Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH:11]=[CH:12][CH:13]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Cl:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCCCCl)c1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(3-chlorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:5]=[CH:4][N:3]=1.[H][H]>[Pd].C(O)C>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[C:7]([NH2:8])=[CH:2][N:3]=[CH:4][N:5]=1
Reactant: Cc1ccccc1-c1ncnc(Cl)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1-c1ncncc1N
Yield: 786.4 %

Procedure:
4-Chloro-5-nitro-6-o-tolyl-pyrimidine (580 mg, 0.23 mmol) and 10% palladium on carbon (125 mg, 0.116 mmol) in ethanol were stirred under 1 atmosphere of hydrogen pressure for 16 hours. Filtration followed by removal of volatiles gave the desired compound as a yellow solid (335 mg, 78%) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[NH:8][C:9]([O:11][C:3]=2[CH:2]=1)=[O:10].Cl[S:13]([OH:16])(=[O:15])=[O:14]>C(Cl)Cl>[Cl:7][C:6]1[C:1]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:2][C:3]2[O:11][C:9](=[O:10])[NH:8][C:4]=2[CH:5]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)c(S(=O)(=O)O)cc2o1

Procedure:
To a stirred mixture of chlorzoxazone (10 g, 58.9 mmol) and CH2Cl2 (˜500 cm3) was added chlorosulphonic acid (4.3 cm3, 64.8 mmol) at room temperature. The reaction was left at room temperature for a week whereupon all the solvent had evaporated leaving a white solid. NMR showed a 1:2 mixture of product and starting material respectively. This crude was extracted with H2O (3×15 cm3), then the aqueous was concentrated in vacuo to a sticky solid which was washed with CH2Cl2 (4×40 cm3) to yield 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonic acid as a fine white solid; δH (300 MHz; D6 DMSO) 7.10 (1H, s, Ar—H), 7.68 (1H, s, Ar—H) and 11.80 (1H, s, N—H); LCMS retention time ˜0.47 min, m/z (FIANEG) 247.9 [Cl35 (M−H)−, 100%] and 249.9 [Cl37 (M−H)−, 33%].
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22](OCC)=[O:23].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38](Cl)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:35][CH:36]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)[C:22](=[O:23])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:27])[F:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1cccc(N=C(Cl)c2ccccc2)c1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3cccc(OC)c3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(3-methoxyphenyl)-benzimidoyl chloride (2.2 g, 8.7%).
Reaction SMILES: [CH3:1][C:2]1[N:11](COC(=O)C(C)(C)C)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:21][N:22]([C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)[CH2:23][CH2:24][O:25]C(=O)C)[CH:8]=2)[N:3]=1.[C:38]([C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH2:44])#[N:39]>>[C:38]([C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH:44][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([N:22]([CH2:21][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[NH:11][C:10]3=[O:20])[CH2:23][CH2:24][OH:25])=[CH:37][CH:36]=1)#[N:39]
Reactant: CC(=O)OCCN(Cc1ccc2nc(C)n(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)O)cc1
Reactant: N#Cc1cccc(CN)c1
Product: Cc1nc2ccc(CN(CCO)c3ccc(C(=O)NCc4cccc(C#N)c4)cc3)cc2c(=O)[nH]1

Procedure:
Using the procedure described in Example 10, p-[N-(3,4-dihydro-2-methyl-4-oxo-3-pivaloyloxymethylquinazolin-6-ylmethyl)-N-(2-acetoxyethyl)amino]benzoic acid was reacted with 3-cyanobenzylamine to give N-(3-cyanobenzyl)-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(2-hydroxyethyl)amino]benzamide, m.p. 110°-112° C., as a foam.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:18])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[O:18])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22]
Reactant: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To propane-1-sulfonic acid {2-fluoro-3-[hydroxy-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-methyl]-phenyl}-amide (19, 74 mg, 0.20 mmol) in 1 mL of tetrahydrofuran, Dess-Martin periodane (95 mg, 0.22 mmol) and sodium bicarbonate (200 mg) were added. The reaction was stirred at room temperature for one hour, then poured into saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 70% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-0008, 62 mg, 84%). MS (ESI) [M+H+]+=363.1.
Reaction SMILES: [CH2:1]([O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:6](O)=[O:7])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:40][CH:41]1[C:66](=[O:67])[N:43]2[C:44]([C:50]([O:52][CH:53]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:51])=[C:45]([CH2:48][Cl:49])[CH2:46][S:47][C@H:42]12.C([O-])(O)=O.[Na+]>ClCCl>[Cl:49][CH2:48][C:45]1[CH2:46][S:47][C@@H:42]2[CH:41]([NH:40][C:6](=[O:7])/[C:5](=[N:4]\[O:3][CH2:1][CH3:2])/[C:9]3[N:10]=[C:11]([NH:14][C:15]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[S:12][CH:13]=3)[C:66](=[O:67])[N:43]2[C:44]=1[C:50]([O:52][CH:53]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:51]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVb) (1.095 g, 2.4 mmoles) in dichloromethane (20 mL) was added phosphorus pentachloride (500 mg). After stirring for 1 hour at room temperature, the mixture was added in one portion to an ice-cooled solution of Compound V (1.083 g, 2.4 mmoles) and BSA (1 mL) in dichloromethane (20 mL). After stirring for 0.5 hour the reaction mixture was poured into 10% aqueous NaHCO3 (200 mL) and extracted with CHCl3 (100 mL). The extract was washed with water, dried over MgSO4, and evaporated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with CHCl3 gave VIb as an amorphous powder, 1.76 g (86%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Te:11][C:12]([CH:15]=[CH:16][CH3:17])=[CH:13][CH:14]=2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Te:11][C:12]([CH2:15][CH2:16][CH3:17])=[CH:13][CH:14]=2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: CC=Cc1ccc(-c2ccc(OCC)c(F)c2F)[te]1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(OCC)c(F)c2F)[te]1

Procedure:
1.50 g (4.77 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)-5-propenyltellurophene are hydrogenated in 15 ml of THF, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane:toluene=3:1). The further purification is carried out by recrystallisation from n-heptane. 2-(4-Ethoxy-2,3-difluorophenyl)-5-propyltellurophene is obtained as a colourless solid (m.p. 76° C.).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH:21]=2)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([C@@H:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]2=[O:31])=[CH:21]1
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC[C@@H](CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Reaction time: 12 h

Procedure:
To a solution of (S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (4.2 g, 9.8 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was added LiOH (234 mg, 9.8 mmol) at room temperature. The solution was stirred at the same temperature for 12 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that precipitated out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product (S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid (3.7 g, 92%). LC-MS (M++1): 406.27.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:8]=2)[NH:3]1
Reactant: Oc1ccc2ccccc2n1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=c1ccc2cc(S(=O)(=O)Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.9 %

Procedure:
To an ice bath cooled stirred slurry of 2-hydroxyquinoline (30.5 g, 0.210 mol) in dichloromethane (300 cm3) was added chlorosulphonic acid (70 cm3, 1.05 mol) in 4 equal sized batches. This was left to stir at room temperature for 2 days then slowly poured onto crushed ice. Large amount of a white solid formed in the lower chlorinated layer. This was filtered off and dried in vacua to yield 2-Oxo-1,2-dihydro-quinoline-6-sulfonyl chloride as a dry white solid (36.3 g); δH (300 MHz; D6 DMSO) 6.51–6.59 (1H, m, 1×Ar—H), 7.29–7.34 (1H, m, Ar—H), 7.71–7.79 (1H, m, Ar—H), 7.90–7.96 (1H, m, Ar—H) and 8.00–8.06 (1H, m, Ar—H); LCMS retention time ˜3.43 min, m/z (FIANEG) 241.9 [Cl35(M)−, 100%] and 244.0 [Cl37(M)−, 33%]. NMR and LCMS showed that this material contained some starting material as a minor impurity but no further purification was performed.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[F:30][C:31]([F:37])([F:36])[S:32](Cl)(=[O:34])=[O:33]>>[F:30][C:31]([F:37])([F:36])[S:32]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:34])=[O:33]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(=O)(=O)C(F)(F)F)C3)cnc21

Procedure:
1-(1-Trifluoromethanesulfonyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and trifluoromethane sulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.C([Li])CCC>C1COCC1.CCCCCC>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:14](=[O:16])[CH2:13][CH2:12]2
Reactant: O=C(O)CCc1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCc2cc(C(F)(F)F)ccc21
Yield: 37.2 %

Procedure:
To a solution of 3-[2-bromo-5-(trifluoromethyl)phenyl]propanoic acid (2.8 g, 9.4 mmol) in THF (100 mL) and hexane (20 mL) at −78° C. was dropwise added a 2.5 M solution of n-butyllithium in hexane (8.3 mL). After the addition had been completed, the reaction was quenched with saturated NH4Cl. The resulting solution was extracted with ethyl acetate twice. The extracts were washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. The crude material was purified by flash chromatography on silica eluting with 10-20% EtOAc/hexane to afford the desired product as a white solid (0.7 g, 37%). LC/MS calculated for C10H7F3O: (M+H)+201; found 201.1.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15](I)[CH:14]=[C:13]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:16]=[C:15]([C:28]2[CH:27]=[CH:31][NH:30][N:29]=2)[CH:14]=[C:13]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(Nc1ccncc1)c1c(Cl)cc(I)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccncc1)c1c(Cl)cc(-c2cc[nH]n2)cc1Cl
Temperature: 160 °C
Yield: 16.6 %

Procedure:
To the solution of 2,6-dichloro-4-iodo-N-(pyridin-4-yl)benzamide (0.17 g, 0.43 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.125 g, 0.65 mmol), Cs2CO3 (0.28 g, 0.86 mmol) in CH3CN/H2O (1 mL/1 mL) was added PdCl2(dppf) (31 mg, 0.043 mmol) under N2 atmosphere. The mixture was heated at 160° C. under the irradiation of microwave for 30 minutes. After the completion of the reaction, the mixture was filtered through Celite and purified by preparative basic HPLC (Gemini, 200 mm×25 mm, gradient: CH3CN/0.05% NH3.H2O, 50-80, 10 min) to afford the desired product (23.8 mg, 17% yield). 1HNMR (DMSO-d6, 400 MHz): 611.19 (s, 1H), 8.49 (s, 2H), 8.29 (s, 2H), 7.88 (s, 2H), 7.65 (s, 2H), 7.07 (s, 1H). LCMS (ESI) m/z: 333.1 [M+H+]
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@H:18]([O:19]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[N:6]([C@H:7]2[O:24][CH2:23][C@H:18]([OH:19])[C@@H:13]([OH:14])[C@@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O[C@H]1[C@H](O)[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
An ethanolic solution of 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-alpha-L-xylopyranosyl)-1H-benzimidazole (0.81 g, 1.54 mmol) was deprotected in a modification of General Procedure VI with 0.64 g (6.03 mmol) of sodium carbonate in 5 ml of water. After stirring overnight at ambient temperature, the mixture was treated as described in General Procedure VI to give crude product which was recrystallized from 1-chlorobutane, ethyl acetate and hexane to give 0.21 g (0.53 mmol, 34% yield) of 2-bromo-5,6-dichloro-1-beta-L-xylopyranosyl-1H-benzimidazole, mp 164-165° C. 1H NMR (CD3OD) δ8.04 (s,1H), 7.83 (s, 1H), 5.53-5.50 (d, 1H), 4.14-4.09 (dd, 1H), 3.93 (bm, 1H), 3.83-3.75 (m, 1H), 3.55-3.46 (m, 2H).
Reaction SMILES: CSC.B.[Si]([O:12][CH2:13][CH2:14][S:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])(C(C)(C)C)(C)C.Cl>C1COCC1>[OH:20][CH2:19][C:18]1[CH:17]=[C:16]([S:15][CH2:14][CH2:13][OH:12])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCCSc1cccc(C(=O)O)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: OCCSc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Borane dimethyl sulfide complex (2M in THF, 17.3 mL) was added dropwise to an ice cold solution of 3-(2-(tert-butyldimethylsilyloxy)ethylthio)benzoic acid (example 65, step a) (2.16 g) in THF (50 mL). The reaction was allowed to warm to RT, then heated at reflux for 2 h. The reaction was cooled in an ice bath and aqueous HCl solution (2M, 50 mL) was added dropwise. The resulting mixture was stirred overnight. The reaction was concentrated to half its original volume and the resulting aqueous extracted with DCM (3×100 mL). The combined organics were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 isohexane:ethyl acetate to 100% ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 0.77 g.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.[C:17](=O)([O-])[O-].[K+].[K+].CC(C)=O.COS(OC)(=O)=O>ClCCl.O>[OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:17])[CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc2cccc(O)c2cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1cc2cccc(OC)c2cc1O
Temperature: 25 °C
Yield: 68.9 %

Procedure:
Methyl 3,5-dihydroxy-2-naphthoate (3.27 g; 15 mmole) was mixed with potassium carbonate (3 g; 22 mmole), acetone (50 μL) was added and then dimethylsulfate (Merck) (1.56 mL; 16.5 mmole) was slowly added drop by drop. The reaction mixture was refluxed for 2 hours, cooled to room temperature and water (100 mL) was added thereto, whereat all potassium carbonate was dissolved. Dichloromethane (100 mL) was added to the solution and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to dryness. The solid residue was recrystallized from methanol and 2.4 g (70%) of methyl 3-hydroxy-5-methoxy-2-naphthoate were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[S:61][C:60]([CH3:62])=[N:59][C:58]=2[C:63](O)=[O:64])=[CH:53][CH:52]=1>CN(C=O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:63]([C:58]1[N:59]=[C:60]([CH3:62])[S:61][C:57]=1[C:54]1[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=1)=[O:64]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: c1ccc2sc(CC3CCCCN3)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3ccccc3s2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Piperidin-2-ylmethylbenzothiazole, D30 (0.135 g), HATU (0.228 g), diisopropylethylamine (0.300 ml) and 5-(4-fluorophenyl)-2-methylthiazol-4-carboxylic acid (0.144 g) were dissolved in dry DMF and shaken at room temperature for 16 hours. The solvent was then evaporated and the residue partitioned between dichloromethane and brine. The organic layer was dried (MgSO4), evaporated and the residue chromatographed over silica gel. Elution with diethyl ether provided the title compound as a foam (220 mg).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1>CS(C)=O>[NH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH2:30][CH2:29][CH2:28][NH:27][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:32]1
Reactant: NCCCc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCCCc2c[nH]c4ccccc24)CO3)N1
Temperature: 75 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino-[2,3-e]indol-8-one (1.5 g, 4.2 mmole) in DMSO (80 ml) was slowly added through a dropping funnel to 3-(3-aminopropyl)indole (1.1 g, 6.3 mmole) in DMSO (50 ml) and the mixture was heated at 75° C. for 17 hours. Most of DMSO was removed under reduced pressure and the residue was then partitioned between water and dichloromethane/isopropanol (3/1) solution. The separated organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and column chromatographed on silica gel using first ethyl acetate/hexane (7/3), then ethyl acetate and finally 5% methanol in ethyl acetate as eluants. The expected product was isolated, treated with 0.25M ethanolic fumaric acid and precipitated with a minimum amount of hexane to give 70 mg of the (S) enantiomer of the title compound as a tan solid fumarate salt, Mass spec (m/e), 377 (M+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[Br:11].[BH4-].[Na+].[Li+].[Cl-].Cl>C1COCC1.CCO>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cc(F)ccc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 2-bromo-5-fluoro-benzoic acid methyl ester (1 g, 4.292 mmol), NaBH4 (0.423 g, 11.159 mmol) and LiCl (0.474 g, 11.159 mmol) in THF/EtOH (20 ml/10 ml) was stirred at room temperature overnight. Aqueous HCl (10 ml, 2N) was added and stirred for about 10 min. Then the organic solvent was removed under low vacuum. The residue was diluted with water and extracted by ethyl acetate. The organic layer was washed with aqueous NaHCO3 (10%), water and brine, and then dried (MgSO4) and concentrated to afford 852 mg (96.8% crude yield) crude product, (2-bromo-5-fluoro-phenyl)methanol, as a white solid, which was used without further purification.