Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:40])[CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:29][CH2:28]4)=[CH:21][CH:20]=3)[C:12]=2[CH2:11]C1>C(Cl)(Cl)Cl>[C:5]([O:4][CH:1]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[O:40])[CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)[C:12]=2[CH2:11][CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3O)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCc2c(Nc3ccc(C(=O)CC4CCN(Cc5ccccc5)CC4)cc3)ncnc21

Procedure:
20 ml of chloroform and 0.65 ml of acetic anhydride were added to 0.35 g of N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline, and the mixture was refluxed under heating for 4 hours. Then, the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.16 g of the title compound as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH3:32])[CH2:26][CH2:27][CH2:28][C:29](O)=[O:30]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:25]([CH3:32])[CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CN(C)CCCC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCN(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-dimethylamino butyric acid to yield (3aR,4S,7aR)-4-(4-dimethylamino-butyryloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 427; RT 5.026 min; LC-MS Method II
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[C:5]2=[N:6][CH:7]=1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(O)CCO>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[O:23]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:12]=4)[C:5]3=[N:6][CH:7]=2)=[CH:24]1
Reactant: Brc1cnc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCCO
Solvent: COCCOC
Product: c1cncc(-c2cccc(-n3cnc4cc(-c5ccoc5)cnc43)c2)c1
Temperature: 90 °C
Yield: 61.5 %

Procedure:
A suspension of 6-bromo-3-[3-(pyridin-3-yl)phenyl]-3H-imidazo[4,5-b]pyridine (351 mg, 1 mmol), 3-furanboronic acid (168 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg) and 1,3-propanediol (360 μl, 5 mmol) in 1,2-dimethoxyethane (6 ml) and 2M sodium carbonate solution (3 ml) was heated at 90° C. for 16 hours. The reaction was cooled and partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was then washed with brine, dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/0.88 NH3 (95:4.5:0.5) furnished the title compound as a cream-coloured solid (208 mg, 62%), m.p. 191-192° C. (Found C, 73.13; H, 3.93; N, 16.01. C21H14N4O. 0.4H2O requires C, 72.99; H, 4.32; N, 16.21); δH (400 MHz, d6-DMSO) 7.17 (1H, s), 7.54-7.57 (1H, m), 7.74-7.85 (3H, m), 8.09 (1H, d, J 8), 8.22 (1H, d, J 8), 8.35 (2H, d, J 6), 8.50 (1H, s), 8.63 (1H, d, J 4), 8.80 (1H, s), 9.05 (1H, s), 9.07 (1H, s); m/z (ES+) 339 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[Cl:31].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH:35]=O.[C:42]([OH:45])(=[O:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:42]([OH:45])(=[O:44])[CH3:43].[Cl:31][C:3]1[CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][CH2:35][C:34]1[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:33]=1[Cl:32]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NCc5c(F)cccc5Cl)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00045 mol) in 1,2-dichloroethane (20 mL) was reacted with 2-chloro-6-fluorobenzaldehyde (0.076 g, 0.00048 mol), acetic acid (0.095 g, 0.00159 mol) and sodium triacetoxyborohydride (0.336 g, 0.00159 mol) at ambient temperature. An additional three equivalents of sodium triacetoxyborohydride (1.008 g, 0.00477 mol) were added in three 24 hour intervals, after which time all the starting material had been consumed. The solvents were removed in vacuo and the residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with chloroform (2×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile-0.1M ammonium acetate over 15 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give to give trans 3-{3-chloro-4-[(2-chloro-6-fluorobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.074 g, 0.00011 mol): 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.52 (d, 1H), 7.35-7.47 (m, 4H), 6.99 (d, 1H), 5.75 (t, 1H), 4.55-4.66 (m, 1H), 4.57 (d, 2H), 2.25-2.61 (m, 1H), 2.16 (s, 3H), 1.91 (s, 3H), 1.87-2.09 (m, 4H), 1.37-1.53 (m, 2H);
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ccc2c(I)n[nH]c2c1
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a solution of 6-fluoro-3-iodo-1H-indazole (8.6 g, 32.8 mmol) in THF (200 mL) at 0° C. was slowly added portionwise sodium hydride (60% in mineral oil, 1.58 g, 39.4 mmol). The reaction mixture was stirred at room temperature for 10 min then cooled to −10° C. and isopropylmagnesium chloride (2.0 M in THF, 19.7 mL, 39.4 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min then additional isopropylmagnesium chloride (2.0 M in THF, 8.2 mL, 16.4 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min then tributylchlorostannane (11.6 mL, 42.7 mmol) was slowly added. Stirring was continued at −10° C. for 20 min then at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl then diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane (0.5% Et3N) to afford 6.53 g (47%) of 6-fluoro-3-tributylstannanyl-1H-indazole as a light brown viscous oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.65 (dd, J=8.7, 5.3 Hz, 1H), 7.20 (dd, J=9.3, 2.1 Hz, 1H), 6.92 (td, J=9.0, 2.1 Hz, 1H), 1.53-1.67 (m, 6H), 1.28-1.43 (m, 6H), 1.20-1.28 (m, 6H), 0.89 (t, J=7.4 Hz, 9H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]3[C:19]([C:20](=[O:27])[N:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:22])=[CH:18][C:17]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[C:14]32)=[CH:9][C:8]=1[O:33][CH3:34])C.[OH-].[K+].Cl>C(O)C.O>[C:23]([N:21]([CH3:22])[C:20]([C:19]1[N:13]2[CH2:12][CH2:11][C:10]3[C:15]([C:14]2=[C:17]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[CH:18]=1)=[CH:16][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([O:33][CH3:34])[CH:9]=3)=[O:27])([CH3:25])([CH3:26])[CH3:24]
Reactant: CCOC(=O)COc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)cc(-c3cccs3)c1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OCC(=O)O)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Temperature: 78 °C
Reaction time: 1 h

Procedure:
A mixture of the product of example 63 (150 mg) and solid KOH (51 mg) in ethanol (5 ml) and water (5 ml) was stirred at 78° C. for 1 h. At room temperature, the reaction mixture was acidified with an aqueous HCl solution (1.0 M) until pH=1-2 and extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: C(=O)(O)[O-].[K+].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:16][C:17]1[C:18](=[O:23])[S:19][S:20][C:21]=1Cl>CO>[Cl:16][C:17]1[C:18](=[O:23])[S:19][S:20][C:21]=1[N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1ssc(Cl)c1Cl
Reactant: CNCCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CN(CCc1ccccc1)c1ssc(=O)c1Cl
Temperature: 20 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
Potassium bicarbonate (6 g) and a solution of N-methylphenethylamine (8 g) in methanol (150 cc) are added to a solution of 4,5-dichloro-1,2-dithiol-3-one (11.2 g) in methanol (350 cc). The reaction mixture is stirred at a temperature of about 20° C. for 20 hours, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (210 cc); the solution obtained is washed 3 times with distilled water (60 cc in total), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The crystals obtained are recrystallized from a mixture of isopropyl ether and ethyl acetate (75/25 by volume); 4-chloro-5-[N-methyl-N-(2-phenylethyl)-amino]-1,2-dithiol-3-one (5.3 g) is thus obtained in the form of yellow crystals of m.p. 75° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:13].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1(Br)[CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][N:8]2[CH:20]2[CH2:23][CH2:22][CH2:21]2)=[CH:4][C:3]=1[F:13]
Reactant: N#Cc1c[nH]c2cc(Br)c(F)cc12
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cn(C2CCC2)c2cc(Br)c(F)cc12
Temperature: 90 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
To 6-bromo-5-fluoro-1H-indole-3-carbonitrile (49.2 g, 206 mmol) [prepared as in Example 6, Step B] was added cesium carbonate (133 g, 408 mmol), DMF (200 mL), and cyclobutylbromide (30 mL, 311 mmol). This mixture was stirred at 90° C. for three days, cooled to room temperature and poured into ice water. The precipitate was collected, washed with water and dried to give 6-bromo-1-cyclobutyl-5-fluoro-1H-indole-3-carbonitrile as a light grey solid (55 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[C:20]#[N:21].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:24]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[F:16])=[C:4]([F:9])[CH:3]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2F)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 1.6 mL (15 mmol) of 4-chloro-2-fluorophenol and 1.68 g (15 mmol) of potassium tert. butoxide in 10 mL DMSO was stirred for one hour at ambient temperature. Then 2.1 g (15 mmol) of 3,4-difluoro-benzonitrile were added and the mixture was stirred overnight at 60° C. The mixture was then combined with approx. 50 mL water, then extracted three times with 30 ml of ethyl acetate. The organic extracts were washed with sodium chloride solution, dried on sodium sulphate and evaporated down. The product thus obtained was reacted further without any further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:5]2[C:6]([N:8]=1)=[N:7][C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:3][N:4]=2
Reactant: C1COCCN1
Reactant: Clc1ccc2ncc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Clc1ccc2ncc(N3CCOCC3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of 3,6-dichloropyrido[2,3-b]pyrazine (E-28) (201 mg, 1 mmol, 1.0 eq) and morpholine (175 μL, 2 mmol, 2.0 eq) and triethylamine (270 μL, 2 mmol, 2.0 eq) in DCM (20 mL) was stirred at RT for 2 h. Then water (20 mL) was added. The organic layer was separated, washed with brine (2×10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product 6-chloro-3-morpholinopyrido[2,3-b]pyrazine (E-29) (100 mg, 40% yield). 1H NMR (300 MHz, CDCl3-d6) δ: 8.59 (s, 1H), 8.15 (d, J=6.6 Hz, 1H), 7.35 (d, J=6.3 Hz, 1H), 3.90 (m, 8H); ESI-MS m/z: 251.00 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:23]1[CH:31]=[CH:30][C:26]2[CH:27]=[CH:28][O:29][C:25]=2[CH:24]=1)[N:7](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[CH3:2]>CCO.O.CC(O)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@H:6]([NH2:7])[C:23]1[CH:31]=[CH:30][C:26]2[CH2:27][CH2:28][O:29][C:25]=2[CH:24]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc2ccoc2c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](N)c1ccc2c(c1)OCC2
Reaction time: 18 h

Procedure:
A mixture of the dibenzylamine 6-5 (1.19 g, 2.78 mmol) in EtOH/H2O/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (1.19 g). The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc, and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (10% ethyl acetate/dichloromethane) to give the ester 6—6 as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25]([OH:26])=[C:24]([O:27][CH3:28])[C:23]([O:29][CH3:30])=[CH:22][C:21]=1[CH3:31].N(S([O-])(=O)=O)(S([O-])(=O)=[O:35])[O].[K+].[K+].O.P(O)(O)([O-])=O.[K+]>CN(C)C=O.CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[C:22](=[O:35])[C:21]=1[CH3:31]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCO)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1080 h
Yield: 60.1 %

Procedure:
The above 18-acetoxy compound was deacetylated by the corresponding procedure of Example 6 and the resultant 6-(18-hydroxyoctadecyl)-2,3-dimethoxy-5-methylphenol (0.5 g) is dissolved in dimethylformamide (1 l). To this solution is added potassium nitrosodisulfonate (13 g), 700 ml of water, 100 ml of methanol and monopotassium phosphate (1 g), and the mixture is stirred at room temperature for 45 days. The product is extracted in the conventional manner and recrystallized from ether-hexane. The above procedure yields 6-(18-hydroxyoctadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as yellow needles (0.31 g), m.p. 81° C.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#C.Cl[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9].[CH2:17](OCC)C>>[O:9]1[CH2:17][C:8]1([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:7][C:1]#[CH:2]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CCOCC
Reactant: C#CC[Mg]Br
Product: C#CCC1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
To a solution of 23.1 g (0.16 mol) of propargylmagnesium bromide (J. Am. Chem. Soc., 83, 1686, 1961) in 50 mL of dry diethyl ether at 25° C. was added 20.0 g (0.115 mol) of 2-chloro-4'-fluoroacetophenone in 150 mL of diethyl ether over a 0.25 hour period. The solution was stirred at 25° C. for 15 hours and then quenched with 50 mL of saturated NH4Cl. The layers were separated and the aqueous phase extracted twice with 100 mL diethyl ether. The combined ether extracts were dried (MgSO4) and the solvent removed at reduced pressure. This residue was dissolved in 250 mL of dry diethyl ether and added to 4.9 g of pulverized NaOH. This mixture was stirred at 24° C. for 3.5 hours and then 0.5 g of NaOH was added. After an additional 2.5 hours, the mixture was poured into 100 mL of H2O and extracted with diethyl ether. The ether layer was separated, dried (MgSO4) and concentrated under reduced pressure. Distillation under reduced pressure (94°-95° C. at 0.65 mmHg) yielded 16 g (79%) of 4,5-epoxy-4-(4'-fluorophenyl)-1-pentyne as an oil, homogeneous by TLC and spectroscopic criteria; Rf 0.75 (1:1 hexanes-diethyl ether): IR (film) 3290, 1600, 1505, 1225 cm-1 ; 1HNMR (300 MHz, CDCl3) δ 7.5-7.4 (m, 2H), 7.1-7.05 (m, 2H, 3.02 (ABq, 2H, JAB =6.0 Hz, ΔνAB =119.8 Hz), 2.92 (t, 2H, J=2 Hz), 2.07 (t, 1H, J=2 Hz).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>C(#N)C>[BrH:14].[CH2:1]([C:8]1[S:12][C:11](=[NH:13])[N:10]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1cnc(N)s1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: Br
Product: CCCCCCCc1cn(CC(=O)c2ccccc2)c(=N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6 parts of 5-heptyl-2-thiazolamine (prepared as intermediate 2), 6 parts of 2-bromo-1-phenylethanone and 120 parts of acetonitrile was stirred overnight at room temperature. The precipitate was filtered off, washed with 2,2'-oxybispropane and dried, yielding 10 parts of 2-(5-heptyl-2,3-dihydro-2-imino-3-thiazolyl)-1-phenylethanone hydrobromide (interm. 3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:24]([O:28][C:29]([NH:31][CH:32]([CH2:36][S:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:41]([O:40][C:38](=[O:39])[S:37][CH2:36][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C:33]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(CSC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)C(CSC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Using General Procedure G: To a solution of COMPOUND 249 (0.1233 g, 0.40 mmol) in DMF (5 mL) were added 2-tert-butoxycarbonylamino-3-tert-butoxycarbonylsulfanyl-propionic acid (0.1414 g, 0.44 mmol), DIPEA (0.14 mL, 0.80 mmol), EDCI (0.0920 g, 0.48 mmol), and HOBT (0.0649 g, 0.48 mmol), and stirred at room temperature for 16 hours. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1652 g (67%) of thiocarbonic acid S-(3-{4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-2-tert-butoxycarbonylamino-3-oxo-propyl) ester O-tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.47 (s, 9H), 1.67 (s, 5H), 2.08 (d, 6H, J=6.0 Hz), 2.39-2.43 (m, 1H), 2.75-3.14 (m, 3H), 3.80-3.83 (m, 4H), 4.13 (d, 1H, J=15.0 Hz), 4.65 (d, 1H, J=15.0 Hz), 4.88-4.89 (m, 1H), 5.52-5.55 (m, 1H), 7.07-7.11 (m, 2H), 7.37 (d, 2H, J=6.0 Hz), 8.34 (d, 2H, J=3.0 Hz).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[N:20]=[C:19]1[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([O:27][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH3:28]
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1nc2cc(O)ccc2n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2n1C
Yield: 28.2 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (254 mg, 0.774 mmol), 1,2-dimethyl-1H-benzimidazole-5-ol (163 mg, 1.06 mmol), potassium carbonate (267 mg, 1.94 mmol) and N,N-dimethylformamide (3.0 mL) as starting materials and in the same manner as in Example 95, the title compound (79 mg, 28%) was obtained as a white powder.