Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[N:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=1)(=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1)=[O:23]>>[C:13]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][N:8]([CH:6]2[CH2:7][C:2]([CH3:12])([CH3:1])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]2)[OH:9])=[CH:39][CH:38]=1)(=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:8]([CH:6]2[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:7]2)[OH:9])=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C(CCCCCCCCC(=O)OCc1ccc(CBr)cc1)OCc1ccc(CBr)cc1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1
Product: CC1(C)CC(N(O)Cc2ccc(COC(=O)CCCCCCCCC(=O)OCc3ccc(CN(O)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-one oxime and di-(4-bromomethylbenzyi) sebacate
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[N:6]=1)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)[N:6]=[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A mixture of 1-benzyl-5-(5-fluoro-pyridin-3-yl)-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (23 mg, 0.056 mmol), β-alanine (495 mg, 5.6 mmol) and NaOMe solution (9 mL, 4.4 mmol) was refluxed for 16 h. After cooling to r.t., solvent was evaporated. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH about 3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/hexanes+2% AcOH). The product isolated was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 10 mg of the title compound. MS: (+) m/z 463.35 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1.[CH:22](O)=[O:23]>O>[O:8]=[C:6]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][NH:1][CH:22]=[O:23])[O:7]1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=CO
Solvent: O
Product: O=CNC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 115 °C

Procedure:
In a four neck round bottom flask charged 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one free base (50 g) ether (450 ml) and formic acid (21.63 g). Reaction mass then heated azeotropically to 110-120° C. employing dean-stark apparatus for 3 to 4 h. (water removed azeotropically) Reaction mass is cooled to 25 to 30° C. Obtained solid is filtered off and washed by toluene.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:9][C:8]([CH2:10][N:11]2[S:15](=[O:17])(=[O:16])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:13](=[O:29])[CH2:12]2)=[CH:7][CH:6]=1)C.Cl>C1COCC1>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][N:14]1[S:15](=[O:17])(=[O:16])[N:11]([CH2:10][C:8]2[S:9][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=2)[CH2:12][C:13]1=[O:29]
Reactant: CCOC(OCC)c1ccc(CN2CC(=O)N(Cc3ccc(OC)cc3OC)S2(=O)=O)s1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C=O)s3)S2(=O)=O)c(OC)c1
Reaction time: 2 h

Procedure:
The title A compound, 5-(5-diethoxymethyl-thiophen-2-ylmethyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (3.91 g, 8.1 mmol) is dissolved in THF (100 mL) and 6N aqueous HCl (2.7 mL) is added. The mixture is stirred for 2 h and the solvent is evaporated. The residue is partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer is dried over anhydrous MgSO4 and concentrated to dryness. The residue is triturated from Et2O to afford 5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carbaldehyde as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[O:4][N:3]=1.Br[C:34]1[CH:46]=[CH:45][C:37]([CH2:38][C:39]2([C:42]([OH:44])=[O:43])[CH2:41][CH2:40]2)=[CH:36][CH:35]=1>>[OH:17][CH:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:18]1[CH:19]=[CH:20][C:21]([C:34]2[CH:46]=[CH:45][C:37]([CH2:38][C:39]3([C:42]([OH:44])=[O:43])[CH2:40][CH2:41]3)=[CH:36][CH:35]=2)=[CH:22][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1C(O)CCCc1ccccc1
Reactant: O=C(O)C1(Cc2ccc(Br)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(CC4(C(=O)O)CC4)cc3)cc2)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-{3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-4-phenyl-butan-1-ol and 1-(4-bromo-benzyl)-cyclopropanecarboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[N-:14]=[N+:15]=[N-:16].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]=[N+:15]=[N-:16])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 15.0 g (0.069 mole) of o-nitrobenzenesulfonyl chloride dissolved in 150 ml ethanol was added 5.89 g (0.090 mole) of sodium azide dissolved in a minimum amount of water. The solution was stirred for 30 minutes and then poured into a 2 liter Erlenmeyer flask containing 500 ml of ice water. The resultant white solid was filtered, dried and recrystallized from ethanol. The purified product had a melting point 73°-74° C. (lit. 73°-74° C.) and was isolated in 92% yield (14.47 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2.CN(C)C=O>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([NH:8][C@H:9]([C:13]([O:15][CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2)=[O:14])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Yield: 39.3 %

Procedure:
A mixture of N-Boc-L-valine (528 mg; 2.1 mmol) and N,N′-dicyclohexyl carbodiimide (250 mg; 1.21 mmol) in dichloromethane (20 ml) was atirred over night at room temperature, dicyclohexylurea filtered off and extracted with a small volume of dichloromethane, and the filtrate evaporated in vacuo to a small volume. (R)-9-[2-Hydroxymethyl-4-(stearoyloxy)butyl]guanine (340 mg; 0.654 mmol), 4-dimethylaminopyridine (25 mg; 0.205 mmol), and dry N,N-dimethylformamide (15 ml) were added and the mixture was stirred for 4h at 50° C. under N2. The solvent was evaporated in vacuo to a small volume. Column chromatography on silica gel, then on aluminum oxide (ethyl acetate methanol: water 15:2:1 as eluent) gave 185 mg (39%) pure title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:9]2[O:16][CH2:17][CH2:18][CH2:19][O:20][C:8]2=[C:7]1[C:21]([O:23]CC)=[O:22])C.O.[OH-].[K+]>CC(C)=O>[C:4]([CH2:5][N:6]1[C:7]([C:21]([OH:23])=[O:22])=[C:8]2[O:20][CH2:19][CH2:18][CH2:17][O:16][C:9]2=[C:10]1[C:11]([OH:13])=[O:12])([OH:26])=[O:3]
Reactant: CCOC(=O)Cn1c(C(=O)OCC)c2c(c1C(=O)OCC)OCCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)Cn1c(C(=O)O)c2c(c1C(=O)O)OCCCO2

Procedure:
To a 100-mL round-bottom flask was added diethyl 7-(2-ethoxy-2-oxoethyl)-2,3,4,7-tetrahydro-[1,4]dioxepino[2,3-c]pyrrole-6,8-dicarboxylate (17.56 g, 47.5 mmol), DI water (45 mL), acetone (25 mL), and potassium hydroxide (13.34 g, 238 mmol). The reaction mixture was bubbled with argon for 20 minutes, then refluxed for 2.5 hours, resulting in a deep brown solution. The organic volatiles were removed in vacuo and the remaining aqueous layer was chilled in an ice bath. To the mixture was added concentrated sulfuric acid until a pH of 6 was reached, whereupon a white solid precipitate formed. This precipitate was filtered from the red aqueous solution and washed with several portions of DI water, and after drying weighed 13.55 g (100%). To confirm the structure NMR analysis was performed on the fully deprotonated version by dissolving into a NaOD/D2O solution. 1H NMR (300 MHz, D2O/NaOD): δ 5.17 (s, 2H), 4.13-4.09 (m, 4H), 2.19 (p, 2H, J=5.7 Hz). 13C NMR (75 MHz, CDCl3): δ 180.9, 171.0, 141.9, 120.3, 74, 9, 51.9, 36.3. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[O:6].[CH3:16][Mg]Br>C(OCC)C>[OH:6][CH:5]([C@@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH:2]([CH3:15])[CH3:1])[CH3:16]
Reactant: C[Mg]Br
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A solution of (S)-tert-butyl (4-methyl-1-oxopentan-2-yl)carbamate (1.3 g, 6.04 mmol) in diethyl ether (50 mL) was cooled to −78° C. and treated with methyl magnesium bromide (1.4 M in diethyl ether) (8.63 mL, 12.08 mmol). The slurry was stirred at 0° C. for 1 h and then stirred for an additional hour at RT. The reaction mixture was quenched with NH4Cl. The reaction mixture was extracted with diethyl ether (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to afford the product, tert-butyl ((3S)-2-hydroxy-5-methylhexan-3-yl)carbamate (1 g, 4.32 mmol, 72% crude yield) as colorless oil. The material was carried on without further purification. 1H NMR (300 MHz, DMSO-d6): δ 0.78-0.93 (m, 6H), 0.98 (d, 3H), 1.11-1.41 (m, 2H), 1.42 (s, 9H), 1.45-1.64 (m, 1H), 3.30-3.63 (m, 2H), 4.37 (d, 1H), 6.19 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Br:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:10]1[C:11]([Br:12])=[C:2]([Br:1])[CH:3]=[C:4]2[C:9]=1[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Br)c(Br)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
The procedure of Cheeseman, G. W. H., J. Chem Soc. 1170 (1962) was adapted. To a stirred suspension of 6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (576 mg, 1.8 mMol) in concentrated H2SO4 (6 mL) at 0° C. for 30 min. was added KNO3 (220 mg, 2.18 mMol, Baker) in one portion. The mixture was stirred at 0° C. for 3 h then at room temperature for one day. The color of mixture was changed from red to yellow brown. Then it was poured into ice (60 g) resulting in the separation of a bright yellow precipitate, which was collected by filtration and washed with distilled water (2×2 mL) followed by ethanol (2×1 mL) to get 498 mg of crude 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (76%, contains minor impurities by NMR). Crystallization from DMSO/H2O gave pure 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione as bright yellow microcrystals; mp: 352°-354° C. (dec.). IR (KBr, cm-1): 3387; 3256; 1756; 1700; 1537. NMR (1H, DMSO-d6): δ 7.475 (s, 1H); 12.217 (s, 1H); 12.265 (s, 1H). HRMS: calcd for C8H3N3O4Br2 (M+) m/z: 362.8489; found: 362.8509.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[Br:19][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:17]2[C:12]=1[C:13]([NH2:18])=[N:14][CH:15]=[N:16]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c(CCN3CCOCC3)ccc12
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCN3CCOCC3)cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of 7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (149 mg, 0.6 mmol) in DMF (3 ml) at −20 C was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (69 mg, 0.24 mmol) in three portions. The reaction was stirred at −20 C for 3 h. Upon the completion, the reaction was quenched with aqueous saturated Na2SO3 and allowed to warm up to rt. The crude was extracted with ethyl acetate. The organic layer was collected and washed with brine, dried over Na2SO4 and concentrated. The resulting crude was purified via column chromatography (95:5 v/v CH2Cl2—CH3OH) to afford 75 mg of the title compound as yellow solid (yield 39%). MS [M+H]+=326.2; LCMS RT=1.15 min.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18](O)[N:19]=[N:20][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:37])=O>>[Cl:37][C:18]1[N:19]=[N:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[N:15]=2)[CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@H](Nc1nccc(-c2cc(O)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](Nc1nccc(-c2cc(Cl)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 90 °C

Procedure:
Compound 9 (3.5 g, 7.96 mmol) and phosphorus oxychloride (20 mL) were combined under argon then heated at 90° C. for 0.5 h. The solution was cooled and poured onto ice. The resulting suspension was made basic with 2N sodium hydroxide and extracted several times with methylene chloride. The combined organic extracts were washed with brine and dried with anhydrous sodium sulfate. Evaporation of the solvent in vacuo gave an oil which was purified by flash column chromatography (hexane ethyl acetate 80:20) to give Compound 10 as a foam: 2.9 g (6.4 mmol, 80%)
Reaction SMILES: [CH:1]([N-:5][CH:6]=[CH:7][N-:8][CH:9]([CH2:11][CH3:12])[CH3:10])([CH2:3][CH3:4])[CH3:2].[Li+].[Li+].[Cl:15][SiH:16](Cl)Cl>CCCCCC>[Cl:15][SiH:16]1[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=[CH:7][N:8]1[CH:9]([CH2:11][CH3:12])[CH3:10]
Reactant: CCC(C)[N-]C=C[N-]C(C)CC
Reactant: Cl[SiH](Cl)Cl
Agent: [Li+]
Solvent: CCCCCC
Product: CCC(C)N1C=CN(C(C)CC)[SiH]1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 42 %

Procedure:
In an argon atmosphere, a dilithium(N,N′-di-sec-butyl-1,2-vinylenediaminide) solution prepared according to the procedure and reagent quantities described in Reference Example-8 was added to a hexane (150 mL) solution containing 25.00 g (184.6 mmol) of trichlorosilane, and the mixture was stirred at room temperature for 6 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./5×102 Pa) to obtain 2-chloro-1,3-di-sec-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(sBuNCHCHNsBu)(H)Cl) as a pale yellow liquid (yielded amount: 18.10 g, yield: 42%). This product was a mixture of a plurality of isomers differing in the steric configuration from each other.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[NH2:26]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1
Reactant: COC(=O)c1cccc(Cn2ccc3ncnc(Cl)c32)c1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
To a solution of methyl 3-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate (670 mg) in 1-methyl-2-pyrrolidone (3.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (549 mg), and the reaction mixture was stirred at 120° C. for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (50 mL), and extracted with ethyl acetate (50 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:hexane/ethyl acetate=9/1→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (1010 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([N:30]([CH3:32])[CH3:31])[S:27][C:26]=2[CH:33]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:29]2[C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:33][C:26]=3[S:27][C:28]=2[N:30]([CH3:32])[CH3:31])=[O:7])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)cc1OC
Temperature: 110 °C
Reaction time: 17 h
Yield: 75.6 %

Procedure:
To a solution of 3,4-dimethoxybenzoyl chloride (1.250 g, 6.231 mmol) in 18 miL of chlorobenzene was added 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene (Part B) (1.059 g, 3.738 mmol). The dark blue reaction mixture was then heated to 110° C. and stirred for 17 h by which time the solution turned to brown. The brown solution was then quenched at 0° C. with 30 mL of saturated aqueous NaHCO3 solution and extracted with EtOAc (2×200 mL). The combined organic layers were washed with 200 mL with brine, dried over MgSO4, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 50:50 EtOAc-hexanes) to afford 1.265 g (2.826 mmol, 76%) of a yellow foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH:21]=2)[OH:19])=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:2]>[Pd].CO>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)[OH:19])=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:10]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)C2=CCCc3ccccc32)c(C)n1
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(O)C2CCCc3ccccc32)c(C)n1
Reaction time: 4 h

Procedure:
10% Palladium on carbon (15 mg) is added to a solution of [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-(3,4-dihydro-naphthalen-1-yl)-methanol (141 mg, 0.34 mmol, step 2, Example 29) in methanol (25 mL) and the reaction mixture is submitted to hydrogenation (Parr shaker) at 55 psi for 4 hours. The resulting mixture is filtered on celite and the filtrate concentrated in vacuo to give crude [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-(1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol, which is used in the next step without further purification.
Reaction SMILES: CN(C=O)C.CS([O:10][CH2:11][C:12]1[O:16][N:15]=[C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[CH:13]=1)(=O)=O.[CH3:38][O:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47].C([O-])([O-])=O.[K+].[K+]>O>[F:35][C:23]([F:36])([C:24]1([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[CH:13]=[C:12]([CH2:11][O:10][C:42]2[CH:43]=[C:44]([O:48][CH3:49])[C:45]([O:46][CH3:47])=[C:40]([O:39][CH3:38])[CH:41]=2)[O:16][N:15]=1)=[O:37]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Reactant: COc1cc(O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCc2cc([C@@H]3CCCN3C(=O)C(F)(F)C3(O)CC(C)(C)CC(C)(C)C3)no2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a DMF (1.0 mL) solution of the compound (20.8 mg) obtained in Example 3-(5) and 3,4,5-trimethoxyphenol (16.0 mg), K2CO3 (24.0 mg) was added and the mixture was stirred at room temperature for 30 minutes, then at 50° C. for 2 hours. The reaction mixture was added to water (20 mL) and the organic layer extracted with AcOEt (20 mL×2) was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by PTLC(NH-form) to give the titled compound (20.5 mg, colorless amorphous.)
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[CH2:34]([NH:41][CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of Compound 3 (100 mg) and benzylamine (70 μL) in acetonitrile (2 mL) was heated at 110° C. over 8 hours. Solvent was removed under reduced pressure and the crude product was stirred in trifluoroacetic acid (1 mL) for 2 hours at room temperature. Finally, trifluoroacetic acid was removed under reduced pressure and the crude product was partitioned between chloroform (20 mL) and 7% aqueous NaHCO3 solution (10 mL). The chloroform layer was dried and concentrated and purified on a silica gel column using 4% ethanol in dichloromethane to obtain the product in 50% yield (57 mg).