Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:16][OH:17])[C:6](=[O:11])[C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Reactant: ClCCOC1CCCCO1
Product: CC1(C)C(=O)N(CCO)c2ccc(Br)cc21

Procedure:
Prepared from 5-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([C:11]1[C:3]([N:2]([CH3:12])[CH3:1])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1cc2ccccn2n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1c(N(C)C)nn2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 2.3g of 2-dimethylaminopyrazolo[1,5-a]pyridine and 30 ml of acetic anhydride in the presence of concentrated sulfuric acid was refluxed for 2.5 hr. After cooling, the mixture was poured into ice water. The solution was neutralized with potassium carbonate and extracted with chloroform. The chloroform solution was dried over sodium sulfate and concentrated. The residue was column chromatographed over alumina to purify the objective product. Recrystallization from n-hexane gave colorless prisms, mp 80.5°-81.5°. Yield 700 mg.
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2+:12][CH3:13])([OH:4])=[O:3].Cl[Si](C)(C)C.C(N(CC)CC)C.C([O:29][C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](Cl)=[O:33])(=O)C.C(O)(=O)C1C(=CC=CC=1)O>ClCCl>[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([N:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[O:33]
Reactant: C[NH2+]CCCCCCCC(=O)O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C(O)c1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCCCCCC(=O)O)C(=O)c1ccccc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 100 ml round bottomed flask fitted with argon purge, magnetic stir bar and condenser was added (7-carboxy-heptyl)-methylammonium hydrochloride (3.25 g, 0.0155 mol, 1.0 eq) and dichloromethane (DCM, 50 ml). Chlorotrimethylsilane (3.37 g, 0.0310 mol, 2.0 eq) was added and the resulting mixture was brought to reflux for approximately 2 h. The flask was removed from the heating mantle and placed in an ice water bath. Once the reaction was cooled to 0° C., triethylamine (3.92 g, 0.0388 mol, 2.5 eq) was added and a white vapor formed over the reaction mixture. The reaction was allowed to stir for approximately 10 min at 0° C. In a separate flask, acetylsalicyloyl chloride (ASCC, 3.08 g, 0.0155 mol, 1.0 eq) was dissolved in DCM (20 ml). The ASCC solution was added dropwise to the reaction mixture, the ice bath was removed, and the reaction mixture was allowed to stir and warm to ambient temperature overnight. The DCM was removed under reduced pressure and aqueous 2N NaOH (20 ml) was added to the residue. The aqueous mixture was allowed to stir at ambient temperature for several hours and was then acidified with aqueous 2N HCl. The aqueous mixture became cloudy and a brow oil separated out. The aqueous mixture was extracted with EtOAc (3×100 ml). The combined EtOAc extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The resulting brown oil was further dried under high vacuum to yield a brown solid. HPLC at this point indicated the solid consisted of two components (rt 2.8 min, salicylic acid and rt 4.0 min, desired product). This mixture was stirred in warm water (40-50° C.) to dissolve the salicylic acid. The remaining solid was filtered off, HPLC indicated this is predominantly desired product, crude yield 3.99 g (0.0136 mol, 87.7%). This material was treated in warm water (40-50° C.) and filtered two more times to produce pure 8-[(2-Hydroxy-benzoyl)-methyl-amino]-octanoic acid. (HPLC rt 4.0 min; NMR consistent with desired product; Elemental analysis Theoretical: C=65.31, H=7.82, N=4.76 Found: C=65.32, H=7.72, N=4.73) This application incorporates by reference in its entirety International Publication No. WO 03/072195, which is also attached as an appendix A to this application.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([C:15]1[S:19][C:18]([C:20]2[CH:21]=[C:22]([NH:26][C:27]3[N:28]=[C:29]([NH:36][C@@H:37]4[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]4[NH2:43])[N:30]=[N:31][C:32]=3[C:33]([NH2:35])=[O:34])[CH:23]=[N:24][CH:25]=2)=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[S:19][C:18]([C:20]2[CH:25]=[N+:24]([O-:9])[CH:23]=[C:22]([NH:26][C:27]3[N:28]=[C:29]([NH:36][C@@H:37]4[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]4[NH2:43])[N:30]=[N:31][C:32]=3[C:33](=[O:34])[NH2:35])[CH:21]=2)=[CH:17][CH:16]=1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(-c2cncc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)c2)s1
Product: CC(=O)c1ccc(-c2cc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)c[n+]([O-])c2)s1

Procedure:
An excessive quantity of m-CPBA was used, and a method similar to that in Example 1 (Step 3) and (Step 4), a method according to these methods, or a combination of them with routine procedures was used for 3-(methylthio)-5-(5-(5-acetylthiophen-2-yl)pyridin-3-ylamino)-1,2,4-triazine-6-carboxamide obtained in Example 15 to obtain the titled compound as a white solid.
Reaction SMILES: [C:1]([O:8]C)(=O)[CH2:2][C:3](OC)=[O:4].[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[O:8])[CH2:2][C:3]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([F:10])=[CH:12][CH:13]=2)=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1ccc(F)cc1
Product: O=C(CC(=O)Nc1ccc(F)cc1)Nc1ccc(F)cc1
Temperature: 200 °C

Procedure:
A mixture of dimethyl malonate (0.5 g, 3.78 mmol) and 4-fluoroaniline (0.93 g, 8.33 mmol) was heated neat to 200° C. for 20 min in the microwave system. After cooling, the solid was filtered and washed with ethyl acetate to provide the desired malonamide which was used without further purification. MS: Cal'd (MH+) 291, exp (MH+) 291.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:41]1([C:48]([C:50]2[CH:55]=[CH:54][C:53](Br)=[C:52]([CH3:57])[CH:51]=2)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([C:48]([C:50]2[CH:55]=[CH:54][C:53]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[C:52]([CH3:57])[CH:51]=2)=[O:49])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: Cc1cc(C(=O)N2CCCCCC2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCCCCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and azepan-1-yl-(4-bromo-3-methyl-phenyl)-methanone (41 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of azepan-1-yl-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-272) as a pale brown powder (16 mg, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]([NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:21])[N:9]=3)[CH:3]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3′-[4-(4-Chloro-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.44) (0.11 g, 0.3 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.09 g, 0.35 mmol) according to the general procedure VI. Obtained as a light brown solid (0.16 g), which was subsequently deprotected.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])C.[OH-].[Na+]>CCO>[CH2:18]([O:17][P:12]([CH2:11][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][C:4]([OH:20])=[O:3])([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)CC(CC(C)C)CP(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CC(CC(=O)O)CC(C)C)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester (1.0 g, 3.2 mmol) and NaOH (1.8 mL, 2.0 M) are combined in 10 mL of EtOH at 0° C. After 15 minutes, the reaction mixture is warmed to room temperature and stirred overnight. The EtOH is evaporated, and 50 mL of 2.0 M NaOH is added. The solution is extracted with Et2O (2×50 mL), and then acidified to pH=1 with concentrated HCl. The acidic solution is extracted with EtOAc (3×50 mL), and the combined extracts are dried over MgSO4 and evaporated to give 0.65 g (72% yield) of 3-(diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid as an oil. NMR (H1, 400 MHz, CDCl3) δ 0.9 (6H, d); δ 1.3 (8H, m); δ 1.6 (1H, m); δ 1.8 (2H, m); δ 2.3 (1 H, m); δ 2.5 (2H, m); δ 4.1 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH3:11])=[O:4].C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH2:11][Br:32])=[O:4]
Reactant: COC(=O)C1=C(C)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.37 g, 1.0 mmol) in CCl4 (5 mL) was added NBS (0.20 g, 1.1 mmol) in portions. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by column chromatography to give (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound C) as a yellow solid. MS: calc'd 445 (MH+), measured 445 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:29][NH:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]([CH3:31])([CH3:30])[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]([CH3:33])([CH3:32])[CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]([CH3:35])([CH3:34])[CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.[N:37]([CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[C:38]=[O:39]>O1CCCC1>[CH3:1][C:2]1([CH3:36])[CH2:3][N:4]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:5][CH2:6][N:7]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:8][C:9]([CH3:35])([CH3:34])[CH2:10][N:11]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:12][CH2:13][N:14]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:15][C:16]([CH3:33])([CH3:32])[CH2:17][N:18]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:19][CH2:20][N:21]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:22][C:23]([CH3:31])([CH3:30])[CH2:24][N:25]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:26][CH2:27][N:28]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:44][CH2:45][CH3:46])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])=[O:39])[CH2:29]1
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Reactant: CC1(C)CNCCNCC(C)(C)CNCCNCC(C)(C)CNCCNCC(C)(C)CNCCNC1
Solvent: C1CCOC1
Product: CCO[Si](CCCNC(=O)N1CCN(C(=O)NCCC[Si](OCC)(OCC)OCC)CC(C)(C)CN(C(=O)NCCC[Si](OCC)(OCC)OCC)CCN(C(=O)NCCC[Si](OCC)(OCC)OCC)CC(C)(C)CN(C(=O)NCCC[Si](OCC)(OCC)OCC)CCN(C(=O)NCCC[Si](OCC)(OCC)OCC)CC(C)(C)CN(C(=O)NCCC[Si](OCC)(OCC)OCC)CCN(C(=O)NCCC[Si](OCC)(OCC)OCC)CC(C)(C)C1)(OCC)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
0.69 g (1.35 mmol) of 6,6,13,13,20,20,27,27-octamethyl-1,4,8,11,15,18,22,25-octaazacyclooctacosane is dissolved in 20 cm3 of anhydrous tetrahydrofuran (THF) in a 200 cm3 Schlenk tube. 3.2 g (12.9 mmol) of (3-isocyanatopropyl) triethoxysilane are rapidly added. The reaction mixture is stirred at room temperature for 12 hours. After evaporating the solvent, the solid obtained is washed twice with 50 cm3 of anhydrous pentahe. 1.97 g of the expected compound are obtained in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Sc1ccccc1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 6.0 kg. of 1-amino-2-nitro-4-chlorobenzene and 7.2 kg. of potassium carbonate in 25 l. of DMF under nitrogen is treated with 4.0 kg. of thiophenol. The mixture is stirred for 2 hours, cooled, and diluted with 140 l. of ice water. The mixture is stirred for 1 hour, and 1-amino- 2-nitro-5-phenylthiobenzene is isolated by filtration.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNCCO
Reactant: BrCC=Cc1ccccc1
Product: CN(CC=Cc1ccccc1)CCO

Procedure:
The title compound was prepared from 3-bromo-1-phenylprop-1-ene (0.77 g) and 2-(methylamino)ethanol (3.1 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:23][C@@H:22]([CH2:24][C:25]([O:27]CC)=[O:26])[C:21]4[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=4[CH2:19][C:18]=3[CH:34]=2)[CH:4]=1.CC1C=CN=C(NCCCOC2C=CC3C[C@@H](CC(OCC)=O)C4C=CC=CC=4CC=3C=2)C=1>>[CH3:35][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:23][C@@H:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21]4[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=4[CH2:19][C:18]=3[CH:34]=2)[CH:4]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(N(C)C)ccn3)cc2Cc2ccccc21
Agent: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(C)ccn3)cc2Cc2ccccc21
Product: CN(C)c1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2[C@H](CC(=O)O)C3)c1

Procedure:
According to the procedure of Example 13 (c), except substituting ethyl (S)-10,11-dihydro-3-[3-[4-(dimethylamino)pyridin-2-ylamino]-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (S)-10,11-dihydro-3-[3-(4-methylpyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as white powder: MS (ES) 446.2 (M+H)+. Anal. Calcd for C27H31N3O3.0.5 H2O. 1.0 HCl: C, 66.04; H, 6.77; N, 8.56. Found: C, 65.96; H, 6.60; N, 8.26.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][CH2:7][C@H:8]([NH:17][C:18](=[O:24])OC(C)(C)C)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)#[N:2].[C:28]([C:30]1[CH:38]=[CH:37][C:33](C(O)=O)=[CH:32][CH:31]=1)#[N:29].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>Cl.O1CCOCC1.O1CCOCC1.O.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][CH2:7][C@H:8]([NH:17][C:18](=[O:24])[C:33]1[CH:37]=[CH:38][C:30]([C:28]#[N:29])=[CH:31][CH:32]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([I:16])=[CH:14][CH:15]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cccc(C#N)c1)Cc1ccc(I)cc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(C(=O)N[C@@H](COc2cccc(C#N)c2)Cc2ccc(I)cc2)cc1
Reaction time: 16 h

Procedure:
1.44 g (3.01 mmol) of t-butyl [(1R)-2-(3-cyanophenoxy)-1-(4-iodobenzyl)ethyl]carbamate was dissolved in 5 ml of 4 N dioxane hydrochloride and 2.5 ml of dioxane, and the solution was stirred for 15 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in 10 ml of dichloromethane. 488 mg (3.3 mmol) of 4-cyanobenzoic acid 1.3 ml (9.3 mmol) of triethylamine, 633 mg (1.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 445 mg (3.3 mmol) of 1-hydroxybenzotriazole were added to the solution, and they were stirred for 16 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water, 1 N sodium hydroxide and saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[OH-:31].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl>O.O1CCOCC1>[OH:31][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Reactant: [OH-]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Temperature: 110 °C
Yield: 34.9 %

Procedure:
A mixture of the product of Example 44, step C (1.41 g, 3.14 mmol), di-palladium-tris(dibenzylideneacetone) (575 mg, 0.62 mmol), potassium hydroxide (387 mg, 6.91 mmol) and 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-1,1′-biphenyl (121 mg, 0.25 mmol) in water (14 mL) and 1,4-dioxane (14 mL) was heated to 110° C. for 24 h. After cooling to ambient temperature, the reaction mixture was neutralized with 1N aqueous HCl, filtered through celite bed and extracted with ethyl acetate (4×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 7:3 hexanes/ethyl acetate) providing tert-butyl 6-hydroxy-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (470 mg, 34%): 1H NMR (CDCl3, 300 MHz) δ 7.93-7.90 (m, 2H), 7.62 (br s, 1H), 7.55-7.43 (m, 3H), 7.39 (d, J=1.8 Hz, 1H), 4.54 (s, 2H), 3.81 (t, J=5.4 Hz, 2H), 2.83 (t, J=5.7 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][OH:21])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>ClCCl>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][O:21][C:25](=[O:26])[NH:24][CH2:22][CH3:23])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCN=C=O
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CO)cn12
Solvent: ClCCl
Product: CCNC(=O)OCc1ccccc1Sc1ccc2nnc(C(C)C)n2c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of [2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-phenyl]-methanol (45.0 mg, 0.15 mmol) in dichloromethane (1.5 mL) under nitrogen at ambient temperature was added ethyl isocyanate (12.0 μL, 0.15 mmol). The reaction was heated to 50° C. for 1 hour. The reaction was cooled, ethyl isocyanate added (30 μL, 0.38 mmol), and stirred at ambient temperature for 16 hours. The reaction was concentrated in vacuo to an oil. The residue was triturated from ether to give the title compound (45 mg, 82%). MS (M+1)=371.4.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:20])[C:13]2[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=2)[OH:15])=[CH:7][CH:6]=1)(C)(C)C.C(C1C=CC(OC(=O)C2C(=CC=CC=2)O)=CC=1)(CC(C)(C)C)(C)C>>[C:8]1([O:11][C:12](=[O:20])[C:13]2[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=2)[OH:15])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(OC(=O)c2ccccc2O)cc1
Agent: CC(C)(C)CC(C)(C)c1ccc(OC(=O)c2ccccc2O)cc1
Product: O=C(Oc1ccccc1)c1ccccc1O

Procedure:
salicylic acid-4-tert.-butylphenyl ester, salicylic acid-4-tert.-octylphenyl ester and the like.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].CN(C)[CH:10]=[C:11]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[C:13]1([C:12]2[C:11]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:10][N:7]=[CH:5][N:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=CN
Reactant: CN(C)C=C(C(=O)c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2cncnc2-c2ccccc2)CC1
Temperature: 140 °C

Procedure:
To a stirred solution of formamidine acetate (2.8 g) in triethylamine (6 ml) in a sealed tube, was added tert-butyl 4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate (1.0 g) and the reaction mixture was heated at 140° C. for 6 h. The reaction mixture was brought to room temperature and triethylamine was removed under reduced pressure. Water (10 ml) was added to the residue and the organic compound was extracted into ethylacetate (4×20 ml). Combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography using methanol/chloroform (1:9) to give tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate.
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17](=[O:30])[C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[S-2:31].[Na+].[Na+].[S].[BH4-].[Na+]>>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:31][C:19]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][CH:25]=3)=[CH:18][C:17](=[O:30])[CH:16]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: [S-2]
Reactant: CC(C)(C)c1ccc(C#CC(=O)C#Cc2ccc(C(C)(C)C)cc2)cc1
Agent: CC[O-]
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(-c2cc(=O)cc(-c3ccc(C(C)(C)C)cc3)s2)cc1

Procedure:
In the reaction of the third stage, sodium ethoxide is allowed to act on (C) 1,5-bis(4-tert-butylphenyl)-penta-1,4-diyn-3-one, and then sodium sulfide prepared from sulfur and sodium borohydride is allowed to act on (C) so as to cause a cycloaddition reaction, there by obtaining (D) 2,6-bis(4-tert-butylphenyl)-4H-thiopyran-4-one.