Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Cl[C:4]1[N:5]=[N+:6]([O-:19])[C:7]2[C:16]3[CH2:15][N:14]([CH3:17])[CH2:13][CH2:12][C:11]=3[CH:10]=[CH:9][C:8]=2[N:18]=1.[Sn](CC)(CC)(CC)[CH2:21][CH3:22]>COCCOC.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>[CH2:21]([C:4]1[N:5]=[N+:6]([O-:19])[C:7]2[C:16]3[CH2:15][N:14]([CH3:17])[CH2:13][CH2:12][C:11]=3[CH:10]=[CH:9][C:8]=2[N:18]=1)[CH3:22]
Reactant: CC[Sn](CC)(CC)CC
Reactant: CN1CCc2ccc3nc(Cl)n[n+]([O-])c3c2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Product: CCc1nc2ccc3c(c2[n+]([O-])n1)CN(C)CC3
Temperature: 85 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
Pd(PPh3)4 (108 mg, 0.09 mmol) was added to a N2-purged, stirred solution of chloride 263 (225 mg, 0.9 mmol) and Et4Sn (0.36 mL, 1.8 mmol) in DME (15 mL) and the mixture was stirred at 85° C. for 18 h under N2. The solution was cooled to 20° C. and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give 1-oxide 264 (130 mg, 60%) as a brown solid: mp 99-102° C.; 1H NMR δ 7.75 (d, J=8.6 Hz, 1H, H-5), 7.62 (d, J=8.6 Hz, 1H, H-6), 4.38 (s, 2H, H-10), 3.05-3.11 (m, 2H, H-7), 2.98 (q, J=7.6 Hz, 2H, CH2), 2.73 (t, J=5.9 Hz, 2H, H-8), 2.57 (s, 3H, NCH3), 1.42 (t, J=7.6 Hz, 3H, CH3); 13C NMR δ 167.1, 148.4, 137.1, 136.9, 136.3, 129.7, 126.1, 57.4, 50.5, 45.9, 30.7, 30.2, 12.2; MS (APCI) m/z (MH+, 100%). HRMS (FAB+) calcd for C13H17N4O (MH+) m/z 245.1402, found 245.1403.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:63]1[C:68]2[O:69][CH2:70][C:71](=[O:73])[NH:72][C:67]=2[C:66]([OH:74])=[CH:65][CH:64]=1)[CH2:10][NH:11][CH2:12][CH2:13]CCC1C=CC(C2C=CC(NC(C3C=C(S(C4C=C5C(=C(C)C=4)N=CC(C(N)=O)=C5NC4C=CC=C(OC)C=4)(=O)=O)C=CC=3)=O)=CC=2)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:75][O:76][C:77]1[CH:78]=[C:79]([NH:83][C:84]2[C:93]3[C:88](=[C:89]([CH3:119])[CH:90]=[C:91]([S:94]([C:97]4[CH:102]=[CH:101][CH:100]=[C:99]([C:103](=[O:118])[NH:104][C:105]5[CH:110]=[CH:109][C:108]([C:111]#[C:112][CH2:113]CC=O)=[CH:107][C:106]=5[CH3:117])[CH:98]=4)(=[O:96])=[O:95])[CH:92]=3)[N:87]=[CH:86][C:85]=2[C:120]([NH2:122])=[O:121])[CH:80]=[CH:81][CH:82]=1>>[Si:1]([O:8][C@H:9]([C:63]1[C:68]2[O:69][CH2:70][C:71](=[O:73])[NH:72][C:67]=2[C:66]([OH:74])=[CH:65][CH:64]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:113][C:112]#[C:111][C:108]1[CH:109]=[CH:110][C:105]([NH:104][C:103]([C:99]2[CH:98]=[C:97]([S:94]([C:91]3[CH:92]=[C:93]4[C:88](=[C:89]([CH3:119])[CH:90]=3)[N:87]=[CH:86][C:85]([C:120]([NH2:122])=[O:121])=[C:84]4[NH:83][C:79]3[CH:80]=[CH:81][CH:82]=[C:77]([O:76][CH3:75])[CH:78]=3)(=[O:95])=[O:96])[CH:102]=[CH:101][CH:100]=2)=[O:118])=[C:106]([CH3:117])[CH:107]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCC=O)cc5C)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8c7OCC(=O)N8)cc6)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7c6OCC(=O)N7)cc5C)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 151, using Intermediate 117 in place of Intermediate 124. ES/MS calcd. for C53H58N6O9SSi 982.4. Found m/z=983 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I.Cl>O>[Cl:1][C:2]1[N:7]=[C:6]([I:15])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Chloro-3-pyridinol (2.0 g, 15.44 mmol) was stirred in water (40 ml) containing sodium carbonate (3.43 g, 32.36 mmol) and iodine (3.92 g, 15.44 mmol) was added. The mixture was stirred at room temperature for 72 hours. The pH was adjusted to pH8 with 1M hydrochloric acid solution and the mixture extracted with ethyl acetate (×2). The combined organic extracts were washed with brine and dried (MgSO4). The aqueous layer was acidified to pH5 with 1M hydrochloric acid solution and extracted with ethyl acetate, which was washed with brine, dried (MgSO4) and the combined solutions evaporated to leave the title compound as a buff solid (3.70 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)=[N:5][C:4]([CH2:26][OH:27])=[N:3]1.[C:28](O)(=[O:30])[CH3:29]>>[C:28]([O:27][CH2:26][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)[N:2]([CH3:1])[N:3]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: Cn1nc(CO)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Product: CC(=O)OCc1nc(NCCCCOc2cccc(CN3CCCCC3)c2)n(C)n1

Procedure:
A solution of 1-methyl-5-[[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-1H-1,2,4-triazole-3-methanol (100 mg) in glacial acetic acid (5 ml) was heated under reflux for 8 h. The mixture was evaporated and the residue was triturated with ether to give the title compound as a white solid (97 mg) m.p. 119°-20°. tlc. System B,Rf 0.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39](O)[CH2:40][C@H:41]([OH:43])[CH3:42]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[C@@H:22]3[O:43][C@H:41]([CH3:42])[CH2:40][CH2:39][O:23]3)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Reactant: C[C@@H](O)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@H]1OCC[C@@H](C)O1
Yield: 73.5 %

Procedure:
A mixture of (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (2.01 g), p-toluenesulphonic acid monohydrate (0.316 g) and (R)-(-)-butane-1,3-diol (98%, 1.37 g) in toluene (130 ml) was heated under reflux with a Dean-Stark trap for 20 h. The mixture was concentrated to ca. 30 ml and purified by FCC eluting with System A (1:4) to give the title product (1.78 g), as a white solid. δ(CDCl3) 1.23 (d, J 6 Hz, 3H, CH3CH--O), 1.42 (d, J 7 Hz, 6H, (CH3)2CH), 1.55-1.8 (m, 2H, OCH(CH3)CH2CH2O), 3.20 (septet, J 7 Hz, 1H, (CH3)2CH), 3.7-3.9 (m, 2H, CH2O), 4.05-4.16 (m, 1H, O--CH(CH3)), 4.95 (d, J 5 Hz, 1H, CH=CHCH(O)2), 5.32 (dd, J 15 and 5 Hz, 1H, NCH=CH), 6.76 (dd, J 15 and 1 Hz, 1H, NCH=CH), 6.89 (t, J 9 Hz, 2H, C-3 and C-5 protons of 4-(4-fluorophenyl)), 7.11 (t, J 9 Hz, 2H, C-3 and C-5 protons of 5-(4-fluorophenyl)), 7.39 and 7.27 (2 dd, J 9 and 6 Hz, 4H, C-2 and C-6 protons of both 4-fluorophenyls).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl.[OH-].[Na+].O>[C:24]([NH:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc(C(=O)O)c(O)n1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(C(=O)O)c(O)n1)c1ccccc1

Procedure:
2-Amino-4-hydroxypyrimidine-5-carboxylic acid (310 mg, 2 mmol) was suspended in chloroform (20 ml) and treated with triethylamine (880 μl, 6.2 mmol) and trimethylsilylchloride (850 μl, 6.2 mmol) at reflux for 4 hours. Benzoyl chloride (250 μl, 2 mmol) was added and the reaction mixture allowed to cool overnight. Water (10 ml) was added with very vigorous stirring and the solid product was dissolved in the aqueous layer by addition of 10% NaOH. After washing the aqueous layer with further chloroform, the product was precipitated by acidification to pH 0. The filtered product was washed with water and ether. Yield 374 mg (72%)
Reaction SMILES: [C:1]1([C:7](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].CC1NC=CN=1>O>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C=C(C(=O)O)c2ccccc2)ccc1O
Agent: Cc1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C=Cc2ccccc2)ccc1O
Yield: 96 %

Procedure:
A mixture of α-phenyl-4-hydroxy-3-methoxy cinnamic acid (0.0083 mol), NaHCO3 (10%, 5 mL), methylimidazole (2 mL) and polyethylene glycol (5 mL) were taken in a 100 ml round bottom flask fitted with a condenser. The flask was shaken well and placed inside the microwave oven and irradiated (200 W, 180° C.) for 10 minutes in parts. After completion of reaction, water added to the reaction mixture and solid precipitate formed were filtered and washed with water to obtain pure product (yield 96%) in most of the cases or further purified in silica-gel column with ethylacetate and hexane (40-60%); solid, (m.p. 132-134° C.); 1H NMR (CDCl3) δ 7.45 (2H, d, J=7.41 Hz), 7.32 (2H, m), 7.21 (1H, m), 7.02 (5H, m), 5.66 (1H, s), 3.89 (3H, s); 13C NMR (CDCl3) δ 146.7, 145.6, 137.6, 130.0, 128.7, 127.2, 126.5, 126.2, 120.5, 114.6, 108.3 and 55.9. HREIMS data: m/z [M+H]+ for C15H15O2, calculated=227.2840; observed=227.2826.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][O:31]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: BrCCCCCCCCCCCOC1CCCCO1
Reaction time: 8 h

Procedure:
Pyridine toluene 4-sulphonate (1,0 g, 4,0 mmol) and 11-Bromo-1-undecanol (10,0 g, 400 mmol) were dissolved in dry CH2CH2 (200 ml) at ambient temperature, and 3,4-dihydro-2H-pyrane (5,0 g, 60 mmol) was added. The reaction mixture was stirred overnight. The crude product was purified by flash chromatography on silica gel eluted with CH2Cl2. The yield of 11-Bromo-1(tetrahydro-2-pyranyloxy)undecane was 10,7 g (80%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[O:19]=[C:20]1[NH:24][CH:23]([CH2:25][C:26](O)=[O:27])[C:22](=[O:29])[NH:21]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26](=[O:27])[CH2:25][CH:23]2[NH:24][C:20](=[O:19])[NH:21][C:22]2=[O:29])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)CC1NC(=O)NC1=O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2NC(=O)NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
A suspension of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.400 g, 1.37 mmol), (2,5-dioxoimidazolidin-4-yl)acetic acid (0.261 g, 1.65 mmol), EDCI (0.311 g, 1.65 mmol), HOBt (0.223 g, 1.65 mmol) and triethylamine (496 μl, 3.56 mmol) in DMF (13 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give crude product. The product was purified by re-crystallization from THF and n-hexane to provide 5-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}imidazolidine-2,4-dione (0.344 g, 70%) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5](=O)[CH2:6][CH:7]([CH3:12])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[C:14]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([C:18]1[CH:23]=[C:22]([S:24][C:5]([S:24][C:22]2[CH:21]=[C:20]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:19]([OH:29])=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:23]=2)([CH2:6][CH:7]([CH3:12])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][CH:2]([CH3:3])[CH3:1])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)CC(=O)CC(C)CC(C)C
Solvent: CO
Product: CC(C)CC(C)CC(CC(C)C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 9.22 grams of 2,6,8-trimethylnonan-4-one, 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, and 150 ml of methyl alcohol. The product is purified by flask chromatography to give a clear syrup whose proton NMR spectrum is consistent with the desired structure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.N>C(#N)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C)c(O)c1C
Agent: N
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COc1c(C)ccc(C)c1C
Yield: 92.1 %

Procedure:
A mixture of 50 g (0.367 mol) of 2,3,6-trimethylphenol, 55 g (0.4 mol) of potassium carbonate and 36 ml (0.38 mol) of dimethylsulphate in 500 ml of acetonitrile was heated under reflux overnight. 35 ml of conc. aqueous ammonia was then added, and the mixture refluxed for 1 hour. After filtration and evaporation, the residue was taken up in ether and washed twice with NaOH-solution and twice with NaHCO3 -solution. Drying (MgSO4) and evaporation gave 50.8 g (92%) of the product.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21]CC4C=CC=CC=4)=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.CCCCCC>C1COCC1.[Pd]>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(O)ccc12

Procedure:
Hydrogenation of 202 mg (0.49 mMol) 6-benzyloxy-benzo[d]isoxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide dissolved in 6 ml THF in presence of 70 mg Pd/C (10%, Engelhard 4505), filtration, concentration of the filtrate and trituration from hexane gives the title compound: MS: [M−1]=321; TLC(hexane/EtOAc 1:1): Rf=0.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3=[CH:27][S:28][CH:29]=[C:23]3[NH:22][C:21]2=[O:30])[CH2:11][CH2:10]1.CN([CH:34]=[O:35])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3=[CH:27][S:28][CH:29]=[C:23]3[N:22]([CH2:5][CH2:4][C:3]([O:35][CH3:34])=[O:2])[C:21]2=[O:30])[CH2:13][CH2:14]1
Reactant: CN(C)C=O
Reactant: COc1ccccc1N1CCN(CCCCCn2c(=O)[nH]c3cscc3c2=O)CC1
Product: COC(=O)CCn1c(=O)n(CCCCCN2CCN(c3ccccc3OC)CC2)c(=O)c2cscc21
Yield: 23 %

Procedure:
The title compound was produced following the procedure of Example 1 using 9.91 g (23 mmol) of 3-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentyl]thieno[3,4-d]-pyrimidine-2,4-dione in DMF for several days to produce methyl 3-[3-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate in 23% yield (2.8 g). A portion of this material was converted to its brown hydrochloride salt using 2-propanol/HCl.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24](O)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:68][C:69]1[S:73][N:72]=[C:71]([CH3:74])[N:70]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:35])[CH3:36])[CH:29]=3)[C:24]([NH:68][C:69]3[S:73][N:72]=[C:71]([CH3:74])[N:70]=3)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1
Reactant: Cc1nsc(N)n1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
DIPEA (0.5 mL, 3.0 mmol) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (485 mg, 1.0 mmol), HATU (4951 g, 1.3 mmol) and 5-amino-3-methyl-1,2,4 thiadiazole (345 mg, 3.0 mmol) in DMF (6 mL). The resulting mixture was stirred at ambient temperature for 16 hours, water (90 mL) was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (580 mg).
Reaction SMILES: II.[CH3:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1C=CC=CC=1.[Zn]>[CH3:3][C:4]([OH:11])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CBr
Reactant: CCCCCCC(C)=O
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCCCCCC(C)(O)CC(=O)OCC
Temperature: 0 °C
Yield: 53.9 %

Procedure:
To a slurry of zinc (65.0 g, 1.0 mol) in benzene (100 ml), containing a small crystal of iodine, refluxed with stirring, was added carefully 60 ml of mixture of octan-2-one (76.8 g, 0.6 mol), ethyl bromoacetate (167.0 g, 1.0 mol) and benzene (100 ml). After initiation of the reaction, the rest of the reaction mixture was added at such a rate that reflux was maintained. After complete addition of the ketone mixture the resultant reaction mixture was boiled at reflux for a further 1 hr. The mixture was then cooled and poured into ice-cold 20% sulphuric acid (400 ml), and the mixture was extracted with diethyl ether (4×200 ml). The combined extracts were washed with water (200 ml), saturated sodium hydrogen carbonate solution (2×250 ml) and saturated sodium chloride solution until neutral. The extract was then dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo to give an oil. This residual oil was distilled to afford ethyl 3-methyl-3-hydroxynonanoate (70.0 g), b.pt. 88°-90° C./0.07 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Yield: 53.7 %

Procedure:
50 ml of a solution of 5 g of 3-nitroaniline and 6.46 g of bis(2-chloroethyl)amine hydrochloride in 1-butanol was heated under reflux for 25 hours. After adding 3.84 g of sodium carbonate, the mixture was further heated under reflux for 60 hours. After allowing to cool, the insoluble matters were collected by filtration, suspended in an aqueous solution of sodium hydroxide and extracted with chloroform. The extract was successively washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=100:3). Thus 4.03 g of the title compound was obtained in the form of a red oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([OH:22])=[O:21].[OH-].[Na+].CC(O)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([C:20]([OH:22])=[O:21])[CH:24]=1)[C:12]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1cccc(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Temperature: 25 °C
Reaction time: 216 h
Yield: 102.9 %

Procedure:
A mixture of 6-benzyloxy-4-chromanone from Step 1 (5.68 g, 20 mmol), 3-carboxybenzaldehyde (30 g, 20 mmol), and 5N NaOH (10 ml, 50 mmol) in MeOH (200 ml) was stirred at r.t. for 9 days. The mixture was diluted with H2O (500 ml), acidified with HOAc to pH 5.6, filtered and air dried to give 7.95 g (98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)O)[CH:16]=3)[N:11]=[C:10]([O:33]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.CO.C(Cl)(Cl)Cl.[NH4+:45].[OH-]>C1(C)C=CC=CC=1>[NH2:45][C:18]([C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([C:20]1[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:33])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanol (20.95 g, 42.76 mmol) in toluene (150 ml) under an atmosphere of dry N2 was added thionyl chloride (31.19 ml, 427 mmol) dropwise. The reaction mixture was heated at 85° C. for 15 hours. Solvent and the excess thionyl chloride were removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum. The resulting solid was dissolved in THF (10 ml) and to this solution at −78° C. was bubbled ammonia gas (NH3) for 10 minutes. The reaction mixture was stirred at ambient temperature under an atmosphere of N2 for additional 1.5 hours. After removal of THF, the product mixture was partitioned between CHCl3 and water. The organic layer was washed, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with CHCl3 then MeOH—CHCl3—NH4OH (2:98:0.1 to 7:93:0.1) as eluents to afford the titled compound (17.89 g, 88% yield).