Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC(F)=C2C=1CC[C@H:6]2[O:12]C1C=CC2[C@H](CC(O)=O)COC=2C=1.FC1[CH:28]=[CH:29][C:30]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[C:31]2[C:35]=1[C@H:34]([O:36][C:37]1[CH:49]=[CH:48][C:40]3[C@H](CC(O)=O)COC=3C=1)[CH2:33][CH2:32]2.B(O)O>>[CH3:32][C:31]1[CH:35]=[C:34]([CH:33]=[C:29]([CH3:28])[C:30]=1[B:50]1[O:51][C:52]([CH3:57])([CH3:58])[C:53]([CH3:55])([CH3:56])[O:54]1)[O:36][CH2:37][CH2:49][CH:48]([CH3:40])[CH2:6][OH:12]
Reactant: CC1(C)OB(c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)OC1(C)C
Reactant: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Agent: OBO
Product: Cc1cc(OCCC(C)CO)cc(C)c1B1OC(C)(C)C(C)(C)O1

Procedure:
Examples 53, 54, and 55 are also obtained via coupling {(S)-6-[(R)-4-bromo-7-fluoroindan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid (Example 63) or {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid with the corresponding coupling partner bearing a metal or pseudo-metal group, e.g., boronic acid or ester, or a leaving group, e.g., Cl or Br, at the carbon to be coupled. Accordingly, Example 53 is obtained from, e.g., 4-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methylbutanol or the corresponding boronic acid (Intermediate 23) and [(S)-6-((R)-4-bromo-7-fluoroindan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid (e.g., as acid or the piperazinium or morpholinium salt) or from, e.g., 4-(4-bromo-3,5-dimethylphenoxy)-2-methylbutanol and {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid (e.g., as acid or the piperazinium or morpholinium salt), as described below.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]([CH3:15])[C:12](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][NH:17][C:18]([NH:20][NH2:21])=[S:19].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C1S(=O)(=O)CCC1.O>[SH:19][C:18]1[N:20]([NH2:21])[C:12]([C@H:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH3:15])=[N:16][N:17]=1
Reactant: C[C@H](C(=O)O)c1ccc2ncccc2c1
Reactant: NNC(=S)NN
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: C[C@@H](c1ccc2ncccc2c1)c1nnc(S)n1N
Temperature: 90 °C
Yield: 63.8 %

Procedure:
As shown in step v of Scheme 1, (S)-2-(quinolin-6-yl)propanoic acid (50 g, 248.5 mmol) and 1,3-diaminothiourea (29.02 g, 273.4 mmol) were suspended in a mixture of tetramethylene sulfone (sulfolane, 38 mL) and water (57 mL). Methane sulfonic acid (35.5 ml, 546.7 mmol) was added to the mixture, whereupon all solids dissolved. The reaction temperature was slowly increased to 90° C. and the reaction was heated at 90° C. for 40 hours, at which time a 68% conversion of starting material to product was observed by HPLC analysis. The reaction mixture was cooled in an ice bath and water (75 mL) was added, followed by the careful addition of saturated sodium bicarbonate (500 mL) until a pH 8 was achieved. The resulting fine purple precipitate was collected by vacuum filtration, washed with water, saturated sodium bicarbonate, water, and methyl t-butyl ether, respectively. The product was dried in a vacuum oven at 55° C. for 2 days to afford 6-((S)-1-(5-mercapto-4-amino-4H-1,2,4-triazol-3-yl)ethyl)quinoline (compound 1005, 43 g): ESMS (M+1), 272.09; 1H NMR (300.0 MHz, DMSO-d6) δ 13.65 (1H, br s), 8.86 (1H, dd, J=1.8, 8.4 Hz), 8.34 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.7, 13.7 Hz), 7.82 (1H, d, J=1.5 Hz), 7.70 (1H, dd, J=1.8, 8.7 Hz), 7.50 (1H, dd, J=1.8, 8.7 Hz), 5.44 (2H, s), 4.57 (1H, q, J=7.2 Hz), 1.65 (3H, d, J=7.2 Hz). The product was 92% pure by 1H NMR analysis, with the major impurities being compound 1004 and sulfolane. Chiral HPLC analysis showed 92% ee (ChiralPak® AD-H, 70% i-propanol/hexanes; retention time: 4.98 min for S-enantiomer, 12.33 min for R-enantiomer). The product was used as is in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[OH-].[K+].C(O)(=[O:14])C.C(O)(=O)C.IC1C=CC=CC=1>CO>[OH:14][CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9]
Reactant: CC(=O)O
Reactant: O=C1CCc2sccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Ic1ccccc1
Product: O=C1c2ccsc2CC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,6-dihydro-cyclopenta[b]thiophen-4-one (36.8 g, 0.266 mol) in MeOH (1000 mL) was added at about 5° C. to a solution of potassium hydroxide 85% (52.7 g, 0.798 mol) in MeOH (500 mL). Between 0° C. and 5° C. iodobenzene diacetate (94.4 g, 0.293 mol) was added in portions and the mixture was allowed to come to room temperature. The mixture was stirred overnight at room temperature. The mixture was evaporated and a 20% solution of potassium carbonate (500 mL) was added. The mixture was extracted for times with DCM dried with sodium sulphate and evaporated under reduced pressure. The residue was dissolved in 1,4-dioxane (400 mL) and water (150 mL) and concentrated hydrochloric acid (150 mL) was added. The mixture was stirred for two hours at room temperature. The mixture was neutralized by the addition of potassium carbonate and extracted four times with dichloromethane. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. The product was crystallized with ether ethyl acetate and the mother liquid was purified by silica gel chromatography with toluene and acetone. Yield: 33.5 g=81.6%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].[H-].[Na+].Br[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:17].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:17])[C:7]2=[O:12]
Reactant: O=C1NCCc2c(Br)cccc21
Reactant: CC(Br)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1ccc(F)cc1)N1CCc2c(Br)cccc2C1=O
Reaction time: 20 h
Yield: 140.7 %

Procedure:
A solution of 0.15 g of 5-bromo-3,4-dihydroisoquinolin-1(2H)-one in 5 cm3 of dimethylformamide is poured into a mixture containing 31 mg of sodium hydride (60% in oil) and 10 cm3 of dimethylformamide at a temperature close to 20° C. under an inert atmosphere. Then a solution of 0.2 g of 1-(1-bromoethyl)-4-fluorobenzene in 5 cm3 of dimethylformamide is poured into the reaction mixture. The latter is stirred for 20 h at a temperature close to 20° C. Water and ethyl acetate are added to the reaction mixture. After decanting, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). The 325 mg of crude product obtained are purified by filtration through a silica pellet (eluent: 20% ethyl acetate/80% cyclohexane). After concentrating the fractions under reduced pressure, 146 mg of 5-bromo-2-[1-(4-fluorophenyl)ethyl]-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a thick pale yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]([CH:20]=[CH:21]N(C)C)=O)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH3:26])[CH:7]=1)=[O:5])C.Cl.[NH2:28][C:29]([NH2:31])=[NH:30].CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C>[NH2:30][C:29]1[N:31]=[C:18]([C:11]2[CH:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[CH2:25][CH3:26])=[CH:13][C:12]=2[F:17])[CH:20]=[CH:21][N:28]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)C=CN(C)C)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3ccnc(N)n3)cc21
Yield: 35.9 %

Procedure:
To 900 mg (2.5 mmol) of the 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 15 ml of t-butanol at 50° C. was added 580 mg (2.5 eq) of guanidine hydrochloride that had been previously treated with 1.35 g (5 eq) of potassium t-butoxide at 50° C. in t-butanol for 30 minutes. The final mixture was stirred for 24 hours at 60° C. It was poured into 8% aqueous acetic acid and extracted into chloroform. The chloroform was extracted three times with water. The chloroform was dried magnesium sulfate and concentrated. The residue was purified by column chromatography and gave 295 mg of 7-(2-amino-4-pyrimidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 245°-247° C.
Reaction SMILES: C(OC([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:32]2[CH:36]=[N:35][C:34]([C@:37]([CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)([OH:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:33]2)[CH2:27][CH2:26]1)C(OC(C)(C)C)=O)=O)(C)(C)C.Cl.C(OCC)C>ClCCl>[NH3:8].[NH2:8][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([CH2:31][N:32]2[CH:36]=[N:35][C:34]([C@@:37]([CH:45]3[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[OH:44])=[N:33]2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: N
Product: NCCCCCCCCCN1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Di-tert-butyl{9-[4-({3-[(R)-cyclohexyl(hydroxy)phenylmethyl]-1H-1,2,4-triazol-1-yl}methyl)piperdin-1-yl]nonyl}imidodicarbonate (Preparation 5, 2.6 g, 3.7 mmol) was dissolved in dichloromethane (15 ml) and hydrogen chloride in diethylether (2M, 15 ml, 30 mmol) added. After stirring at room temperature for 5 hours the solvent was removed in vacuo, the residue was partitioned between dichloromethane (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (97.5:2.5:0.25, by volume) to furnish the title compound as a clear oil, in 70% yield, 1.29 g (contains 10% of other triazole regio-isomer).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:34][NH:35][O:36][CH3:37]>ClCCl.O.C(N(CC)CC)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([N:35]([O:36][CH3:37])[CH3:34])=[O:10])[CH:3]=1
Reactant: Cn1nc(C(=O)O)cc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
5-Chloro-1-methyl-1H-pyrazole-3-carboxylic acid (982 mg) was added to a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.39 g), 1-hydroxybenzotriazole (252 mg), and N,O-dimethylhydroxylamine hydrochloride (1.21 g) in dichloromethane (50 ml). Triethylamine (2.4 ml) was added dropwise to the mixture, and the resulting mixture was stirred overnight at room temperature. The reaction solution was diluted with dichloromethane (20 ml). Water (50 ml) was added to the dilution to separate the aqueous and organic layers. The organic layer was washed with water (50 ml). The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (1.14 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:30]([C:31]([O:33][CH3:34])=[O:32])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:15][CH:16]=2)[C:8]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 322 mg (0.81 mmol) of 3-butyl-4-(4-hydroxybenzyl)-5-(4-nitrobenzylthio) -(4H-1,2,4-triazole (Example 1, Step E), 278 mg (1.21 mmol) of methyl α-bromophenylacetate, 168 mg (1.22 mmol) of anhydrous K2CO3, and 3 ml of dry DMF was stirred under N2 at 60° C. for 24 hours. The mixture was concentrated in vacuo (oil pump, 50° C.), and the residue was partitioned between EtOAc and H2O. The organic solution was dried (MgSO4), filtered, and concentrated. The residual oil was chromatographed on a column of silica gel (elution with a gradient of 0.5-10% MeOH in CH2Cl2). TLC (97:3 CHCl3 -iPrOH and 98:2 CH2Cl2 -MeOH) and NMR were used to identify the appropriate product fractions, which were combined and concentrated to give the product as a gum.
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1.[Cl:14][C:15]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH:19]1[O:21][CH2:20]1>CO>[Cl:14][C:15]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: Cc1cccc(OCC2CO2)c1Cl
Reactant: CC(C)(N)COc1ccc(Cl)nn1
Solvent: CO
Product: Cc1cccc(OCC(O)CNC(C)(C)COc2ccc(Cl)nn2)c1Cl
Yield: 66.6 %

Procedure:
A solution of 6.04 g of 3-(2-amino-2-methylpropoxy)-6-chloropyridazine obtained in Example 1, (a) and 5.95 g of 1-(2-chloro-3-methylphenoxy)-2,3-epoxypropane in 120 ml of methanol was refluxed for 3 hours. The solvent was evaporated under reduced pressure. A solution of the residue in benzene was extracted with 175 ml of 0.2N hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was evaporated and the residue (10 g) was purified by column chromatography (50 g of Florisil; eluted with chloroform) to give 7.98 g of 1-(2-chloro-3-methylphenoxy)-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol as a colorless oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C(OCC)(=O)C>[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][CH:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=C1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CC(Nc1ccc3c(c1)OCCO3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-indanone (2 g, 15.1 mmol) in DCE (50 mL) were added 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (2.28 g, 15.1 mmol), Na(OAc)3BH (4.81 g, 22.6 mmol), AcOH (1.8 mL) successively at 0° C. and the mixture was stirred overnight at rt. The reaction mixture was dissolved in ethyl acetate and was washed with 1N NaOH, water and brine. The solution was dried over Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatography eluting with 9-10% ethyl acetate-hexane to get compound 57.
Reaction SMILES: [Al](Br)(Br)Br.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1)(=[O:7])[CH3:6].CCCCCC.C(OCC)(=O)C.Cl>C1C=CC=CC=1>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Agent: Br[Al](Br)Br
Agent: Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of AlBr3 (12.6 g, 47.4 mmole) in benzene (45 mL) is added dropwise under nitrogen a solution of the methylether (5 g, 18.45 mmole) of Step A in benzene (12 mL) over 30 minutes. The resulting solution is stirred at room temperature for 3.5 hours. (TLC, 8:2 hexane-ethyl acetate). The mixture is cooled in an ice bath and the complex is decomposed by the dropwise addition of 6N-HCl (ca. 37 mL). The organic layer is separated and the aqueous phase is reextracted with ether (3×). The combined extracts are concentrated to a small volume and extracted again with 2.5N-NaOH (2×50 mL+1×10 mL). The basic extracts are cooled and acidified with concentrated HCl (to pH 2). The solid is collected and dried (4.27 g, 90%). It is used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:19][OH:20])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>>[C:1]1([CH2:19][O:20][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: OCc1scc2c1-c1ccccc1Sc1ccccc1-2
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCOCc1scc2c1-c1ccccc1Sc1ccccc1-2

Procedure:
Starting from the alcohol 15 (0.67 mmole) and 2-dimethylaminoethylchloride-hydrochloride (6.7 mmoles), an oily product was obtained;
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.BrC1C=CC=[C:34]2[C:30]=1[C:31]1([C:47]3=[CH:48][C:49]4OCO[C:50]=4[CH:54]=[C:46]3OC1)C(=O)[N:33]2CCCCC.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.CN(C)C1N=CC(B(O)O)=CC=1>>[CH:13]1([CH2:12][CH2:11][N:6]2[C:7]3[C:3](=[C:2]([C:30]4[CH:34]=[N:33][C:48]5[C:47]([CH:31]=4)=[CH:46][CH:54]=[CH:50][CH:49]=5)[CH:10]=[CH:9][CH:8]=3)[C:4]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:5]2=[O:16])[CH2:14][CH2:15]1
Reactant: O=C1N(CCC2CC2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cnc2ccccc2c1
Product: O=C1N(CCC2CC2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(2-cyclopropylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and quinolin-3-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained: MS (ES+) m/z 477.5 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)([O-])[O-].[K+].[K+].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1/[CH:23]=[CH:24]/[S:25]([NH2:28])(=[O:27])=[O:26].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][S:25](/[CH:24]=[CH:23]/[C:19]1[S:18][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)/C=C/c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)/C=C/c1cccs1)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Yield: 29 %

Procedure:
2,4-Dichlorobenzoyl chloride (53 μL, 0.375 mmol) was added to a mixture of potassium carbonate (69 mg, 0.5 mmol) and (E)-2-thiophen-2-yl-ethenesulfonic acid amide (47 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL) at ambient temperature. The mixture was heated at 80° C. for 16 hours then allowed to cool to room temperature whereupon 1N HCl (2 mL) was added in one portion. The mixture was extracted with ethyl acetate (2 mL) and the organics were dried with MgSO4, filtered and concentrated in vacuo. The resultant residue was purified by preparative HPLC to afford (E)-2-thiophen-2-yl-ethenesulfonic acid 2,4-dichloro-benzoylamide (26.3 mg, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(O[N:43]1N=N[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NC1C=CC=CC=1>CN(C=O)C>[NH:43]([C:22]([C:20]1[CH:19]=[CH:18][C:17]2[N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH:14]=[N:15][C:16]=2[CH:21]=1)=[O:24])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)O)ccc21
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Nc1ccccc1
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic acid (50 mg, 148 μmol) in DMF (3 μL) was added N,N-diisopropylethylamine (50 μL, 287 μmol) and TBTU (57 mg, 177 μmol). The solution was stirred at room temperature for 0.5 hour, aniline (20 μL, 220 μmol) was added, and stirring continued at room temperature for 72 hours. The solution was evaporated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.30 min, MH+ 414].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([S:13]([CH3:15])=O)[N:9]=[C:8]([NH2:16])[N:7]=1.SC[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([S:13][CH2:15][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCCc2ccccn2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in dioxane. ES-MS m/e (%): 425 (M+H+, 100).