Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[S:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[C:3]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[S:24][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=c1c2ccccc2[nH]c(=S)n1Cc1ncc(C(F)(F)F)cc1Cl
Reactant: Clc1ccc(CBr)cc1
Product: O=c1c2ccccc2nc(SCc2ccc(Cl)cc2)n1Cc1ncc(C(F)(F)F)cc1Cl

Procedure:
This compound was prepared from the product of Example 10 and 4-chlorobenzylbromide in analogous fashion to Example 8, m.p. 137° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](Cl)=[C:12](Br)[C:11](=[O:16])[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCO[C:44]([CH3:46])=O>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[C:12]([C:46]2[CH:44]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[C:11](=[O:16])[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1c(Br)c(Cl)n(Cc2ccccc2)c(=O)n1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)n(Cc2ccccc2)c(=O)n1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1,3-dibenzyl-5-bromo-6-chloropyrimidine-2,4(1H,3H)-dione (6.0 g, 14.8 mmol) in toluene (50 mL) at room temperature under argon was added 4-chlorophenylboronic acid (7.0 g, 44.77 mmol), tetrakis(triphenylphosphine)palladium (1.03 g, 0.89 mmol), and a solution of Na2CO3 (4.7 g, 44.34 mmol) in water (10 ml). The resulting suspension was stirred at reflux under argon for 6 h. After the reaction mixture was cooled to room temperature, water (50 mL) and EtOAc (75 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted 15% ethyl acetate-hexanes to obtain 7.2 g of the title compound as a white solid. HPLC/MS (MeOH-water with 10 mM NH4OAc): retention time=4.241 min, [M+H]30 =513.
Reaction SMILES: C[NH:2]/C(/C)=C\C(OC)=O.[Cl:10][C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1OCCOC1C=C(C=CC=1)C(Cl)=O.C[NH:31]/[C:32](/[CH3:57])=[C:33](/[C:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])[CH:40]=1)\[C:34]([O:36][CH3:37])=[O:35].O.NN>>[CH3:57][C:32]1[NH:31][N:2]=[C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][CH2:47][C:12]3[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=3[Cl:10])[CH:40]=2)[C:33]=1[C:34]([O:36][CH3:37])=[O:35].[CH3:57][C:32]1[NH:31][N:2]=[C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[Cl:55])[CH:40]=2)[C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: O=C(Cl)c1cccc(OCCOc2ccccc2Cl)c1
Reactant: CN/C(C)=C\C(=O)OC
Reactant: CN/C(C)=C(\C(=O)OC)C(=O)c1cccc(OCCOc2ccccc2Cl)c1
Agent: NN
Solvent: O
Product: COC(=O)c1c(-c2cccc(OCCOc3ccccc3Cl)c2)n[nH]c1C
Product: COC(=O)c1c(-c2cccc(OCCc3ccccc3Cl)c2)n[nH]c1C

Procedure:
Using a procedure similar to that described in Example 1, 0.5 mole of methyl 3-methylaminocrotonate and 0.5 mole of 3-[2-(2chlorophenoxy)-ethoxy]-benzoyl chloride are converted to methyl 3-methylamino-2-[3-(2-(2-chlorophenoxy)-ethoxy)-benzoyl]-crotonate of melting point 131°-133° C., the yield being 58%. When reacted with hydrazine hydrate by a procedure similar to that described in Example 1, this ester gives 5-methyl-4-methoxycarbonyl-3-[3-(2-(2-chlorophenoxy)-ethoxy)-phenyl]-pyrazole of melting point 127°-129° C., the yield being 59%.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9]Br)[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1.CCOC(C)=O>CC#N.O>[CH3:6][O:5][C:3]([C@@H:2]1[CH2:7][CH2:8][CH2:9][N:26]1[C@H:24]([C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)[CH3:25])=[O:4]
Reactant: COC(=O)C(Br)CCCBr
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1CCCN1[C@@H](C)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
The following procedure was adapted from W. A. J. Starmans, R. W. A. Walgers, L. Thijs, R. de Gelder, J. M. M. Smits, and B. Zwanenburg, Tetrahedron 54 (1998) 4991-5004. To a mixture of methyl 2,5-dibromopentanoate (0.401 ml, 2.56 mmol) and K2CO3 (706 mg, 5.11 mmol) in MeCN (7 ml) and water (0.7 ml) was added dropwise a solution of (S)-1-(4-bromophenyl)ethanamine (0.405 ml, 2.81 mmol) in MeCN (3.5 ml) at 80° C. After the addition, the reaction mixture was further stirred at 80° C. for 14 h then cooled to RT, diluted into AcOEt (50 ml) and washed with water (40 ml). The aqueous phase was further extracted with AcOEt and the combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified and both diastereoisomers separated by reversed phase prep-HPLC (gradient elution, MeCN/water containing 20 mM ammonium formate). Fractions containing pure material were combined and concentrated under vacuum. The resulting aqueous mixture was basified by the addition of Na2CO3 2M and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield the title compounds as light yellow oils. Intermediate 89.1:240 mg, 0.77 mmol, 30%; HPLC: AtRet=1.15 min, CtRet=4.07 min; LC-MS: m/z 314.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.38 (d, J=6.6, 3H), 1.76-1.99 (m, 3H), 2.04-2.16 (m, 1H), 2.52 (q, J=8.1, 1H), 3.05-3.13 (m, 1H), 3.47 (dd, J=9.4, 3.5, 1H), 3.51 (s, 3H), 3.66 (q, J=6.6, 1H), 7.21-7.26 (m, 2H), 7.39-7.45 (m, 2H). Intermediate 89.2: 222 mg, 0.71 mmol, 28%; HPLC: AtRet=1.15 min, CtRet=5.18 min; LC-MS: m/z 314.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.36 (d, J=6.8, 3H), 1.73-1.84 (m, 1H), 1.84-1.96 (m, 2H), 2.03-2.14 (m, 1H), 2.54-2.63 (m, 1H), 2.93-3.02 (m, 1H), 3.31 (dd, J=9.2, 4.0, 1H), 3.69 (s, 3H), 3.72 (q, J=6.6, 1H), 7.17-7.22 (m, 2H), 7.42-7.47 (m, 2H). The configuration of each diastereoisomers was attributed by comparing the 1H NMR spectra with published 1H NMR data of close analogues (see R. Almansa, D. Guijarro and M. Yus Tetrahedron: Asymmetry 18, 2007, 2828-2840).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[H-].[Na+].[O:13]1[CH:15]([CH2:16][O: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][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:14]1>>[OH:13][CH:15]([CH2:16][O: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][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:14][O:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Reactant: OCCCc1cccnc1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCOCC(O)COCCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
To 3-pyridinepropanol (41.9 g), 60% oily sodium hydride (0.74 g) was added, followed by stirring at room temperature for 15 minutes. Crude 1,2-epoxy-3-octadecyloxypropane (10 g), an intermediate in Reference Example 1, was then added, followed by stirring at room temperature for 67 hours. The excess portion of the 3-pyridinepropanol was distilled off under reduced pressure. After adding a small volume of water to the residue, extraction was conducted with a mixture of hexane and ethyl acetate (1:1, 300 ml). After the extract was washed with water and dried, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (carrier, 250 g; developing solvent, hexane:ethyl acetate:acetone=4:1:0→3:1:1) to yield the desired compound (5.79 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=[O:18]>C(#N)C>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]([NH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1)=[O:18]
Reactant: Nc1cc[nH]n1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred solution of 3-aminopyrazole (60 g, 0.722 mol, ABCR) in acetonitrile (500 ml) at 0° C. (ice/brine bath) was added, dropwise, triethylamine (201 ml, 1.44 mol) at such a rate to keep the temperature below 5° C. The reaction mixture was stirred at 0° C. for 0.5 h then a solution of 2,6-difluorobenzoyl chloride (127.5 g, 0.722 mol, Aldrich) in acetonitrile (200 ml) was added over approximately 1 h, keeping the temperature between 0-7° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water (250 ml) and EtOAc (500 ml). Some solid formed at the interface, this was filtered off and turned out to be product—combined with isolated product at the end for drying. The aqueous layer was separated and extracted with EtOAc (2×500 ml). The combined organics were washed with water (500 ml), dried (MgSO4), charcoaled, filtered and concentrated under reduced pressure to give a yellow solid. The combined residues were triturated with DCM (500 ml) then water (100 ml) and the solid collected by filtration and dried on the sinter, then under high vacuum overnight to give the title compound as a white solid (108.5 g);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:26]([CH3:32])[CH2:27][C:28](=[O:31])[NH:29][N:30]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=O)[CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>C(O)(=O)C>[C:17]1(=[O:18])[N:13]([CH2:12][CH2:11][CH2:10][C:9]2[NH:8][C:7]3[CH:6]=[CH:5][C:4]([C:25]4[CH:26]([CH3:32])[CH2:27][C:28](=[O:31])[NH:29][N:30]=4)=[CH:3][C:2]=3[N:1]=2)[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCCN2C(=O)c3ccccc3C2=O)c(N)c1
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN3C(=O)c4ccccc4C3=O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
14.1 g (32.5 mmol) of 6-[3-amino-4-[[4-(phthalimido) butyryl]amino]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone are boiled under reflux in 100 ml of glacial acetic acid for 2 hours. The solution is concentrated by extensive evaporation under vacuum and 200 ml of ethanol are added to the residue. After 30 minutes stirring at room temperature, the reaction mixture is cooled to 5° C. and the resulting precipitate is suction filtered. 7.7 g (57%) of a solid melting at 260° to 261° C. are obtained.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:4]=1[CH2:21]O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:4]=1[CH2:21][Cl:1]
Reactant: Cl
Reactant: OCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Solvent: Cc1ccccc1
Product: ClCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reaction time: 4 h

Procedure:
Hydrogen chloride gas is introduced into a mixture of 15 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenylpyrazole and 25 ml of concentrated hydrochloric acid and heating is carried out for 4 hours at boiling point. Following this 25 ml of toluene are mixed in. The layers are separated and the aqueous phase with toluene is removed. The organic layers are reduced in bulk by evaporation in vacuo, toluene is again added and reduction in bulk is repeated. 5-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole is obtained with a quantitative yield; F 96.5°-97° (from petroleum ether).
Reaction SMILES: [CH3:1][C:2]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10](=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10](=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1=CCCCCCCC(=O)OCCCCC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCCCCCCC(=O)OCCCCC1
Reaction time: 6.5 h
Yield: 0.1 %

Procedure:
1.14 g of 10 percent palladium-on-carbon were added to 13.5 g (57 mol) of 10-methyloxacyclopentadec-9-en 2-one in 60 ml of ethanol and the mixture was subsequently hydrogenated under normal pressure for 6.5 hours. Then, it was suction filtered over Celite and the solution was concentrated, chromatographed and distilled in a bulb-tube. 8.4 g (62%) of 10-methyloxacyclopentadecan-2-one were obtained having the following characteristics:
Reaction SMILES: [N:1]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:2]1[C:3]([N:5]([CH3:31])[C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:42][C@@H:43]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH2:72])=[O:71])[CH2:66][CH2:67][S:68][CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1.CC(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:2]1[C:3]([N:5]([CH3:31])[C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:42][C@@H:43]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH2:72])=[O:71])[CH2:66][CH2:67][S:68][CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 20 %

Procedure:
Condensation of BocPro-MeDTrp-PheOH (3.68 g.) and HDTrp-Leu-MetNH2 acetate salt (part B of Example 17, 3.32 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MeDTrp-Phe-DTrp-Leu-MetNH2 in 20% yield. De-t-butoxycarbonylation of BocPro-MeDTrp-Phe-DTrp-Leu-MetNH2 (1.00 g.) using trifluoroacetic acid in methyl ethyl sulfide and ethanedithiol gave HPro-MeDTrp-Phe-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate salt monohydrate in 67% yield.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: CSc1nc(-c2cccc(OC(=O)OCc3ccccc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with benzyl chloroformate (368 μl) was performed according to the methods described in example 1g. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:21](=O)[CH:22]([CH3:24])[CH3:23])=[N:17][CH:18]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.O.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[CH:22]([C:21]1[N:17]2[CH:18]=[C:13]([C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:14]=[CH:15][C:16]2=[N:19][N:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1nc(-c2ccccc2)c(-c2ccc(NNC(=O)C(C)C)nc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc(-c2ccccc2)c(-c2ccc3nnc(C(C)C)n3c2)o1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
A mixture of 23 mg of isobutyric acid N′-[5-(2-methyl-4-phenyl-oxazol-5-yl)-pyridin-2-yl]-hydrazide in 0.68 mL of phosphorous oxychloride was heated at 60° C. for 16 hours. The mixture was cooled to 22° C. and carefully added to 25 mL of water. The aqueous mixture was made basic with 3 N sodium hydroxide and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (sodium sulfate), filtered, and the filtrate was concentrated to a dark yellow oil. This oil was purified by flash chromatography (eluting with 97:3 ethyl acetate/methanol) to give 14 mg of 3-isopropyl-6-(2-methyl-4-phenyl-oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine as a light yellow solid. LCMS (m/z) 319 M+1. 1H NMR (400 MHz, CDCl3 δ8.18 (s, 1 H), 7.85 (d, 1 H, J=9.8 Hz), 7.60-7.62 (m, 2 H), 7.42-7.49 (m, 4 H), 3.32-3.34 (m, 1 H), 2.63 (s, 3 H), 1.51 (d, 6 H, J=6.7 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[C:13]([OH:26])[CH:12]=1.[CH3:27][NH:28][CH2:29][CH:30]=[CH2:31].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:29]([N:28]([CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[C:13]([OH:26])[CH:12]=1)[CH:30]=[CH2:31]
Reactant: C=CCNC
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(OCCCCCCCCBr)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C)CCCCCCCCOc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Yield: 43.2 %

Procedure:
To a stirred solution of 4-chlorobenzoyl chloride (1.0 g, 5.8 mmol) and 1,3-dimethoxybenzene (788.5 mg, 5.8 mmol) in CH2Cl2 (150 mL) at 0° C. was added AlCl3 (841.5 mg, 6.4 mmol). The reaction mixture was warmed to room temperature. After 12h the reaction mixture was poured into aq. NaHCO3 and extracted with CH2Cl2 (twice). The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo to provide a 1:1 mixture of(4-chlorophenyl)(2-hydroxy-4-methoxyphenyl)methanone and (4-chlorophenyl)(2,4-dimethoxyphenyl)methanone. Purification by silica gel chromatography provided methoxyphenyl)methanone (650 mg, 2.5 mmol) and (4-chlorophenyl)(2,4-dimethoxyphenyl)methanone(700 mg, 2.5 mmol). The combined molecules (2.7 g) were dissolved in AcOH (50 mL) and 49% HBr (50 mL) was added. After 12h at 90° C. all volatiles were evaporated in vaccuo to afford (4-chlorophenyl)(2,4-dihydroxyphenyl)methanone in quantitative yield. Without purification this was subjected to alkylation with 1,8-dibromooctane (4.0 g, 14.7 mmol) and K2CO3 (2.0 g, 14.7 mmol) in DMF (50 mL). After 12 h the reaction mixture was diluted with water (150 mL) and the water phase was extracted with EtOAc (twice). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vaccuo to give the crude product. Purification by silica gel chromatography provided (4-(8-bromooctyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone(1.9 g, 4.4 mmol). To a stirred solution of (4-(8-bromooctyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone (1.9 g, 4.4 mmol) in THF (25 mL) was added N-methylprop-2-en-1-amine (938.1 mg, 13.2 mmol) and NaHCO3 (13.2 mmol). After 36h at room temperature the reaction mixture was filtered through a glass-filter. The filtrate was evaporated in vaccuo. Purification by silica gel chromatography provided (4-(8-(allyl(methyl)amino)octyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone (1.8 g, 1.9 mmol); 1H-NMR (300 MHz, CDCl3) 12.6 ppm (s, 1H) , 7.64 (d, J=9.6 Hz, 2H), 7.60-7.48 (m, 3H), 6.59 ( s, 1H), 6.45 (d, J=9.6 Hz, 1H), 6.05-5.84 (m, 1H), 5.39-5.12 (m, 2H), 4.05 (t, J=7.7 Hz, 2H), 3.21-2.99 (m, 2H), 2.51-2.11 (m, 7H), 1.92-1.80 (m, 2H), 1.79-1.21(m, 8H); 13C-NMR (75 MHz, CDCl3) 196.3 ppm, 162.5, 138.1, 137.8, 134.2, 132.3, 131.7, 128.5, 110.9, 101.8, 68,8, 60.4, 57.0. 43.8, 29.6, 29.3, 27.3, 28.1; ESI-MS calcd for C25H33ClNO3 [M+H+]: 430.2. found 430.2.
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.I[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:14]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccnc2)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of potassium tert-butoxide in THF (1.0 M, 8.73 mmol) was slowly added to a solution of 3-hydroxypyridine (830 mg, 8.73 mmol) in anhydrous DMF (5.0 mL) and was stirred for 2 hours. A solution of 4-iodobenzonitrile in DMF (5.0 mL) was then added to the reaction mixture and was then heated at 160° C. for 18 hours. The mixture was cooled and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were dried with MgSO4, filtered and concentrated in vacuo. The crude oil was placed on a silica gel column and purified (EtOAc/Hex 1:8) to give the product as a yellow oil (640 mg, 75%). 1H NMR (500 MHz, CDCL3) δ(ppm): 7.05 (2H, d, J=9.0 Hz), 7.10 (1H, dd, J=8.4, 4.6 Hz), 7.24 (1H, ddd, J=8.4, 2.6, 1.6 Hz), 7.65 (2H, d, J=9.0 Hz), 8.46 (1H, d, J=2.6 Hz), 8.22 (1H, dd, J=4.6, 1.6 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 107.1, 118.3 (CH), 118.6, 124.7 (CH), 127.5 (CH), 134.5 (CH), 142.8 (CH), 146.4 (CH), 151.8, 160.9. MS (FAB+): 197 (MH+). HRMS for C12H8N2O (MH+): calculated: 197.0713; found 197.0696.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@@H:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[Li+].[OH-]>>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:31][CH2:32][CH3:33])[C:4]([OH:34])=[O:3])=[CH:12][CH:11]=2)=[CH:19][CH:20]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(Cc3ccccc3)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCCCOc2ccc(Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acid ethyl ester by the standard hydrolysis procedure C (LiOH). MS(ES) for C27H30O5 [M−H]−: 433.1