Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.I[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1>COCCOC.[Cu]Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Ic1cccs1
Agent: Cl[Cu]
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: c1ccc(COc2cccs2)cc1
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
To a solution of benzyl alcohol (3.45 mL, 33.3 mmol) in 1,2-dimethoxyethane (80 mL) was added n-butyl lithium (2.6M hexane solution, 13.5 mL, 33.3 mmol) dropwise, which was then stirred for 10 minutes. Copper(I) chloride (5210 mg, 49.45 mmol) was added thereto, followed by stirring for 10 minutes on an ice bath, then, it was stirred for 2.5 hours at room temperature. 2-Iodothiophene (4995 mg, 23.78 mmol) and pyridine 320 mL were further added, and the solution was stirred for 13 hours under reflux. Ethyl acetate was added to the reaction mixture, which was sequentially washed with 1N hydrochloric acid, an aqueous solution of sodium hydrogen sulfate and brine, dried over anhydrous magnesium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (420 mg, 2.21 mmol, 9.5%) was obtained.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7])C.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:23])[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([O:23][C:4](=[O:3])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7])[CH:20]([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC(C)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)COC(=O)c1ccccc1N
Reaction time: 8 h
Yield: 96 %

Procedure:
467 parts of anthranilic acid ethyl ester are heated with 1000 parts of isobutanol and 10 parts of potassium carbonate. The separated ethanol is distilled off over a column, this operation requiring about eight hours. After collecting an intermediate fraction being the mixture of both alcohols, the excess quantity of isobutanol is distilled off, the remaining residual quantity being removed in vacuo. The catalyst is filtered off. There are obtained 556 parts of anthranilic acid isobutyl ester (nD25 1.540; anthranilic acid ethyl ester content according to gas chromatography below 2%). The filtrate maintains its limpid character even at prolonged storage. The yield is 96% of the theory.
Reaction SMILES: O.C[O-].[Na+].[SH:5][CH:6]([C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8].Cl[CH:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]>CO>[CH2:18]([CH:17]([S:5][CH:6]([CH:7]([CH3:9])[CH3:8])[C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[O:15])[C:20]([CH2:21][CH2:22][CH3:23])=[O:24])[CH3:19]
Reactant: CC(C)CC(=O)C(S)C(C)C
Reactant: CCCC(=O)C(Cl)CC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC(=O)C(CC)SC(C(=O)CC(C)C)C(C)C
Reaction time: 0.03 h

Procedure:
Into a 50 ml, round bottom, three-necked flask equipped with magnetic stirrer, pot thermometer, "Y" tube, nitrogen inlet tube, reflux condenser with cotton plug, and water bath is placed a solution of 0.65 grams (0.012 moles) of sodium methoxide dissolved in 10 ml anhydrous methanol. While maintaining the temperature of the reaction mass at 24°-27° C, a solution of 2.1 grams of 3-mercapto-2,6-dimethyl-4-heptanone dissolved in 12 ml anhydrous methanol is added to the sodium methoxide solution. 1.78 grams of 3-chloro-4-heptanone is then added to the reaction mass with stirring over a period of 2 minutes, the reaction mass temperature rising to 38° C. Two ml anhydrous methanol used as rinse is then added to the reaction mass, and with stirring the reaction mass temperature cools to 25° C. The reaction mass is continued to be stirred at 25° C for a period of 5 hours. At this point 25 ml distilled water is added, and the resulting solid dissolves. The oil phase is extracted with three 15 ml portions of methylene chloride, and the extracts are combined and washed with one 10 ml portion of water. The extracts are then dried over anhydrous sodium sulfate and gravity filtered and concentrated on a rotary evaporator using water aspirator vacuum to a weight of 3.20 grams (yellow oil). GLC analysis (8' × 1/4 inch SE-30 column), NMR, IR and mass spectral analyses of GLC isolated material yield the information that the resulting product is 85% pure and has the structure: ##STR71##
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][CH2:11]1>[Pd]>[CH:10]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Agent: [Pd]
Product: c1ccc2c(c1)CCC2
Product: c1ccc2c(c1)Cc1ccccc1-2

Procedure:
A portion of the 2:1 fraction (by molar ratio) of indene and tetrahydrofluorene obtained in Example 1 was charged in an autoclave, and was then reacted and processed in a similar manner as in Example 1 except that Pd/C (5% Pd supported on charcoal) was added as a catalyst in a proportion of 0.5%. As a result of an analysis by gas chromatography, fluorene and indane were found to have been formed with a yield of 91% (based on tetrahydrofluorene) and with a yield of 93% (based on indene), respectively.
Reaction SMILES: [C:1]12(CO)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH3:10][SiH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[C:25](C)([O-:27])C.[K+]>>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH:6]2[CH2:25][O:27][Si:11]([CH3:10])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: C[SiH](c1ccccc1)c1ccccc1
Reactant: OCC12C=CC(CC1)C2
Agent: [K+]
Product: C[Si](OCC1CC2C=CC1C2)(c1ccccc1)c1ccccc1

Procedure:
and reacting norbornene methanol (IB) with methyldiphenylsilane in the presence of a suitable solvent and potassium tert-butoxide to obtain (bicyclo[2.2.1]hept-5-en-2-ylmethoxy)(methyl)diphenylsilane (VB) of at least 99.5 percent purity.
Reaction SMILES: O[C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].CN(C=[O:25])C>>[CH3:13][C:14]([Si:17]([CH3:19])([CH3:18])[O:25][C@H:3]1[CH2:2][CH2:7][O:6][C:4]1=[O:5])([CH3:16])[CH3:15]
Reactant: O=C1C[C@H](O)CO1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Reaction time: 2.5 h

Procedure:
3.92 g (38.4 mmol) of (S)-3-hydroxybutyrolactone with 5.23 g (2 equivalents, 76.8 mmol) of imidazole are introduced at 0° C. into 50 ml of absolute DMF. 7.53 g (1.3 equivalents, 49.92 mmol) of TBSCl is now slowly added and stirred for 2.5 hours.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].O1CCOCC1.O>CCOC(C)=O>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:18]1[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[CH:11]=[CH:10]2
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)cc1
Reaction time: 1 h

Procedure:
Followed Scheme 3 starting from 2-chloroquinolin-6-ol (Intermediate 2) and 4-cyanophenylboronic acid, and using 1,4-Dioxane:H2O solution. Reaction was run at 100° C. in a microwave reactor for 1 hour. Ethyl acetate workup was followed by column chromatography (5% to 50% EtOAc in hexanes gradient).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.N1C=CN=C1.[C:32]([Si:36]([CH3:39])([CH3:38])Cl)([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O.C(OCC)C>[Si:36]([O:25][C:3]1[CH:2]=[CH:1][C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C:5]=2[C:4]=1[O:19][C@H:18]4[C:20](=[O:21])[CH2:22][CH2:23][C@@:9]35[OH:24])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 76 %

Procedure:
3.49 g of naltrexone hydrochloride was suspended in 10.5 ml of N,N-dimethylformamide. After adding 3.46 g of imidazole, 3.48 g of tert-butyldimethylchlorosilane was added followed by stirring for 35 minutes at room temperature. 30 ml of water and 50 ml of diethyl ether were added to the reaction system followed by separation. The aqueous layer was extracted twice with 30 ml of diethyl ether. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The resulting residue was recrystallized from ethanol to obtain 3.2 g of the target compound (yield: 76%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][C:20]([OH:28])([CH3:27])[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1>>[CH3:19][C:20]([OH:28])([CH3:27])[CH2:21][C:22]1[S:23][C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:25][CH:26]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(O)Cc1cccs1
Product: CC(C)(O)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-methyl-1-thiophen-2-yl-propan-2-ol.
Reaction SMILES: O[CH2:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O=S(Cl)[Cl:19].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: OCC(CN1CCOCC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCC(CN1CCOCC1)c1ccccc1
Yield: 76.6 %

Procedure:
To a solution of 1-hydroxy-3-morpholino-2-phenylpropane (650 mg, 2.94 mmol) prepared in the above (3) dissolved solved in dichloromethane (10 ml), SOCl2 (420 mg, 3.53 mmol) in dichloromethane (5 ml) was added while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 23 hours, saturated aqueous sodium bicarbonate was added while chilling with ice. The prepared solution was extracted with dichloromethane, and the extract was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography using acetone/hexane=1/5 to obtain 540 mg of the titled compound as a colorless oil (yield: 76.6%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:13]2[CH:14]=[CH:15][C:16](=[O:18])[O:17][C:12]=2[CH:11]=1)(=O)=O.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH3:23][CH:22]([O:21][C:20]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[CH:14][C:13]=2[CH:19]=1)[CH3:24]
Reactant: CC(C)Oc1cc2ccc(=O)oc2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)Oc1cc2ccc(=O)oc2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 69 %

Procedure:
Method B (24 h at 60° C.); starting materials: 7-[3-(methanesulfonyloxy)propoxy]-6-(1-methylethoxy)-2H-1-benzopyran-2-one (example 73) and 4-phenylpiperidine; yield 69%; fusion point 86°-87° C. (from TBME). Fumarate: method E; yield 90%; fusion point 164°-167° C. (from ethanol and acetone).
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([O:8][CH2:9][C:10]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=2)([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:10]([CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:45][CH:44]=2)([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[CH:39][CH:40]=2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCC(COc2ccc([N+](=O)[O-])cc2)(COc2ccc([N+](=O)[O-])cc2)COc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(OCC(COc2ccc(N)cc2)(COc2ccc(N)cc2)COc2ccc(N)cc2)cc1
Yield: 90 %

Procedure:
A mixture of 1,3-bis(4-nitrophenoxy)-2,2-bis[(4-nitrophenoxy)methyl]propane (15.43 grams, 24.87 mmol; prepared as described in Part B of this Example) and Pd/C 10% (1.58 grams, obtained from Aldrich Chemical Co.) was stirred for 70 hours in tetrahydrofuran (400 milliliters) under 180 pounds per square inch of hydrogen gas. The mixture was then filtered over CELITE; and the solvent was removed by evaporation under reduced pressure. The residue was recrystallized from nitrobenzene/benzene to afford pure 1,3-bis(4-aminophenoxy)-2,2-bis [(4-aminophenoxy)methyl]propane (11.17 grams, 22.31 mmol, 90 percent yield) as small light brown crystals: mp 210-211° C.; IR (KBr) 3434, 3351, 3050, 2932, 1625, 1511, 1467, 1232, 1041, 1172, 831, 523 cm−1; 1H NMR (400 MHz, DMSO-d6) δ6.66 (d, 8H, 3J=8.4 Hz), 6.47 (d, 8H, 3J=8.4 Hz), 4.62 (s, 8H), 4.03 (s, 8H); 13C NMR (100 MHz, DMSO-d6) δ150.14, 142.73, 115.76, 114.86. 67.06, 44.59; MS (FAB, 3-nitrobenzyl alcohol) m/e 500.3; Anal. Calcd for C33H24N4O4: C, 69.58; H, 6.44; N, 11.19. Found: C, 69.33; H, 6.78; N, 10.91.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:28])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=3)=[O:17])[CH:10]=2)[CH2:6]1>CS(C)=O.CC#N.CC#N.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:28])[C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]([F:26])[F:27])=[CH:22][CH:23]=3)=[O:17])[CH:10]=2)[CH2:6]1
Reactant: COC(=O)CC1CC(c2cccc(C(=O)C(=O)c3ccc(OC(F)F)cc3)c2)C1
Agent: Cl[Pd]Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: COC(=O)C=C1CC(c2cccc(C(=O)C(=O)c3ccc(OC(F)F)cc3)c2)C1
Temperature: 145 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
In a 250 ml round bottom flask was dissolved (3-{3-[2-(4-Difluoromethoxy-phenyl)-2-oxo-acetyl]-phenyl}-cyclobutyl)-acetic acid methyl ester (1.348 g, 3.66 mmol) in DMSO (45 mL). Bis(acetonitrile)dichloropalladium was added and the flask heated (oil bath; 145° C.) for 4 hours. More Bis(acetonitrile)dichloro-palladium (90 mg) was added and heating was continued for another 4 hours. The crude material was partitioned between water (50 mls) and dichloromethane. Dichloromethane extracts (2×50 mls) were combined and concentrated onto silica gel. Purification by column chromatography (gradient; 10-20% EtOAc in hexanes) afforded 1.17 gm of a yellow oil (80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90-3.02 (m, 1H) 3.05-3.16 (m, 1H) 3.22-3.28 (m, 1H) 3.49-3.59 (m, 1H) 3.62-3.64 (m, 3H) 3.72-3.82 (m, 1H) 5.73-5.77 (m, 1H) 7.39 (dt, J=9.3, 2.5 Hz, 2H) 7.46 (t, J=73.0 Hz, 2H) 7.59 (t, J=7.8 Hz, 1H) 7.72-7.80 (m, 2H) 7.85 (t, J=1.9 Hz, 1H) 8.02 (dt, J=9.4, 2.6 Hz, 2H); MS (ES) m/z 401.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1)=[O:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nccs1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nccs4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-aminothiazole (49 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 31 mg of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]1=[O:4].[CH2:15]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=1[C:33]#[N:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:1][C@@H:2]2[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]2=[O:4])=[O:29])=[CH:26][C:25]=1[C:33]#[N:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1C#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)O[C@@H]2CC[C@@H](CCCCCC)OC2=O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
In 1 ml of dehydrated benzene were suspended 100 mg of (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone synthesized in the same manner as described in Referential Example 2 and 120 mg of 4-octyloxy-3-cyanobenzoic acid, and 0.1 ml of diethyl azodicarboxylate was added to the suspension with stirring at room temperature. Then, 150 mg of triphenylphosphine was added to the mixture and reaction was carried out overnight with stirring. The reaction mixture was concentrated under a reduced pressure and the residue was separated and purified by the silica gel column chromatography using an n-hexane/benzene (1/4) mixed solvent as the developing solvent. Recrystallization from ethanol gave 90 mg of (2R,5R)-(4'-octyloxy-3'-cyanobenzoyloxy)-5-hexyl-δ-valerolactone. When the phase transition behavior of the obtained compound was measured by a differential thermal scanning calorimeter and a polarization microscope, the following results were obtained: ##STR88##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:14](=O)[CH3:15])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[H-].[Na+].[Br:19][CH2:20][C:21](Cl)=[O:22]>O1CCCC1>[C:11]([C:10]1[C:14]([CH3:15])=[C:20]([Br:19])[C:21](=[O:22])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)(=[O:13])[CH3:12]
Reactant: O=C(Cl)CBr
Reactant: CC(=O)C(=NNc1ccc(Cl)cc1)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)c(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pentan-2,3,4-trione 3-(4-chlorophenylhydrazone) (23.90 g) was added to a suspension of 66% sodium hydride (7.64 g) in anhydrous tetrahydrofuran (300 ml) under ice cooling, followed by stirring at room temperature for 30 minutes. Then, a solution of bromacetyl chloride (9.1 ml) in anhydrous tetrahydrofuran (100 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (acetone:hexane=1:9), and crystallized from hexane to obtain 6-acetyl-4-bromo-2-(4-chlorophenyl)-5-methyl-3(2H)-pyridazinone (11.96 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:20][CH2:21][Cl:22])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC#N>[Cl-:22].[CH2:1]([N+:8]12[CH2:21][CH2:20][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:10][CH2:9]1)[CH2:12][CH2:13][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CCCl)CCCN(Cc2ccccc2)CC1
Solvent: CC#N
Product: CCOC(=O)C12CCC[N+](Cc3ccccc3)(CC1)CC2
Product: [Cl-]
Yield: 100 %

Procedure:
A solution of ethyl 1-benzyl-4-(2-chloroethyl)azepane-4-carboxylate (4.1 g) in MeCN (200 mL) was stirred at 40° C. for 10 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-benzyl-5-(ethoxycarbonyl)-1-azoniabicyclo[3.2.2]nonane chloride (4.1 g) as a colorless oily substance.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[F:5][CH:6]([Cl:12])[C:7](OCC)=[O:8]>C(O)C.C(O)CO>[CH:1]([NH:4][C:7](=[O:8])[CH:6]([Cl:12])[F:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(F)Cl
Reactant: CC(C)N
Solvent: CCO
Solvent: OCCO
Product: CC(C)NC(=O)C(F)Cl
Reaction time: 2 h

Procedure:
A solution of 11.8 grams (0.2 mole) isopropyl amine in 20 milliliters ethyl alcohol were added dropwise at 10°-15° C. with stirring to a solution of ethyl fluorochloroacetate and 5 drops of ethylene glycol in 80 milliliters ethyl alcohol. The solution was stirred at 10°-20° C. for 2 hours and was then stored at -15° C. for 3 days. At this time, the solution was evaporated to leave a liquid, 25.2 grams, nD30 1.4395, identified as the title compound by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20](C(O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:61][O:62][CH2:63]CN.[CH3:66][N:67]([CH:69]=[O:70])C>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C:18]4([C:69]([NH:67][CH2:66][CH2:61][O:62][CH3:63])=[O:70])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: COCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)C1(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)CCCCC1

Procedure:
(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarboxylic acid (HCl salt) (0.05 g, 0.12 mmol), HATU (0.09 g, 0.24 mmol), diisopropylethylamine (0.06 g, 0.47 mmol) and 2-methoxyethanamine (0.04 g, 0.47 mmol) were stirred together in 1 ml each of DMF and CH3CN at room temperature overnight. All volatiles were removed with a stream of nitrogen and heat. The residue was dissolved in methanol and purification with phase preparatory HPLC with 10-90% MeOH/water (HCl modifier) gave the desired product as the HCl salt.