:18]=3)=[CH:15][N:16]=2)[CH2:8][CH2:7]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:30][C:28]1[CH:27]=[CH:26][N:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:14]3[S:13][C:12]([N:9]4[CH2:8][CH2:7][CH:6]([CH2:5][CH2:4][C:3]([OH:31])=[O:2])[CH2:11][CH2:10]4)=[N:16][CH:15]=3)[CH:22]=[CH:21][CH:20]=2)[CH:29]=1
Reactant: COC(=O)CCC1CCN(c2ncc(-c3cccc(Nc4cc(C)ccn4)n3)s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(CCC(=O)O)CC4)s3)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.8 %

Procedure:
To a mixed solution of 3-(1-{5-[6-(4-methyl-pyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}piperidine-4-)propionic acid methyl ester (250 mg, 0.57 mmol) obtained in Step 3 in tetrahydrofuran (5 ml) and methanol (5 ml), 4N sodium hydroxide (1.5 ml, 6.0 mmol) was added and the mixture was stirred at room temperature for 12 hours. The concentrate obtained by concentrating the reaction solution in vacuo was neutralized with 0.1N hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and the title compound (142 mg, 59%) was obtained.
Reaction SMILES: C[Si](O/C(=N/[Si](C)(C)C)/C)(C)C.[F:13][C:14]1[C:15](=[NH:22])[N:16]([CH3:21])[C:17](=[O:20])[NH:18][CH:19]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:27](Cl)=[O:28]>C(#N)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:27]([N:18]1[CH:19]=[C:14]([F:13])[C:15](=[NH:22])[N:16]([CH3:21])[C:17]1=[O:20])=[O:28]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Cn1c(=O)[nH]cc(F)c1=N
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC#N
Product: Cn1c(=N)c(F)cn(C(=O)c2cc(Cl)cc(Cl)c2)c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
In a capped vial, (E)-trimethylsilyl-N-(trimethylsilyl)acetimidate (157 mg, 0.774) was added to 5-fluoro-4-imino-3-methyl-3,4-dihydropyrimidin-2(1H)-one (100 mg, 0.704 mmol) and acetonitrile (1.0 mL) and heated at 70° C. for 30 min. The solution was cooled to room temperature and 3,5-dichlorobenzoyl chloride (133 mg, 0.633 mmol) was added dropwise and the contents were stirred overnight at room temperature. The reaction was concentrated with a stream of nitrogen. Diethyl ether (Et2O; 3 mL) was added and the vial was recapped and shaken briefly. The solids were filtered and washed with a small amount of Et2O and air dried to provide the title compound as a white solid (78 mg, 35%): mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=5.5 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.49 (d, J=1.8 Hz, 2H), 3.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.97, 136.71, 135.23, 135.12, 132.76, 132.37, 127.95, 126.48, 114.66, 114.27, 29.56, 29.01; ESIMS m/z 317 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:28]([O:35][C:36](=[O:39])[CH2:37]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36](=[O:39])[CH2:37][N:14]([S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:12])=[O:13])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: O=C(CBr)OCc1ccccc1
Product: COc1ccc(S(=O)(=O)N(CC(=O)OCc2ccccc2)c2ccc(N3CCC(=O)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 242) and benzyl-2-bromoacetate according to the procedure of Example 251 as an orange gum; 1H NMR (300 MHz, CDCl3) δ 2.53 (t, J=6.06 Hz, 4H), 3.59 (t, J=6.00 Hz, 4H), 3.79 (s, 3H), 3.93 (s, 3H), 4.50 (s, 2H), 5.13 (s, 2H), 6.78–6.87 (m, 2H), 7.07–7.10 (m, 2H), 7.15 (d, J=2.1 Hz, 1H), 7.27–7.37 (m, 7H); MS (ES) m/z: 539.0 (MH+); HRMS found for C28H30N2O7S (MH+): 539.1842.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16][CH:15]([C:22]([OH:24])=[O:23])[CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16][CH:15]([C:22]([OH:24])=[O:23])[CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C1CC(C(=O)O)CN(S(=O)(=O)c2cccc([N+](=O)[O-])c2)C1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: Nc1cccc(S(=O)(=O)N2CC(C(=O)O)CC(C(=O)O)C2)c1
Yield: 130.5 %

Procedure:
A solution of 1-(3-nitro-benzenesulfonyl)piperidine-3,5-dicarboxylic acid (Example 45, 2.5 g, 4.2 mmol) in 150 ml of methanol was hydrogenated in Parr apparatus at 25 Psi over 0.15 g of the palladium catalyst (10% palladium on carbon) for 1 h. Filtration of the catalyst and solvent removing gave 1.8 g (79%) of the desired product as a white solid. MS (ES) m/z 329.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:30][CH2:29][C:24]3(OCC[O:25]3)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1.Cl.[OH-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:22][CH2:23][C:24](=[O:25])[CH2:29][CH2:30]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(Cl)cnc2c1C(=O)Nc1cnccc1N1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nn2cc(Cl)cnc2c1C(=O)Nc1cnccc1N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-6-chloro-N-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared according to a procedure similar to Example 1) (420 mg, 0.9771 mmol) in tetrahydrofuran (10 mL) was added HCl (4.886 mL of 2 M, 9.771 mmol). The resulting mixture was stirred at room temperature overnight. The resulting reaction mixture was diluted with water (100 mL), made basic with 2.5 N aqueous sodium hydroxide, and extracted three times with dichloromethane (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-amino-6-chloro-N-(4-(4-oxopiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a pale yellow solid which was used without further purification. MS (ES+) 386.1.
Reaction SMILES: C([C:4]1[NH:16][C:15]2[C:14](=[O:17])[N:9]([CH2:10]C(O)=O)[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[N:5]=1)CC.ON1C(=O)CCC1=O.O>CN(C=O)C>[N:9]1([C:14](=[O:17])[C:15]2[NH:16][CH:4]=[N:5][C:6]=2[N:7]([CH3:19])[C:8]1=[O:18])[CH3:10]
Reactant: CCCc1nc2c([nH]1)c(=O)n(CC(=O)O)c(=O)n2C
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 mg of 8-propylcarboxytheophylline was dissolved in 1 ml of DMF, and added with 3 mg of N-hydroxysuccinimide and 5 mg of water-soluble carbodiimide, followed by stirring at room temperature for 2 hours, to obtain activated theophylline. 10 mg of bovine serum albumin (BSA) was dissolved in 1 ml of a 0.1M aqueous solution of sodium hydrogencarbonate and added with 500 μl of the aforementioned activated theophylline solution. The mixed solution was allowed to stand at room teperature for an hour, and then unreacted substances were removed through a Sephadex-G25 column preliminarily equilibrated with PBS to obtain 9 mg of the objective large molecule antigen (theophylline-BSA conjugate)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][NH2:13])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc([N+](=O)[O-])cn1

Procedure:
To a solution of 2-chloro-5-nitropyridine (30 mmol, 5.0 g) in absolute ethanol was added a solution of hydrazine hydrate (320 mmol, 15.8 g) in ethanol using syringe pump. At the end of the addition, the reaction was refrigerated. The named product precipitated from the reaction medium, was collected by filtration, and recrystallized from ethanol.