Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.ClC1C2C=CSC=2CCC1.[NH2:21][C:22]([NH2:24])=[O:23]>S(Cl)(Cl)=O.CN(C)C=O.C(N(C(C)C)CC)(C)C>[S:7]1[CH:8]=[CH:9][C:10]2[CH:2]([NH:21][C:22]([NH2:24])=[O:23])[CH2:3][CH2:4][CH2:5][C:6]1=2
Reactant: OC1CCCc2sccc21
Reactant: NC(N)=O
Agent: ClC1CCCc2sccc21
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)NC1CCCc2sccc21
Temperature: 50 °C

Procedure:
A 1 gram sample of 4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene is stirred in the cold for several hours in thionyl chloride (5 ml.) and the mixture is evaporated to dryness. The crude 4-chloro-4,5,6,7-tetrahydrobenzo[b]thiophene is then added to a mixture of urea (1-5 mole-equivalents) in dimethylformamide and diisopropyl ethylamine. The mixture is warmed, after several hours, to 50° C. and after 4 hours is poured on ice and the product, 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, is collected by filtration.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:2]1=[O:15].Cl[C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([O:24][C:25]2[CH:34]=[C:33]([CH3:35])[C:28]3[NH:29][C:30](=[O:32])[O:31][C:27]=3[CH:26]=2)[CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][C:33]1[C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=[C:25]([O:24][C:19]2[CH:18]=[C:17]([N:12]3[CH2:11][CH2:10][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][C:2]4=[O:15])[CH2:14][CH2:13]3)[N:22]=[C:21]([CH3:23])[N:20]=2)[CH:34]=1
Reactant: O=C1Nc2ncccc2C12CCNCC2
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)C(=O)Nc2ncccc23)n1

Procedure:
36 mg (0.15 mmol) spiro[piperidin-4.3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 44 mg (0.15 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 91 μL (0.536 mmol) DIPEA in 2.0 mL DMF were stirred for 48 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and lyophilised.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To a stirred solution, under nitrogen, of 89.5 g of 2-chlorophenylhydrazine hydrochloride in 600 ml of pyridine, cooled in an ice bath, was added, dropwise, 87.2 g of 2-fluorobenzoyl chloride, such that the reaction temperature did not exceed 15° C. The reaction mixture was stirred at ambient temperature for 16 hours and then poured into water. Crystallization of the resultant oil was induced by scratching. Recrystallization from toluene yielded 65.7 g (60%) of 2-fluorobenzoic acid, 2-(2-chlorophenyl)hydrazide, m.p. 105°-107° C.
Reaction SMILES: CS([C:5]1[N:14]2[C:8]([CH:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)(=O)=O.[CH3:25][O-:26].[Na+]>>[CH3:25][O:26][C:5]1[N:14]2[C:8]([CH:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Product: COc1nnc2n1C=Cc1ccccc1C2c1ccccc1

Procedure:
The reaction of 3-methylsulfonyl-11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3-methoxy-11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless prisms (as recrystallized from aqueous methanol), melting point: 183°-184° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].CO.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.O1CCCC1>[CH3:28][O:29][CH2:30][C:31]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1)=[O:32]
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Reactant: COCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COCC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.9 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) in N,N-dimethylacetamide (5 mL) was added methoxyacetyl chloride (92.0 μL, 1.01 mmol), and the mixture was stirred at room temperature for 15 hr. Methanol, tetrahydrofuran and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was stirred at 60° C. for 17 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→85% ethyl acetate-hexane) to give the title compound (115 mg, 32%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9](S(C)=O)[N:8]=1.[N:32]1[CH:33]=[CH:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][C:36]=12.C(N(CC)CC)C.CN(C)C(=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9]([N:38]2[CH2:39][CH2:40][N:35]3[CH:34]=[CH:33][N:32]=[C:36]3[CH2:37]2)[N:8]=1
Reactant: c1cn2c(n1)CNCC2
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(C)=O)nc1N1CCC(O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of whole amount) of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylsulfinylpyrimidine (prepared in the above (5)), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 73 mg, triethylamine 0.083 ml and N,N-dimethylacetamide 4 ml is stirred at 110° C. for 4 hours. After cooling the reaction mixture is diluted with a 10% aqueous citric acid solution and washed with ethyl acetate. The organic layer is extracted with a 10% aqueous citric acid solution. The water layer is made basic with sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:methanol=100:1→50:1), and then crystallized from a mixture of ethyl acetate, methanol and isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless crystalline powder 20 mg.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1c[nH]c2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2c[nH]c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(1 H-indol-3-yl)-1-hexanone were reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(1H-indol-3-yl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][S:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: OB(O)c1ccsc1
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)n1nc2c(c1-c1ccsc1)CCNCC2
Yield: 99.7 %

Procedure:
The title compound (95 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 126 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H23N3S, 289.16; found, m/z 290.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.68-7.64 (m, 1H), 7.52-7.48 (m, 1H), 7.12-7.07 (m, 1H), 3.93-3.86 (m, 1H), 3.44-3.39 (m, 2H), 3.34-3.28 (m, 2H), 3.22-3.17 (m, 2H), 2.85-2.79 (m, 2H), 1.95-1.84 (m, 2H), 1.79-1.69 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[I-:11].[K+].II.[NH:15]1[CH2:19][CH2:18][NH:17][C:16]1=[S:20]>CO.O>[IH:11].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[S:20][C:16]1[NH:17][CH2:18][CH2:19][N:15]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [I-]
Reactant: S=C1NCCN1
Reactant: Cc1cc2ccccc2[nH]1
Agent: II
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1[nH]c2ccccc2c1SC1=NCCN1
Product: I

Procedure:
A solution of 13.1 g of 2-methylindole in 175 ml of warm methanol is added to a well-stirred solution of 50 g of potassium iodide and 25.4 g of iodine in 150 ml of water. This mixture is further treated with a hot solution of 10.2 g of 2-imidazolidinethione in 150 ml of warm methanol. The reaction is carried out and worked up in the manner described under Example 1 to yield 2-methyl-3-(2-imidazolin-2-ylthio)-indole hydriodide which melts at 227°-228° (with decomposition) after recrystallization from a mixture of methanol, ethyl acetate and ether.
Reaction SMILES: [O:1]([CH3:13])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4].CO[CH:16](OC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[CH3:13][O:1][C@H:2]1[O:10][C@@H:9]2[CH2:11][O:12][CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C@H:7]2[C@@H:5]2[O:6][CH:35]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:4][C@H:3]12
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: COC(OC)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1O[C@@H]2COC(c3ccccc3)O[C@H]2[C@@H]2OC(c3ccccc3)O[C@H]12
Temperature: 0 °C

Procedure:
A mixture of methyl α-D-mannopyranoside (Compound I, 50 g, 258 mmoles), α,α-dimethoxytoluene (92 g, 600 mmoles), and anhydrous p-toluene-sulfonic acid (1 g) in N,N-dimethylformamide (300 ml), in a 1-liter flask fitted with an air condenser attached to a water aspirator, was stirred magnetically and heated in an oil bath for 3 hours at 65°-75° C. None of the starting Compound I remained after this time (t.l.c., 4:1 ether-petroleum ether). The mixture was poured with vigorous stirring into 1 liter of ice-water containing sodium hydrogen carbonate (30 g). The resultant precipitate was filtered off, resuspended in ice-water, filtered off again, and dried in air and finally in vacuo over phosphorus pentaoxide; yield 90.6 g (95%), m.p. 120°-160° C, [α]D23 -33° (c 1, chloroform).
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[H-].[Na+].[H][H].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>C(OCC)C>[CH3:1][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C
Yield: 56 %

Procedure:
The 2-methyl-5-nitropyridine of formula (BB) was prepared according to prior art literature (Odashima, T.; Sakakura, K.; Kohata, K.; Ishii, H., Bull. Chem. Soc. Jpn., 1993, 66, 797 and references therein). A reaction vessel charged with diethyl malonate (12.5 g, 78.0 mmol) in diethyl ether (450 mL) was further charged with sodium hydride (3.2 g of a 60% slurry in mineral oil, 79 mmol). When the evolution of hydrogen gas subsided, the 2-chloro-5-nitropyridine of formula (AA) (12.5 g, 79.0 mmol) was charged to the vessel with stirring. The solvent was then removed by evaporation and the red, tarry residue was heated to 110° C. for 1 hour. At this point, 6 M H2SO4 (90 mL) was charged to the vessel and the mixture was heated to reflux overnight. The solution was cooled in an ice bath and was neutralized with potassium hydroxide solution. The solids were removed by filtration and washed with chloroform. The filtrate was extracted with chloroform and the combined chloroform fractions were evaporated. The resulting crude material was purified by flash chromatography to yield 6.1 g (56%) of the 2-methyl-5-nitropyridine of formula (BB) as a pale orange solid.
Reaction SMILES: [N:1]1[CH:6]=[N:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Li+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]=[C:22]2[CH2:33][C:34]([O-])=[O:35])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]=[C:22]2[CH2:33][C:34]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[N:3]=[CH:4][N:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[O:35])=[CH:19][CH:20]=1
Reactant: c1ncnc(N2CCNCC2)n1
Reactant: O=C([O-])Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1)N1CCN(c2ncncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
22 mg 1-(1,3,5-triazin-2-yl)-piperazine was added to 40 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid lithium salt, 45 mg TBTU, 0.03 mL DIPEA in 0.75 mL DMF. The reaction was stirred overnight at RT. 5 mL water was added to the reaction and the mixture was stirred 1 h. The precipitate was filtered and dried to give 37 mg desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH:18](C)[CH2:19][N:20]([CH3:22])[CH3:21].[CH3:24]C(O)C>>[CH3:21][N:20]([CH3:22])[CH:19]([CH3:24])[CH2:18][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3][C:2]1=[NH:1]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CC(Cl)CN(C)C
Reactant: CC(C)O
Agent: Cl
Product: CC(Cn1c(=N)sc2cc(OC(F)(F)F)ccc21)N(C)C
Reaction time: 24 h

Procedure:
2-Amino-6-trifluoromethoxybenzothiazole (9.4 g) and 2-chloro-1-dimethylaminopropane hydrochloride (7.0 g) are heated for 1 hour to 130.C. 2-Propanol (20 cc) is added and heating is continued for 24 hours to boiling. After cooling of the mixture to a temperature in the region of 20.C, the precipitate is filtered off and then treated with IN sodium hydroxide (80 cc) in distilled water (100 cc). The residue obtained by extraction with dichloromethane, drying over magnesium sulphate and concentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa) is purified by chromatography on a silica column with a mixture of ethyl acetate and methanol (80:20 by volume) as eluent. (RS)-3-(2-Dimethylaminopropyl)2-imino-6-trifluoromethoxybenzothiazoline (3.3 g) is obtained in the form of a yellow oil, which is converted to a dihydrochloride subliming at about 190° C.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:71])([C:67]([F:70])([F:69])[F:68])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH:65]=[CH2:66])[C:55]([O:57]CC)=[O:56]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH:54]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:71])[C:67]([F:68])([F:69])[F:70])[C:55]([OH:57])=[O:56])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared in Example 11, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid.
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5][C:6]1[NH:11][C:10](=[O:12])[C:9]([CH2:13][CH2:14][OH:15])=[C:8]([CH3:16])[N:7]=1)[CH3:4].I[CH3:18].O>CS(C)=O>[CH2:3]([S:5][C:6]1[N:11]([CH3:18])[C:10](=[O:12])[C:9]([CH2:13][CH2:14][OH:15])=[C:8]([CH3:16])[N:7]=1)[CH3:4]
Reactant: CCSc1nc(C)c(CCO)c(=O)[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1nc(C)c(CCO)c(=O)n1C
Temperature: 65 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Potassium hydroxide (8.4 g) was added to a solution of intermediate 2 (33 g) in dimethyl sulfoxide (150 ml). The mixture was stirred for 1 hour at 60-70 ° C. The mixture was cooled to 20° C. and iodomethane (21.3 g) was added dropwise. The reaction mixture was stirred overnight at RT. The mixture was poured out into water and extracted with toluene. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from 4-methyl-2-pentanone and the precipitate was filtered off and dried, yielding 16 g (46%) of 2-(ethylthio)-5-(2-hydroxy-ethyl)-3,6-dimethyl-4(3H)-pyrimidinone (intermediate 3).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[C:9]([NH:14][C:15](=O)[CH2:16][O:17][CH2:18][CH3:19])[CH:10]=[N:11]2)=[CH:6][CH:5]=1>O.C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:21]([CH2:22][C:23]([CH3:25])([OH:26])[CH3:24])[C:15]([CH2:16][O:17][CH2:18][CH3:19])=[N:14][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1
Reactant: CCOCC(=O)Nc1cnc2cc(Br)ccc2c1NCC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Yield: 49.3 %

Procedure:
A solution of sodium hydroxide (25 g, 0.625 mol) in water (205 mL) was added to a solution of N-[7-bromo-4-(2-hydroxy-2-methylpropylamino)quinolin-3-yl]-2-ethoxyacetamide (170.88 g, 0.431 mol) in ethanol (700 mL), and the reaction was heated at reflux under a nitrogen atmosphere for two hours. Upon cooling the reaction, a precipitate formed and was isolated by filtration. The solid was purified by flash column chromatography on silica gel (eluting sequentially with chloroform, 99:1 chloroform:methanol, and 97:3 chloroform:methanol) to provide 80.31 g of 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: OB(O)c1ccccc1
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1F

Procedure:
4-Fluoro-3-nitrobiphenyl (1e) was prepared analogously from 1g and phenylboronic acid.
Reaction SMILES: [CH:1]1[C:13]2C[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]([Cl:18])(Cl)(Cl)[Cl:15]>>[Cl:15][C:14]1([Cl:18])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:13][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: ClC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Product: ClC1(Cl)c2ccccc2-c2ccccc21

Procedure:
To the reactor which has been purged with nitrogen is charged 400 mL carbon tetrachloride such that its level just comes to the bottom of the sixth stage. NaOH solution (the same solution used in Recycle run #2, 25 percent by weight, 6.14 moles, 245.6 g dry weight, 983 g solution weight, 774.0 mL) is then charged to the reactor, and fills all six of the stirred zones. The stirrer is started and its speed adjusted to 1500 rpm. Fluorene (0.185 moles, 30.75 g) dissolved in carbon tetrachloride (2.24 moles, 344.8 g, 225.35 mL) is fed into the catalyst saturator containing the catalyst solution using a metering pump at a rate of 5.5 mL/min. The product solution is collected at the overflow and washed and dried as in Recycle run #2. The total product solution collected in this fashion is 1046 g which is evaporated to dryness on the rotary evaporator leaving 41.11 g of very light yellow crystals, 9,9-dichlorofluorene (94.5 percent of a theoretical yield of 3.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:35][C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH2:38][S:39][CH3:40].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:35][C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH2:38][S:39][CH3:40])=[O:24])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: CSCC[C@H](N)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@@H](CCSC)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (237 mg, 0.5 mmol) and L-methionine (149 mg, 1 mmol) in N,N-dimethylformamide (1 ml) was added triethylamine (0.21 ml, 1.5 mmol). The mixture was stirred at room temperature for 16 hours. After removal of the solvent, the residue was dissolved in ethyl acetate (10 ml) and the solution was washed with 1N hydrochloric acid (5 ml×3) and saturated aqueous sodium chloride (5 ml×3) in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was chromatographed on a column of silica gel (7 g). Elution was carried out with chloroform-methanol (4:1, v/v) and with chloroform-methanol-acetic acid (32:8:1, v/v) in the order mentioned. The fractions containing the desired compound were combined and the solvent was distilled off under reduced pressure to give 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-L-methionine (150 mg), melting at 83°-85° C.