Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:7]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[F:18][C:19]1[CH:20]=[C:21]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:7]=2)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: FC(F)(F)c1cccc(-c2csc(CI)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, to a mixed solvent of the compound (270 mg, 0.72 mmol) obtained in Example 190c, 3-fluoro-4-methoxycarbonylphenylboronic acid (170 mg, 0.86 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in tetrahydrofuran-water (v/v=5/1, 6 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (120 mg, 0.14 mmol), and the mixture was stirred at 90° C. overnight. The resulting salt was filtered and removed, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound as colorless crystals.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:20][N:21]1[C:35]2[C:36]3[C:23]([CH2:24][C@@H:25]4[C@@H:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:29][C@@H:28]([CH2:37][NH:38][NH2:39])[CH2:27][N:26]4[CH3:40])=[CH:22]1>C(#N)C>[CH3:20][N:21]1[C:35]2[C:36]3[C:23]([CH2:24][C@@H:25]4[C@@H:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:29][C@@H:28]([CH2:37][NH:38][NH:39][C:1](=[O:4])[CH3:2])[CH2:27][N:26]4[CH3:40])=[CH:22]1
Reactant: CC(=O)O
Reactant: CN1C[C@H](CNN)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(=O)NNC[C@@H]1C[C@@H]2c3cccc4c3c(cn4C)C[C@H]2N(C)C1
Temperature: -15 °C
Yield: 59.1 %

Procedure:
0.6 g of acetic acid are dissolved in 25 ml of acetonitrile with stirring. The solution is cooled to -15° C., and 1.39 ml of isobutyl chloroformate and 1.1 ml of N-methyl-morpholine are added. After 5 minutes of stirring a solution of 2.8 g of 1,6-dimethyl-8β-hydrazinomethyl-ergoline in 10 ml of acetonitrile is added to the mixture. The mixture is slowly (within 30 minutes) warmed to room temperature, stirred at room temperature for 2 hours, then evaporated in vacuo. The residue is dissolved in 200 ml of chloroform, and 100 ml of water are added. The pH of the aqueous phase is adjusted to 8 with 10% aqueous ammonia, and the mixture is shaken. The organic phase is separated, and the aqueous phase is extracted thrice with 100 ml of chloroform. The chloroform fractions are combined and evaporated to dryness in vacuo. The residue is subjected to column chromatography in order to remove the occasional impurities. 60 g of silica gel are used as adsorbent, and the column is eluted with a 30:0.3:9 mixture of chloroform, water and methanol. The effluent is analyzed by thin layer chromatography. The fractions containing a substance with an Rf value of 0.75 are combined, evaporated in vacuo, and the residue is crystallized from alcohol. 1.9 g (60.4%) of 1,6-dimethyl-8β-[(N'-acetyl-hydrazino)-methyl]-ergoline are obtained; m.p.: 190°-192° C., [α]D20 =-29.7° (c=1, in 96% ethanol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])[CH:8]=2)[CH:3]=[CH:2]1.I[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH:13][CH2:14][C:15]#[C:16][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: C#CCNC(=O)Cc1ccc2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: O=C(Cc1ccc2cc[nH]c2c1)NCC#Cc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 8 a], 2-(1H-indol-6-yl)-N-prop-2-ynyl-acetamide (example 13 a]) was reacted with 4-iodobenzotrifluoride in the presence of PdCl2(Ph3P)2 and cuprous iodide to give the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[CH:11](O)=O.O.N>Cl>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]2[N:9]=[CH:11][NH:10][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Nc1cc(Br)cc(N)c1N
Agent: Cl
Agent: N
Solvent: O
Product: Nc1cc(Br)cc2[nH]cnc12
Yield: 96.3 %

Procedure:
To a stirred suspension of 5-bromobenzene-1,2,3-triamine (81.5 g, 403 mmol) in HCl conc (2400 mL) at rt was added formic acid (46 mL, 1210 mmol, 3 eq). After stirring at reflux for 90 min, water (500 mL) was added to the suspension, and the pH was adjusted to 8 using ammonia (33% aqueous solution). After extraction with ethyl acetate (3×1000 mL), the organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vaccuo. The crude product was trituarated with diethyl ether (200 mL), filtered and dried to yield 82.3 g (96.3%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:6](=[O:16])[N:5]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:4]=2[N:3]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].C(N(CC)CC)C.O>O1CCCC1>[NH2:1][C:2]1[N:10]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:6](=[O:16])[N:5]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:4]=2[N:3]=1
Reactant: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nc2c(c(=O)n(CC3CC3)c(=O)n2CC2CC2)n1S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
8-Amino-1,3-di(cyclopropylmethyl)xanthine (2.7 g, 10 mmol), 4-nitrobenzenesulphonyl chloride (5.5 g, 25 mmol) and triethylamine (3 ml, 20 mmol) were stirred together in tetrahydrofuran (THF) (40 ml) at ambient temperature for 24 hr. After adding to water (100 ml) the mixture was extracted into ethyl acetate (150 ml) and the organic solution dried (MgSO4) and evaporated. Chromatography of the residue on silica, (hexane/acetone gradient) gave 8-amino- 1,3-di(cyclopropylmethyl)-7-(4-nitrobenzenesulphonyl)xanthine followed by 1,3-di(cyclopropylmethyl)-8di(cyclopropylmethyl)-8-di(4-nitrobenzenesulphonyl)aminoxanthine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:32]([CH3:33])[CH3:31])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Reactant: CNC
Product: CN(C)C(=O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Yield: 50 %

Procedure:
Following the procedure of Example 91, 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and dimethylamine were reacted to give 220 (yield 50%). MS: (ESI+) 471.1
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2C=C[CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.[C:41](O)([C:43](F)(F)F)=O>C(Cl)Cl>[F:22][C:17]1[CH:18]=[CH:19][CH:43]=[CH:41][C:16]=1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:29]=3)[CH2:25][C:24](=[O:39])[NH:23][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(C#Cc3ccccc3F)cc2N1

Procedure:
Prepared from {4-(2-fluoro-phenylethynyl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K38) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (99 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: O=S([O-])([O-])=S
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To as solution of Example 36B (20 g, 41.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (16.85 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium (4.84 g, 4.19 mmol) in N,N-dimethylformamide (500 mL) was added a solution of sodium bicarbonate (7.04 g, 84 mmol) in water (40 mL) and the mixture was stirred at 80° C. for 12 hours. Saturated aqueous sodium thiosulfate and water were added and the mixture was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[NH2:12])=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:12][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)=[CH:2]1
Reactant: Cc1noc([C@H](N)Cc2c[nH]c3ccccc23)n1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1noc([C@@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-2-(1H-Indol-3-yl)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (400 mg, 1.65 mmol) and 4-dimethylamino-4-phenylcyclohexanone (358.7 g, 1.65 mmol) in anhydrous tetrahydrofuran (50 mL) was mixed with sodium sulphate (1.1 g) and stirred for 2 h at room temperature. After adding acetic acid (248 mg, 4.1 mmol) sodium triacetoxyboron hydride (524 mg, 2.47 mmol) was added and the reaction mixture stirred for 16 h at room temperature. The solvent was removed in a vacuum, the residue mixed with 1M potassium carbonate solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product was purified by flash chromatography (400 g, 20×5.6 cm) with ethyl acetate/isopropanol/triethylamine (10:0.3:0.01→5:1:0.1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C2OCCO2)cc1Br
Yield: 89.1 %

Procedure:
11.8 g (60 mmol) of 3-bromo-4-methylbenzaldehyde are placed in 150 ml of toluene in a round-bottomed flask and under nitrogen. 16.5 ml (300 mmol) of ethylene glycol and 571 mg (3 mmol) of para-toluenesulfonic acid are added. The mixture is refluxed for 36 hours and the water formed is separated out using Dean-Stark apparatus. At room temperature, the reaction medium is poured into saturated aqueous sodium hydrogen carbonate solution and then extracted with ether. The organic phase is dried over magnesium sulfate, filtered and evaporated. 13 g (89%) of the expected product are obtained in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[N:16]=[C:15]([O:17][CH2:18][CH3:19])[S:14][N:13]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:13]2[C:12](=[O:11])[N:16]=[C:15]([O:17][CH2:18][CH3:19])[S:14]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCOc1nc(O)ns1
Solvent: C1CCOC1
Product: CCOc1nc(=O)n(C(=O)Nc2cccc(Cl)c2)s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
43 g of 3-chlorophenyl isocyanate were added to a solution of 29.4 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 300 ml of tetrahydrofuran and the mixture was stirred for 21/2 hours at 20° C. The mixture was evaporated to dryness under reduced pressure and the residue was crystallized from ethyl acetate to obtain 26 g of 2-(N-m-chlorophenylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 141° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1C(=O)N([I:50])C(=O)C1>C(Cl)Cl.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([I:50])=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (38B) (2.2 g, 3.53 mmol) in DCM (30 mL) was added NIS (0.795 g, 3.53 mmol). The mixture was stirred at r.t. overnight. The mixture was then diluted with EtOAc (300 mL) and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% EtOAc in hexanes to provide 2.6 g of the desired product. LC/MS (APCI): m/z 749.2 (M+H).
Reaction SMILES: B.O1CCCC1.[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[C:19]([CH2:22][CH:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25])[CH:18]=[CH:17]2.CO>O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[C:19]([CH2:22][CH:23]([CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25])[CH:18]=[CH:17]2
Reactant: COCCOc1cccc2ccc(CC(C(=O)O)C(C)C)cc12
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cccc2ccc(CC(CO)C(C)C)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3 ml of borane-tetrahydrofuran complex (1M in tetrahydrofuran) are added dropwise at 0° C. to the solution of 0.32 g of 2-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-3-methylbutyric acid in 2 ml of tetrahydrofuran. After 2 hours at room temperature, the reaction mixture is cooled to 0° C., admixed cautiously with 5 ml of methanol and subsequently stirred at room temperature for 1 hour. The reaction mixture is concentrated by evaporation—the residue is dissolved once again in methanol and concentrated by evaporation to dryness. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCCC1=N
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)N=C2CCCN2C)c1
Temperature: 25 °C

Procedure:
Conversion of the hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g; 0.05 mole) to the free base (4.9 g. assuming 100% conversion) is carried out in the usual manner. After drying over K2CO3, the benzene layer is stirred at room temperature and 7.45 g. (0.05 mole) of m-methoxyphenylisocyanate is added. The reaction mixture is stirred overnight and then taken to dryness in vacuo to give a white solid residue of 1-m-methoxyphenyl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 123°-125° C. Recrystallizations from acetone affords the pure product, m.p. = 128°-129.5° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]3[CH:16]=[CH:17][C:18]([C:21](=[O:23])[CH3:22])=[C:19]([OH:20])[C:13]=3[CH2:12]2)=[C:7]([CH2:26][CH2:27][CH3:28])[CH:6]=1.[OH-].[Na+]>C1COCC1>[C:3]([CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]3[CH:16]=[CH:17][C:18]([C:21](=[O:23])[CH3:22])=[C:19]([OH:20])[C:13]=3[CH2:12]2)=[C:7]([CH2:26][CH2:27][CH3:28])[CH:6]=1)([OH:29])=[O:2]
Reactant: CCCc1cc(CC(=O)OC)ccc1OCC1Cc2c(ccc(C(C)=O)c2O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1cc(CC(=O)O)ccc1OCC1Cc2c(ccc(C(C)=O)c2O)O1
Temperature: 25 °C

Procedure:
The compound of Example 6 (600 mg, 1.51 mmoles) was taken up in THF (5 ml) to which was added 1N NaOH (4 ml). The reaction mixture was stirred at room temperature. The THF was removed in vacuo and the residue was diluted with H2O and extracted with CHCl3. The aqueous phase was acidified with conc. HCl and extracted with CHCl3. The organic extract was dried and concentrated in vacuo. The title compound was crystallized from ether/hexane.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][C:23]1([CH3:29])[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1.C(OCC)C>[CH3:22][C:23]1([CH3:29])[NH:24][CH2:25][CH2:26][N:27]([C:2]2[C:3]([F:21])=[CH:4][C:5]3[C:6]([CH:20]=2)=[N:7][C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=2[CH:14]=3)[CH2:28]1
Reactant: CC1(C)CNCCN1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)(C)C4)cc3nc21
Yield: 63.8 %

Procedure:
A suspension of 2 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 7.44 g of 2,2-dimethylpiperazine and 20 cm3 of pyridine is heated at a temperature close to 115° C. for 44 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at about 60° C. The residue is taken up in 50 cm3 of ethanol and again concentrated, under reduced pressure, under the above conditions. The solid obtained is taken up in 50 cm3 of diethyl ether, drained, washed with twice 30 cm3 of the same solvent and taken up in 120 cm3 of water and 2 g of methanesulphonic acid. A very small amount of insoluble matter is removed by filtering through diatomaceous silica. 2 cm3 of 50% aqueous potassium hydroxide solution are added to the solution obtained. The precipitate formed is drained and washed with 3 times 25 cm3 of water and a single amount of 50 cm3 of ethanol at about 50° C. 1.6 g of 8-(3,3-dimethyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 362°-365° C., solvated by 4.9% of water.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]1[CH:37]=[CH:36][C:35]3=[C:38]4[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]4[C:29]1[C:30]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:31]4[CH:48]=[CH:47][CH:46]=[CH:45][C:32]4=[C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:34]=13)[CH:17]=[CH:16]2>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C:23]2[CH:37]=[CH:36][C:35]4=[C:38]5[C:24]=2[CH:25]=[CH:26][CH:27]=[C:28]5[C:29]2[C:30]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[C:31]5[CH:48]=[CH:47][CH:46]=[CH:45][C:32]5=[C:33]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:34]=24)[CH:17]=[CH:16]3)=[CH:5][CH:4]=1)#[N:2]
Reactant: Brc1ccc2cc(-c3ccc4c5c(cccc35)-c3c-4c(-c4ccccc4)c4ccccc4c3-c3ccccc3)ccc2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc3cc(-c4ccc5c6c(cccc46)-c4c-5c(-c5ccccc5)c5ccccc5c4-c4ccccc4)ccc3c2)cc1

Procedure:
It was carried out in a similar manner as Synthesis Example 1 except that 4-cyanophenyl boronic acid was employed instead of 9,9-dimethyl-9H-fluorene-2-yl boronic acid, and that 3-(6-bromonaphthalen-2-yl)-7,12-diphenylbenzo[k]fluoranthene was employed instead of 3-bromo-7,12-dibenzo[k]fluoranthene in Synthesis Example 1 to obtain 3-(6-(4-cyanophenyl)naphthalen-2-yl)-7,12-diphenylbenzo[k]fluoranthene (Compound 5-12).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])[C:5](Cl)=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>COCCOC>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:5]2[C:4]([C:9]3[N:10]=[CH:11][S:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[Cl:21])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cccc(-c2scnc2-c2cc(Br)cnc2Cl)c1Cl
Solvent: COCCOC
Product: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Yield: 85 %

Procedure:
A solution of 5-bromo-2-chloro-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridine (520 mg, 1.24 mmol) and p-methoxybenzyl amine (373 mg, 2.72 mmol) in DME (12 mL) was stirred at 80° C. for 48 hours. The reaction mixture was concentrated and the residue purified by silica gel chromatography (0-25% EtOAc/hexanes) to give N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine as a pale yellow solid [631 mg, 85% yield; LC-MS, M+H=519.9; 1H-NMR (300 MHz, CDCl3) 8.85 (1H, s), 8.00 (1H, d, J=2.3 Hz), 7.45 (1H, dd, J=1.9, 7.6 Hz), 7.10-7.17 (4H, m), 7.01 (1H, d, J=2.4 Hz), 6.77 (1H, t, J=6.7 Hz)].