Azzindani/Open_Reaction_Data huggingface dataset:
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:70])([C:66]([F:69])([F:68])[F:67])[CH2:49][CH2:50][CH2:51][CH2:52][CH:53]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]=[CH2:65])[C:54]([O:56]CC)=[O:55]>>[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][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH:53]([CH2:52][CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:70])[C:66]([F:67])([F:68])[F:69])[C:54]([OH:56])=[O:55])[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(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared in Example 9, 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-(5,5,6,6,6-pentafluorohexyl)decanoic acid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCN1CCNC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCN1CCNC1=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 25 mg, 0.058 mmol), 1-(2-aminoethyl)imidazolidin-2-one (22.46 mg, 0.087 mmol), 4-methylmorpholine (23.45 mg, 0.232 mmol), and HATU (28.7 mg, 0.075 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(2-(2-oxoimidazolidin-1-yl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13.2 mg, 0.024 mmol, 42.0% yield): LCMS=543.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.23 (2 H, m), 7.54-7.73 (7 H, m), 5.11 (1 H, s), 3.32-3.49 (6 H, m), 3.21-3.29 (2 H, m); HPLC peak RT=2.4 min (Method E).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10]O)[CH:7]=[CH:6][S:5]2.BrCC1N2C(SC=C2)=NC=1Cl.[CH3:23][C:24]1[N:29]=[C:28]([SH:30])[N:27]=[C:26]([OH:31])[CH:25]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10][S:30][C:28]1[N:27]=[C:26]([OH:31])[CH:25]=[C:24]([CH3:23])[N:29]=1)[CH:7]=[CH:6][S:5]2
Reactant: OCc1c(Cl)nc2sccn12
Reactant: Cc1cc(O)nc(S)n1
Agent: Clc1nc2sccn2c1CBr
Product: Cc1cc(O)nc(SCc2c(Cl)nc3sccn23)n1
Yield: 22 %

Procedure:
{6-chloroimidazo[2,1-b][1,3]thiazol-5-yl}methanol was converted to 5-(bromomethyl)-6-chloroimidazo[2,1-b][1,3]thiazole, which was then reacted with 6-methyl-2-sulfanylpyrimidin-4-ol to give the title compound as a white solid (0.27 g, 22% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.67 (s, 2H), 6.04 (bs, 1H), 7.42 (d, J=4.7 Hz, 1H), 8.02 (d, J=4.7 Hz, 1H); M+312.8.
Reaction SMILES: C([O:8]C1C=CC(C(O)=O)=CC=1)CCCCCC.ON1C2C=CC=CC=2N=N1.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.NC1C=CC=CC=1O>O1CCCC1>[CH:37]1([NH:36][C:35](=[O:8])[NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: Nc1ccccc1O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.7 g of p-heptyloxybenzoic acid, 2.7 g of 1-hydroxybenztriazole (HOBT) and 50 ml of tetrahydrofuran was added 4.2 g of dicyclohexylcarbodiimide (DCC) under ice cooling. After stirring at room temperature for 1 hour, 9 g of o-aminophenol was added to the mixture. The resulting mixture was stirred at room temperature overnight. Dicyclohexyl urea formed was filtered off and the filtrate was concentrated. The residue was dissolved in 500 ml of ethyl acetate. The solution was washed subsequently with diluted hydrochloric acid, a diluted sodium hydrogen carbonate solution and then water, dried over anhydrous magnesium sulfate and the concentrated under reduced pressure. The residue was applied to silica gel column chromatography (using 500 ml of silica gel), eluted with a toluene-ethyl acetate (1:1) mixture and further recrystallized from ethanol to obtain 5.6 g of p-heptyloxy-N-(o-hydroxyphenyl)benzamide.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[N:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C[O:30][C:31](=[O:40])[CH:32](Br)[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([CH2:33][CH:32]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:6]=[N:5]2)[C:31]([OH:30])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Oc1ccccc1N1CCCCC1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2N2CCCCC2)cc1=O
Yield: 97 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-(piperidin-1-yl)phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(2-piperidin-1-yl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (3.3 g, 97%) as a white solid; ESI-MS 412 [M+H+]; HPLC conditions (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), purity>98%. 1H-NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.08 (m, 4H), 5.99 (s, 1H), 5.52 (m, 1H), 2.93 (m, 4H), 2.35 (m, 1H), 2.12 (m, 1H), 1.60 (m, 13H), 1.16 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][CH:14]2[N:18]=[C:17](C(Cl)(Cl)Cl)[O:16][N:15]2[NH2:23])=[CH:7][CH:6]=1)[CH3:3].[CH3:24][NH2:25]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][CH:14]2[N:18]=[C:17]([NH:25][CH3:24])[O:16][N:15]2[NH2:23])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN
Reactant: CN(C)Cc1ccc(CSCCC2N=C(C(Cl)(Cl)Cl)ON2N)o1
Solvent: CCO
Product: CNC1=NC(CCSCc2ccc(CN(C)C)o2)N(N)O1
Temperature: 50 °C

Procedure:
The oxadiazole from Example 16 (3 g, 7.5 mmol) is dissolved in 25 ml of ethanol saturated with methylamine and the solution heated in a sealed tube at 50° C. for 16 hours. The mixture is concentrated to provide 3-[2-[(5-Dimethylaminomethyl-2-furanyl)methylthio]ethyl]-amino-5-methylamino-1,2,4-oxadiazole as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:2]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:24]=[CH:23][C:20](/[CH:21]=[N:15]/[NH:14][C:12](=[O:13])[CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:19][CH:18]=1
Reactant: NNC(=O)CCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C(CCc1c[nH]c2ccccc12)N/N=C/c1ccc(F)cc1
Yield: 98.7 %

Procedure:
A solution of 3-(1H-Indol-3-yl)-propionic acid hydrazide (0.300 g, 1 eq) and 4-fluorobenzaldehyde (0.183 g, 1 eq) in toluene (7 ml) is refluxed overnight and then evaporated to dryness, to afford 0.450 g of white product that is purified by flash chromatography using neutral alumina and eluting with 1% methanol in chloroform (0.269 g, 59% yield).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:51]([NH:50][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:47]([F:48])=[CH:46][C:45]=1[F:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 15 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 4.20 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 3.30 g of 2-amino-6-(t-butylamino)-3,5-difluoropyridine. The solution was concentrated under reduced pressure to obtain orange-colored solid residue. To this residue were added 4.0 g of annydrous potassium carbonate and 8 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 10 minutes and allowed to cool. The solution was separated by adding 50 ml of chloroform and 500 ml of distilled water, and the chloroform layer was washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 4.67 g of the title compound as a colorless powder.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[NH:27][C@H:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][S:24]1.[C:35]([O:39][C:40]([NH:42][CH2:43][C:44](O)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(#N)C>[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]([N:27]1[C@H:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][S:24][C@@H:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2F)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)N1[C@@H](c2ccccc2F)SC[C@H]1C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
(2R,4R)-tert-Butyl 3-(2-tert-butoxycarbonylamino)-2-(2-fluorophenyl)-thiazolidine-4-carboxylate can be prepared in the following manner: a solution of 18.2 g of N,N'-dicyclohexylcarbodiimide in 75 cm3 of anhydrous acetonitrile is added over 30 minutes to a solution of 25.0 g of (2RS,4R)-tert-butyl 2-(2-fluorophenyl)thiazolidine-4-carboxylate and of 15.5 g of 2-tert-butoxycarbonylaminoacetic acid in 150 cm3 of anhydrous acetonitrile, maintained at a temperature close to 0° C. The reaction mixture is stirred for 16 hours at a temperature close to 25° C. The insoluble product is separated off by filtration, washed with 3 times 20 cm3 of acetonitrile, and the filtrate is concentrated to dryness at reduced pressure at 40° C. The crude product obtained is purified by chromatography on silica [eluent: ethyl acetatecyclohexane (30-70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness at reduced pressure at 40° C. 25.0 g of (2R,4R)-tert-butyl 3-(2-tert-butoxycarbonylaminoacetyl)-2-(2-fluorophenyl)thiazolidine-4-carboxylate are thus obtained in the form of an oil, which is employed as it is in the subsequent syntheses.
Reaction SMILES: [CH2:1]([Br:4])[CH:2]=[CH2:3].C(NCC)C.[CH2:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:11]=[CH2:12]>>[Br-:4].[CH2:1]([N+:13]([CH2:10][CH:11]=[CH2:12])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCN(CC)CC
Reactant: C=CCBr
Solvent: CCNCC
Product: C=CC[N+](CC)(CC)CC=C
Product: [Br-]

Procedure:
The present invention is directed to a process which comprises (a) reacting allyl bromide with diethyl amine in a molar ratio of at least about 1 mole of allyl bromide per about 1.15 moles of diethyl amine and in a molar ratio of no more than about 1 mole of allyl bromide per about 2 moles of diethyl amine, thereby generating allyl diethyl amine in a monomer reaction mixture; (b) subsequently filtering the monomer reaction mixture to remove impurities; (c) subsequently reacting the allyl diethyl amine with allyl bromide, thereby generating solid diallyl diethyl ammonium bromide; (d) subsequently isolating the solid diallyl diethyl ammonium bromide; (e) subsequently dissolving the diallyl diethyl ammonium bromide in a solvent and adding thereto a polymerization initiator to form a polymerization reaction mixture; (f) subsequently heating the polymerization reaction mixture in a vessel equipped with a reflux condenser to a temperature of from about 90 to about 100° C., thereby generating poly(diallyl diethyl ammonium bromide); and (g) subsequently optionally isolating the poly(diallyl diethyl ammonium bromide) from the polymerization reaction mixture.
Reaction SMILES: [Cl-].[Cl:2]C1N(C)CC[NH+]1C.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](O)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([Cl:2])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)Cl)cc1
Yield: 93.2 %

Procedure:
To 9.72 g (0.0575 mole) of 2-chloro-1,3-dimethylimidazolinium chloride, 83 g of toluene was added and successively 8.61 g (0.05 mole) of p-toluenesulfonic acid was added. The mixture was reacted at 110° C. for 4 hours. The reaction mass was analyzed by gas chromatography. p-Toluenesulfonyl chloride was obtained in the yield of 93.2%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:43]>C(Cl)Cl.CCN(CC)CC>[CH2:42]([N:44]1[CH2:49][CH2:48][N:47]([C:16]([C@@H:14]2[CH2:15][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]2([CH3:20])[CH3:19])=[O:18])[CH2:46][CH2:45]1)[CH3:43]
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reactant: CCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(C(=O)[C@@H]2C[C@H](NC(=O)OCc3ccccc3)C2(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (1.0 g) in DCM (30 ml) at 0° C. EDCI (800 mg) and HOBt (700 mg) were added, after 10 minutes N-Ethylpiperazine (800 mg) and Et3N (3 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine. The organic layer was concentrated under reduced pressure then the resulting crude was purified by silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 780 mg; Yield: 57.9%. 1H NMR and Mass complies with the required product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C(N(CC)CC)C.Cl.[C:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)(=[NH:32])[NH2:31].Cl[C:43]([O:45][CH3:46])=[O:44]>ClCCl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([C:30](=[NH:32])[NH:31][C:43]([O:45][CH3:46])=[O:44])=[CH:34][CH:35]=3)[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)Cl
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: N=C(N)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)NC(=N)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (143 mg) and triethylamine (208 mg) in dichloromethane (10 ml) was added 4-amidinobenzoylchloride hydrochloride (108 mg), and the solution was stirred at room temperature for 1 hour, to which were added DMF (10 ml) and methyl chloroformate (200 mg). The solution was stirred at 50° C. for 30 minutes and the reaction solution was concentrated . The residue was dissolved in ethyl acetate, washed with water and sodium chloride solution, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate/methanol=40:1) to give colorless crystals of the title compound (41 mg).
Reaction SMILES: [CH3:1]N(C)CCNC.[Li]CCCC.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.CI>C1COCC1.Cl>[CH3:1][C:22]1[C:17]2[O:16][CH2:15][CH2:14][O:13][C:18]=2[CH:19]=[CH:20][C:21]=1[CH:23]=[O:24]
Reactant: CNCCN(C)C
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C=O)ccc2c1OCCO2
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a solution of N,N,N′-trimethylethylenediamine (3.3 g, 32.3 mmol) in THF (100 mL) at −15° C. was dropwise added n-BuLi (19.2 mL, 30.5 mmol, 1.6 M in THF). After stirring at −15° C. for 15 minutes, a solution of solution of 1,4-benzodioxane-6-aldehyde (5.0 g, 30.5 mmol) in THF (10 mL). After 20 minutes, another batch of n-BuLi (5 mL, 3.1 mmol, 1.6 M in THF) was added and stirred for 3 h. The resulting solution was cooled down to −72° C. and the mixture was treated with MeI (25.9 g, 182.5 mmol) slowly. After stirring at −72° C. for 3 h, the mixture was diluted with HCl solution (1M in water). The aqueous layer was extracted several times with diethyl ether. The organic fractions were combined, concentrated and purified with column chromatography (silica, 5-40% ethyl acetate in hexane) to provide the title compound as an off-white compound (1.0 g, 18%): %): MS (ES) m/z 179 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:16][OH:17]>C(Cl)Cl>[Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH:16]=[O:17]
Reactant: OCc1cccc2c(Cl)c3ccccc3cc12
Solvent: ClCCl
Product: O=Cc1cccc2c(Cl)c3ccccc3cc12
Yield: 69.2 %

Procedure:
10-Chloro-1-anthracenemethanol (37C, 8.8 g, 0.036 mol) was dissolved in CH2Cl2 (200 mL) and treated with BaMnO4 (Aldrich, 15 g, 0.059 mol) for 3 days and briefly brought to reflux. The reaction mixture was filtered, and the filtrate reduced to dryness. The residue was chromatographed by preparative HPLC using PhCH3 as the eluting solvent to give 6.0 g (69%) of crude 10-chloroanthracene-1-carboxaldehyde, which was used without further purification. An analytical sample was recrystallized from CH2Cl2 /hexane mp 139°-140.5°. (C.H.Cl).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>>[CH3:9][C:7]1([CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3](=[O:18])[CH:2]([NH:1][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH2:8]1
Reactant: COCC(=O)Cl
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Product: COCC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O

Procedure:
N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2-methoxy-acetamide was prepared from 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one and Methoxyacetyl chloride in an analogous manner to Example 1271d (338 mg, 66%).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]3[N:29]=[C:30]([CH2:32]O)[CH:31]=[C:25]3[C:24]2=[O:34])=[N:21][CH:22]=1.FC1C=CC(N2CCN3N=C(COC4C=CC(C)=CC=4)C=C3C2=O)=CC=1>>[C:5]([Si:2]([CH3:4])([CH3:3])[O:1][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:32][C:30]2[CH:31]=[C:25]3[C:24](=[O:34])[N:23]([C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:22][N:21]=4)[CH2:28][CH2:27][N:26]3[N:29]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reactant: O=C1c2cc(CO)nn2CCN1c1ccc(F)cn1
Agent: Cc1ccc(OCc2cc3n(n2)CCN(c2ccc(F)cc2)C3=O)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2cc3n(n2)CCN(c2ccc(F)cn2)C3=O)cc1

Procedure:
The compound was prepared from 4-(tert-butyldimethylsiloxy)phenol and 5-(5-fluoro-pyridin-2-yl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one using the method described in the preceding example 55 (5-(4-fluorophenyl)-2-(p-tolyloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=1)=[O:7].Cl>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Reaction time: 15 h
Yield: 61 %

Procedure:
0.5 g (11.92 mmol) of lithium hydroxide monohydrate and 15 cm3 of water are added to a solution at a temperature in the region of 22° C. of 1.1 g (3.64 mmol) of 3-methoxycarbonyl-1-(isoquinol-3-yl)-1H-indole in 15 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), the residue is triturated in water and the resulting suspension is filtered. The solid obtained is suspended in 20 cm3 of water adjusted to pH 7 with N hydrochloric acid. After stirring at a temperature in the region of 22° C. for 1 hour, the solid is filtered off and dried under reduced pressure (2.7 kPa) to give 0.64 g of 3-carboxy-1-(isoquinol-3-yl)-1H-indole in the form of a white solid. IR spectrum (KBr): 1661, 1629, 1593, 1540, 1464, 1217 and 748 cm−1.