Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[C:11]([OH:13])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1(Br)[CH2:27][CH2:26][CH2:25]1>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[C:11]([O:13][CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH:12]=1
Reactant: COCOc1ccc(Br)cc1O
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Br)cc1OC1CCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To 10 ml of N,N-dimethylformamide solution containing 1.73 g (7.4 mmol) of 5-bromo-2-methoxymethoxyphenol obtained in Reference Example 5-(b) were added 1.0 g (7.2 mmol) of potassium carbonate and 1.0 g (7.4 mmol) of cyclobutyl bromide, and the mixture was stirred at 100° C. for 5 hours. After completion of the reaction, 10 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.4 g of the title compound as a colorless oil. (Yield: 66%)
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1[C:5]1[CH:6]=[CH:7][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:24]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1sccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1sccc1Cl
Yield: 12 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 3-chlorothiophene-2-boronic acid (available from Combi-Blocks Inc.; 81 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(3-Chloro-thiophen-2-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (14 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 13.23 (br s, 1H), 8.50 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.27 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.74-7.81 (m, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.15 (d, J=5.3 Hz, 1H), 7.15 (d, J=5.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[O:17])=[CH:11][CH:10]=2)[S:4][N:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+].O>CCOC(C)=O>[C:7]([C:6]1[C:2]([NH:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[N:3][S:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[F:26])=[O:17])=[CH:11][CH:10]=1)#[N:8]
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(Cl)c3C#N)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(NCCCN4CCOCC4)c3C#N)cc2)c1
Temperature: 70 °C
Yield: 16 %

Procedure:
A mixture of 1-[4-(3-chloro-4-cyanoisothiazol-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea (50 mg, 0.13 mmol) and 0.2 mL 3-morpholinopropylamine was heated at 70° C. for 18 hours. Then an aqueous Na2CO3/brine mixture and EtOAc workup was done, and the resulting material chromatographed eluting with CHCl3/MeOH. The resulting solid was then triturated with a 1:1/CHCl3/hexane mixture which gave the title compound as a pale yellow solid (10 mg, 16%).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:4])[CH:2]=[O:3].O.[N+:17]([C:20]1[CH:43]=[CH:42][CH:41]=[CH:40][C:21]=1[CH2:22][O:23][C:24]([NH:26][CH:27]([C@H:29]1[C@H:32]([CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[NH:31][C:30]1=[O:39])[CH3:28])=[O:25])([O-:19])=[O:18]>C1C=CC=CC=1>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][O:5][C:1]([CH:2]([OH:3])[N:31]1[C@@H:32]([CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:29]([CH:27]([NH:26][C:24]([O:23][CH2:22][C:21]2[CH:40]=[CH:41][CH:42]=[CH:43][C:20]=2[N+:17]([O-:19])=[O:18])=[O:25])[CH3:28])[C:30]1=[O:39])=[O:4])([O-:15])=[O:14]
Reactant: O=CC(=O)OCc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OCC[C@@H]1NC(=O)[C@H]1C(C)NC(=O)OCc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)OCC[C@H]1[C@H](C(C)NC(=O)OCc2ccccc2[N+](=O)[O-])C(=O)N1C(O)C(=O)OCc1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
Ortho-nitrobenzyl glyoxalate prepared from (0.650 g, 0.00153 mole) of di-o-nitrobenzyl tartarate, is dissolved in 20 ml benzene and refulxed using a Dean-Stark water separator containing CaH2 for an hour. Trans-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(2-acetoxyethyl)-2-azetidinone (0.580 g, 0.00153 mole) is added and the mixture is refluxed for 8 hrs, cooled, evaporated. The residue is column chromatographed ##STR215## to give 0.775 g (0.00132 mole, 87% yield) of the product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:31][CH2:30][CH2:29][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:32])=[O:8])=[CH:2]1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=C(O)c1cc[nH]c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCNC(=O)c1cc[nH]c1)OCc1ccccc1
Reaction time: 24 h

Procedure:
Into a solution of 1.67 g (15 mmol) of 3-pyrrolecarboxylic acid and 6.33 g (18 mmol) of β-alanine benzyl ester p-toluenesulfonate in 20 ml of dimethylformamide, a solution of 2.94 g (18 mmol) of diethyl phosphorocyanidate in 10 ml of dimethylformamide was added dropwise under ice cooling and stirring. A solution of 3.64 g (36 mmol) of triethylamine in 20 ml of dimethylformamide was then added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 24 hours.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.S(=O)(=O)(O)O.[N+:12]([O-])([OH:14])=[O:13]>>[CH3:1][C:2]1[NH:3][C:4]([N+:12]([O-:14])=[O:13])=[CH:5][N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ncc[nH]1
Agent: O=S(=O)(O)O
Product: Cc1ncc([N+](=O)[O-])[nH]1

Procedure:
In a bottle of 1 liter capacity, an untreated mixture obtained by nitration of the 2-methylimidazole as in examples I, III and V were placed and while stirring and mixing, 100 g of 2-methylimidazole were dissolved in such a manner, that the temperature did not exceed 70°. Then a reflux-condenser was connected and 200 ml of nitric acid of a density of about 1.50 were added, and thereafter sulphuric acid of 1.84 density was gradually introduced such that the temperature increased to 110°. The reaction, which started at once without delay, was intensive with violent liberation of nitric oxides. Then as the intensity of the reaction declined, further quantities of sulphuric acid were added until exhaustion of a quantity of 100 ml, and after the exothermic effect diminished the reflux condenser was changed to a normal one, whereby the temperature of the mixture increased to about 140° by simultaneous distilling off several ml of volatile components. After the reaction the solution was divided, and 1/3 remained for the treatment in the same way as the following charge and from the remaining 2/3 of the solution there were isolated 98 g of 2-methyl-5-nitroimidazole corresponding to about 66% of theoretical.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CC#N>[CH2:19]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([O:8][CH3:7])=[O:17])=[CH:11][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Temperature: 70 °C

Procedure:
Anhydrous K2CO3 (18.43 g, 0.13 mol) was added to 300 mL of CH3CN, and the solution was degassed with N2 for 20 minutes. Methyl-4-hydroxybenzoate (6.27 g, 41.2 mmol) was added to the reaction flask, which was heated to 70° C., following which 1-bromodecane (8.8 mL, 42.5 mmol) was added. The above solution was refluxed for 12 hours, and upon cooling the solvent was removed under reduced pressure. The residue was taken in CH2Cl2 (200 mL) and washed with 1 M HCl (100 mL). The organic layer was washed with distilled H2O (100 mL), and the solvent was removed under reduced pressure. Yield 12.0 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 0.90 (3
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:4]([F:15])[CH:3]=1
Reactant: [H][H]
Reactant: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)Oc1cc(Nc2ccccc2)c(F)cc1Cl
Yield: 69.3 %

Procedure:
A suspension of 4-chloro-2-fluoro-5-isopropoxynitrobenzene (13.5 g) and platinum dioxide (0.4 g) in ethanol (300 ml) was subjected to catalytic reduction with hydrogen under room temperature and atmospheric pressure, whereby a designed amount of hydrogen was absorbed. The resultant mixture was filtered to remove insoluble materials, and the filtrate was concentrated. The residue was subjected to purification by silica gel chromatography to obtain 5.6 g of 4-chloro-2-fluoro-5-isopropoxyphenylaniline. nD24.5 1.5360.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Al].[Pb](Br)Br.[C:15](Cl)([Cl:18])([Cl:17])[Cl:16]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:15]([Cl:18])([Cl:17])[Cl:16])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: Br[Pb]Br
Agent: [Al]
Solvent: CN(C)C=O
Product: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1Cl
Yield: 89 %

Procedure:
3-Chloro-4-hydroxy benzaldehyde (15.6 g, 0.1 mol) was added to 200 ml of dimethylformamide, a mixture was stirred, aluminium (8.09 g, 0.3 mol) and leadbromide (3.67 g, 0.01 mmol) were added thereto. CCl4 (61.53 g, 0.4 mol) was slowly added to the reaction mixture. The mixture was stirred at room temperature for 10 hours, and unreacted solid was filtered to remove therefrom. After sequentially adding 5% HCl, ethylacetate and water thereto, the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled. The resulting residue was subjected to column chromatography (ethyl acetate: n-hexane=1:4) to obtain the title compound (24.55 g, 89%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](=[O:30])[CH2:28]Br)=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](=[O:30])[CH2:28][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH2:15])=[N:12][O:13][N:14]=2)=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.228 g, 1.14 mmol), potassium carbonate (0.40 g, 2.85 mmol) and 4-chloro-3-nitrophenacyl bromide (0.35 g, 1.25 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a solid, m.p. 198-200° C. (This compound is also listed as Example 66 in Table 1.)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][C:12]([NH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[CH:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)[N:28]=2)=[CH:23][CH:22]=1)=[O:16])=[S:13])([CH3:3])[CH3:2].[C:43]([O-])(=[O:45])[CH3:44].[Na+].C(O)C.BrCC(OC)=O>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:43](=[O:45])[CH2:44][S:13]/[C:12]/1=[N:14]\[C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[CH:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:41])([F:42])[F:40])=[CH:34][CH:33]=3)[N:28]=2)=[CH:23][CH:22]=1)=[O:16])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)C)c(NC(=S)NC(=O)NCCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Reactant: CC(=O)[O-]
Agent: COC(=O)CBr
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 70 °C
Yield: 67.5 %

Procedure:
To 1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea (F21) (0.110 g, 0.184 mmol) in a 25 mL vial equipped with a stir bar and Vigreux column was added sodium acetate (0.0600 g, 0.735 mmol), ethanol (2 mL) and methyl bromoacetate (0.0250 mL, 0.276 mmol). The reaction was heated to 70° C. overnight. The reaction was cooled and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography using 0-30% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided a solid which was dried overnight at 50° C. in vacuo to afford the title compound as a white solid (0.0791 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([C:14]2[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]3([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]3)[CH2:21][NH2:22])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[N:19][C:14]([CH:11]2[CH2:12][CH2:13]2)=[CH:15][CH:16]=1)[CH2:23][C:24]1([C:27]([F:28])([F:29])[F:30])[CH2:26][CH2:25]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=423.1, tR (minutes, Method G)=2.04
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:29]=1.BrBr>>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][CH:35]([CH2:34][C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1)[C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cccnc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: BrBr
Product: O=C(O)C(Cc1cccnc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from 2,6-dibromo-4-(6-bromo-benzo[b]naphtho [2,3-d]thiophen- 1 -yl)-phenol (Example 21) and 3-pyridin-3-yl-propionic acid, ethyl ester (Example 104). White solid: NMR (DMSO-d6); δ8.98 (s, 1 H), 8.82 (d., J=5 Hz, 1 H), 8.57 (d, J=8 Hz, 1 H), 8.28 (d, J=8 Hz, 1 H), 8.07 (d, J=8 Hz, 1 H), 7.96 (dd, J=8, 6 Hz, 1 H), 7.82 (d, J=2 Hz, 1 H), 7.79 (m, 1 H), 7.78 (d, J=2 Hz, 1 H),7.62 (dd, J=8, 1 Hz, 1 H), 7.57-7.50 (m, 2 H), 7.27 (dd, J=8, 1 Hz, 1 H), 6.67 (d, J=8 Hz, 1 H), 5.45 (dd, J=6, 2, 1 H), 3.60 (m, 2 H); MS (+FAB): [M+H]+, 3 bromine isotope pattern, 710, 712, 714, 716; Anal. Calc. for C30H18Br3NO3S.HCl: C, 48.13, H, 2.56, N, 1.87. Found: C, 48.12, H, 2.86, N, 1.65.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][CH:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:25][CH:24]=3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:36](=[NH:41])(OCC)[CH3:37].C(N(CC)CC)C.Cl>C(O)C>[ClH:1].[ClH:1].[C:36]([N:32]1[CH2:33][CH2:34][C@H:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([CH:17]([CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][CH:8]=4)[CH:13]=3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:24][CH:25]=2)[CH2:31]1)(=[NH:41])[CH3:37]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCNC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCN(C(C)=N)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 193.4 %

Procedure:
In 1,000 ml of ethanol was dissolved 105.3 g of ethyl (+)-3-(7-amidino-2-naphthyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride. With stirring at room temperature, the thus prepared solution was mixed with 51.5 g of ethyl acetimidate hydrochloride. With ice cooling and stirring, 89 ml of triethylamine was added dropwise to the above solution while keeping the inner temperature at 3° to 5° C., and the stirring was continued for 2.5 hours while keeping the temperature at 5° C. or below. After distilling off the solvent under a reduced pressure at a low temperature, the resulting reaction solution was adjusted to pH 4-5 with dilute hydrochloric acid, followed by further distillation under a reduced pressure to remove the solvent. The resulting residue was purified by subjecting it to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Thereafter, thus eluted fractions of interest were pooled, mixed with a small amount of dilute hydrochloric acid, and then concentrated to dryness. In this way, 110.1 g of the title compound was obtained in the form of a colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl>CS(C)=O>[C:20]1([S:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COc1ccc(S(=O)O)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(O)cc1)c1cccc2ccccc12
Reaction time: 36 h
Yield: 42.2 %

Procedure:
A mixture of 344 mg (2.0 mmol) 4-methoxybenzene sulfinic acid, 688 mg (4.0 mmol) 1-naphthyl boronic acid, 1.39 mL (10.0 mmol) triethylamine, 363 mg (2.0 mmol) cupric acetate, 350 mg 4A molecular sieves, and 10 mL dry dimethylsulfoxide was stirred under a stream of air for 36 hours. The mixture was then poured into dilute aqueous hydrochloric acid, extracted into ethyl acetate, and the organic layer washed with water, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane as eluant to afford 240 mg (40%) of 4-(1-napthylsulfonyl)phenol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1

Procedure:
Following the general procedure of Example 39, Step 2, and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.2982 g) and 1-[3-(trifluoromethyl)phenyl]piperazine (Aldrich; 0.34 mL) are converted to product, followed by chromatography on silica gel using methanol/dichlormethane (2/98). Crystallization from ethyl acetate and then from ethyl acetate/dichloromethane gives 0.053 g of the title compound; mp 145-145.5° C.; MS m/z 394; IR (mineral oil) 1117, 1163, 1451, 1073, 1339 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.28, 3.78, 7.12, 7.34, 7.52, 7.54, 8.14.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH2:22]([N:24]1[CH2:28][CH2:27][C:26]2([CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25]1)[CH3:23]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:30]3[CH2:31][CH2:32][C:26]4([CH2:27][CH2:28][N:24]([CH2:22][CH3:23])[CH2:25]4)[CH2:29]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CCN1CCC2(CCNC2)C1
Agent: Cl
Product: CCN1CCC2(CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(CC)c4c3F)C2)C1

Procedure:
The title compound was prepared according to example 26 by reacting 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with 2-ethyl-2,7-diazaspiro[4.4]nonane dihydrochloride, mp 199°-202° C. (dec).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([S:29][CH2:30][C@@H:31]([C:33]([NH:35][CH2:36][CH2:37][CH3:38])=[O:34])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH2:22]([S:29][CH2:30][C@H:31]([NH:32][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:33](=[O:34])[NH:35][CH2:36][CH2:37][CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCNC(=O)[C@@H](N)CSCc1ccccc1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNC(=O)[C@H](CSCc1ccccc1)NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.34 g), S-benzyl-N-propyl-L-cysteinamide (0.27 g), 1H-1,2,3-benzotriazol-1-ol (0.22 g) and N,N-dimethylformamide (15 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.27 g) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (285 mg, yield 49%) as colorless crystals. melting point 124-125° C.