Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[N+:12]([C:10]1[CH:9]=[CH:8][C:6]2[NH:7][CH2:2][CH2:3][S:4][C:5]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1SCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)SCCN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a stirred solution of 2-(2-chloroethylthio)-4-nitroaniline (5.13 g, 22.05 mmol) in DMF (70 mL) was added potassium carbonate (9.14 g, 66.1 mmol), followed by sodium iodide (0.330 g, 2.205 mmol). The resulting suspension was stirred at room temperature overnight. The mixture was then diluted with water, and the resulting crystals were collected by vacuum filtration, giving the desired product (4.06 g, 94%). 1H NMR (DMSO-d6) δ 7.81-7.73 (m, 3H), 6.58 (t, J=9.0 Hz, 1H), 3.65-3.60 (m, 2H), 3.01-2.97 (m, 2H); ESI-MS (m/z, %): 197 (MH+, 100), 180 (99).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([I:16])[CH:15]=[C:10]3[N:9]=[C:8]2[NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:4][C:3]=1[O:25][CH3:26].[OH-].[Na+].Cl[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[N:35][CH:36]=1>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[I:16][C:14]1[CH:15]=[C:10]2[N:9]=[C:8]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([O:1][CH2:30][C:31]4[CH:36]=[N:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)=[C:3]([O:25][CH3:26])[CH:4]=3)[C:11]2=[N:12][CH:13]=1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Reactant: COc1ccc(CCl)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirred solution of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate ( ) (1.30 g, 2.78 mmol) and 5M aqueous sodium hydroxide solution (0.8 mL, 4.00 mmol) in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL) was added 5-(chloromethyl)-2-methoxypyridine (0.567 g, 3.60 mmol). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was diluted with brine (40 mL) and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to provide 1.10 g (71%) of ethyl (6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[N:27]1.N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:31]([C:29]2[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=2)(=[O:33])=[O:32])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:5][N:4]=1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(=O)(=O)c1cnn(C)c1
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 111 mg (0.61 mmol) 1-methyl-1H-pyrazole-4-sulfonyl chloride and 72 μL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 101 mg (70%). HPLC-MS: M+H=470; tR=0.72 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[O:11][CH3:12])[CH3:2].[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>>[CH2:1]([C:3]1[CH:8]=[C:7]([C:13](=[O:16])[CH2:14][CH3:15])[CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[O:11][CH3:12])[CH3:2]
Reactant: CCc1cccc(CC)c1OC
Reactant: CCC(=O)Cl
Product: CCC(=O)c1cc(CC)c(OC)c(CC)c1

Procedure:
2,6-Diethylanisole and propionyl chloride were treated in the same way as in step (a) of Example 30 to give 2,6-diethyl-4-propionylanisole.
Reaction SMILES: FC1C=C(C=CC=1)CSC1OC(C2C=CN=C(N)C=2)=NN=1.C(N(CC)CC)C.C(Cl)(=O)C=C.[C:34]([N:38]([C:43]1[CH:48]=[C:47]([C:49]2[O:50][C:51]([S:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[CH:57]=3)=[N:52][N:53]=2)[CH:46]=[CH:45][N:44]=1)C(=O)C=C)(=[O:37])[CH:35]=[CH2:36]>O1CCCC1.C(OCC)(=O)C>[F:62][C:58]1[CH:57]=[C:56]([CH:61]=[CH:60][CH:59]=1)[CH2:55][S:54][C:51]1[O:50][C:49]([C:47]2[CH:46]=[CH:45][N:44]=[C:43]([NH:38][C:34](=[O:37])[CH:35]=[CH2:36])[CH:48]=2)=[N:53][N:52]=1
Reactant: C=CC(=O)N(C(=O)C=C)c1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Agent: C=CC(=O)Cl
Agent: Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 4-[5-[(3-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]pyridin-2-amine (1.35 g, 4.75 mmol) and triethylamine (1.98 mL, 14.25 mmol) in tetrahydrofuran (100 mL) was added acryloyl chloride (0.97 mL, 11.88 mmol) at 0° C., and the resulting mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) to give a mixture (1/1, 1.08 g, yield 61%) of N-[4-[5-[(3-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]-2-pyridyl]acrylamide and N-acryloyl-N-[4-[5-[(3-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]-2-pyridyl]acrylamide as pale-yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:14][C:11]1([F:13])[CH2:12][NH:8][CH:9]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OCC2CC(F)(F)CN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CC(F)(F)CN2)cc1
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of methyl 4-[1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (830 mg, 2.23 mmol) and TFA (5 ml) in CH2Cl2 (5 ml) was stirred for 3 h and concntrated in vacuo. The residue was made basic with sat. NaHCO3 and extracted with CHCl3 (2×200 ml). The combined extracts were dried over K2CO3 and concntrated in vacuo to give methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate (550 mg, 91%) as a pale yellow solid. 1H-NMR (CDCl3) δ 2.19 (m, 1 H), 2.43 (m, 1 H), 3.19–3.41 (m, 2 H), 3.77 (m, 1 H), 3.89 (s, 3 H), 4.00–4.09 (m, 2 H), 6.92 (d, J=9.0 Hz, 2 H), 7.99 (d, J=9.0 Hz, 2 H); MS (FAB) m/z 272 (M++1); Anal. Calcd for C13H15F2NO3: C, 57.56; H, 5.57; N, 5.16. Found: C, 57.65; H, 5.67; N, 5.16.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([O:21][C:22]([NH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][C:30](=[O:34])[NH:31]2)=[CH:27][CH:26]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:23])[NH:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29](=[CH:7][C:6]3[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=3)[C:30](=[O:34])[NH:31]2)=[CH:27][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(NC(=O)OC(C)(C)C)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-tert-butyloxycarbonylamino-2-oxindole to give 0.35 g of [3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-carbamic acid tert-butyl ester as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=3[C:10](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:9]2)[CH:7]=1
Reactant: Cc1cc(C)c2c(n1)CC(c1cc(F)ccc1C)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(n1)CC(c1cc(F)ccc1C)CC2=NNC(=N)N
Yield: 85.7 %

Procedure:
A solution of 7-(5-fluoro-2-methylphenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.52 g) in ethanol (30 ml) was combined with concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was heated under reflux for 12 hours. The mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound L) (1.25 g) as a colorless crystal.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].C1COCC1.C(Cl)(=O)C([Cl:26])=O>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:26])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1

Procedure:
3,5-Diacetoxybenzoic acid (15 g, 63 mM) was suspended in dichloromethane (100 mls), THF(20 mls) with oxalyl chloride (7.34 mls, 69.3 mM) and DMF(2–3 drops) added. The resultant mixture was stirred for three hours at ambient temperature in a flask fitted with a gas bubbler. This gave a pale brown solution. After concentration ‘in vacuo’ the residue was triturated with diethyl ether. This gave a colourless solid, 3,5-diacetoxybenzoyl chloride (15.95 g) which was used for the next stage without further purification.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].I[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.Cl>O1CCCC1>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([C:7]2[C:8]([CH:9]=[O:10])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccccc1Br
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=Cc1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 136.3 %

Procedure:
To magnesium turnings (1.23 g, 50.7 mmol) in a dry flask under nitrogen was added anhydrous tetrahydrofuran (THF, 10 mL). The mixture was mechanically stirred while a solution of 1,2-dibromoethane (1.22 g, 6.5 mmol) in THF (10 mL) was added dropwise. Upon completion, a solution of the dimethyl acetal of 2-bromobenzaldehyde (3.00 g, 13.0 mmol) and 1,2-dibromoethane (2.44 g, 13.0 mmol) in THF (10 ml) was added at a rate to maintain gentle reflux. Upon completing, a second solution of 1,2-dibromoethane (1.22 g, 6.5 mmol) in THF (10 mL) was added dropwise. The mixture was then refluxed an additional 20 minutes and decanted into an addition funnel attached to a second reaction flask containing a solution of 4-iodobenzotrifluoride (2.72 g, 10.0 mmol) and iodo(4-trifluoromethyl)bis(triphenylphosphine)palladium (II) (0.21 g, 0.9 mmol) in refluxing THF (20 mL). The Grignard reagent was added dropwise and the mixture refluxed for 11/2 hr. After cooling to room temperature, 3N hydrochloric acid was added (30 mL) and the THF evaporated on the rotary evaporator. The residue was extracted with diethyl ether. The ether extract was washed with 3N hydrochloric acid (20 mL) water (4×25 mL), and saturated sodium chloride solution (10 mL). The ether solution was then dried (MgSO4), treated with charcoal, filtered and evaporated to give a dark yellow oil (3.41 g). This was chromatographed on the Waters Prep 500 HPLC using a 1:1 mixture of methylene chloride and hexane. The product was isolated after evaporation of solvent as a light yellow oil (2.41 g, 96.4%). 'H NMR (CDCl3): 7.6 (m, 7, Ar--H), 8.0 (m, 1, 3-H), 9.9 (s, 1, CHO).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[NH3:11].[BH4-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH2:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(=O)c1ccc(C)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: Cc1ccc(C(C)N)cn1
Yield: 81 %

Procedure:
Stir a mixture of 1-(6-methylpyridin-3-yl)-ethanone (10 g, 74 mmol) in titanium tetra(isopropoxide) (42.1 g, 148 mmol) and ammonia (370 mmol, 2 M in methanol) under N2 for 6 h at RT. To this mixture add sodium tetrahydroborate (4.2 g, 111 mmol) and stir overnight. Quench the reaction mixture with ammonium hydroxide and filter the mixture. From the filtrate, remove the solvent and extract the residue with DCM, wash with saturated aqueous sodium chloride and dry over Na2SO4, filter, and remove the solvent to obtain the title compound as a dark yellow oil (8.16 g). MS (ES) m/z 137 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:15]([Br:25])[CH:14]=3)=O)=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:40]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C1COCC1.O.[OH-].[Na+]>[Br:25][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH2:19][N:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1)[CH2:11][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][C:7]=2[S:8][C:9]=1[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[CH:30][CH:31]=1
Reactant: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [H-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(Cc3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To 4-[3-bromo-4-[(1-pyrrolidinyl)methyl]phenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Example 137; part C) (0.2 g; 0.32 mmol) in 3.0 mL of THF was added 18.4 mg (0.48 mmol) of LAH at 0° C. The bath was removed and the mixture was stirred for 1 h. Hydrolysis was effected by addition of 1 drop of water, 1 drop of 5N NaOH, and 3 drops of water, followed by stirring for 1 h. The mixture was filtered, the filtrate was concentrated and, the intermediate carbinol was dried in vacuo for 25 min. The carbinol was dissolved in methylene chloride (3.0 mL) under argon atmosphere and cooled in an ice-water bath. Triethylsilane (0.36 mL; 2.26 mmol) was added, followed by dropwise addition of 0.25 mL (3.23 mmol) of TFA. Upon completion of addition of TFA, the bath was removed and stirring was continued for 2 h. Saturated aqueous sodium bicarbonate (25 mL) was added, and extraction was carried out with EtOAc. The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound (0.14 g; 72% yield) was isolated as a colorless oil by flash chromatography on silica gel eluting with a gradient of EtOAc(100-95%)/Et3N(0-5%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(-c2ccc(OCc3ccccc3)cc2)c1

Procedure:
9.0 g (32 mmol) of sodium metaborate octahydrate and 1.3 g (1.82 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 200 ml of water and 40 ml of THF, a solution of 55 g (171 mmol) of 1,3,5-tribromobenzene in 80 ml of THF is added, and a solution of 10 g (45.5 mmol) of 4-benzyloxybenzeneboronic acid is added dropwise under reflux. The batch is heated under reflux for 16 h, added to water and extracted three times with MTB ether. The combined org. phases are washed with sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is chromatographed on silica gel with heptane/ethyl acetate (19:1) and recrystallised from ethanol, giving 4′-benzyloxy-3,5-dibromobiphenyl as colourless crystals.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:13][CH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])[O:17]1.C([O-])(O)=O.[Na+]>C1COCC1.CO.C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[NH:13][CH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])[O:17]1)[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(F)cc1CCC1CCC(CCN)O1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)NCCC1CCC(CCc2cc(F)ccc2OC)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a flame dried 20 mL vial was placed K2CO3 (239 mg, 1.73 mmol, 6.0 eq) and anhydrous THF (5.0 mL). The vial was purged with Ar(g) and then cooled in an ice bath. Ethyl chloroformate (156 mg, 1.44 mmol, 5.0 eq) was then added via syringe followed by slow addition of 14 (77 mg, 0.29 mmol, 1.0 eq) dissolved in THF (1.5 mL). The reaction was stirred at 0° C. for 0.5 hrs and then warmed to rt and allowed to stir an additional 3 hrs. The reaction was then stopped with sat. NaHCO3(aq) and extracted with EtOAc (3×20 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated under reduced pressure to yield crude product that was used in the next step of the synthesis. TLC: MeOH/CH2Cl2 (2:98, v:v), Rf 0.4; 1H NMR (CDCl3, 500 MHz) 6.87-6.82 (m, 2 H), 6.74-6.71 (m, 1 H), 4.12 (q, J=7.1 Hz, 2 H), 4.05-3.77 (m, 2 H), 3.78 (s, 3 H), 2.71-2.56 (m, 2 H), 2.08-1.51 (m, 10 H) 1.3 (t, J=7.2 Hz, 3 H). LRMS (ESI) [M+H]+ calcd for C18H27FNO4 340 found 340.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[NH:14][CH:13]=[N:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26].O>CN(C=O)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:14]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:13]=[N:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc(S(=O)(=O)c2[nH]cnc2-c2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)ncn2COCC[Si](C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[5-(Toluene-4-sulfonyl)-1H-imidazol-4-yl]-pyridine (Tetrahedron Lett. 1976, 285) (1.65 g, 5.51 mmol) in dry DMF (15 mL) was added NaH (60% in mineral oil, 0.36 g, 9.0 mmol) at room temperature under N2. After 30 minutes stirring, SEM-Cl (1.21 mL, 6.83 mmol) was added through a syringe. The slurry was further stirred at room temperature for 6 hours, and then poured into cold H2O (100 mL), extracted with dichloromethane (3×50 mL). Combined dichloromethane solution was washed with H2O (2×50 mL) and brine (50 mL). Flash silica gel chromatography (hexane to 2:1 hexane/ethyl acetate) afforded the 2-[5-(Toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine as a syrup intermediate in the forms of 1:1 regioisomers (1.89 g, 80%). 1H NMR δ−0.09 (s, 9H), 0.75 (t, 2H, J=7), 2.38 (s, 3H), 3.30 (t, 2H, J=7), 5.40 (s, 2H), 7.22 (d, 2H, J=8), 7.4 (t, 1H, J=6), 7.65-7.95 (m, 5 H), 8.70 (d, 1H, J=4) ppm; the other regio-isomer shows chemical shift at δ−0.02 (s, 9H), 0.8 (t, 2H, J=7), 2.41 (s, 3H), 3.41(t, 2H, J=7), 5.65 (s, 2H), 7.2-7.35 (m, 2H), 7.70-7.90 (m, 5H), 8.1 (d, 1H, J=8), 8.68 (d, 1H, J=4)ppm; (ESMS calcd for (C21H27N3O3SSi): 429.2; found: 430.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([B:16]([OH:21])[OH:17])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2ccsc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OB(O)c1cc2cccc(Cl)c2s1
Temperature: -30 °C
Yield: 96.2 %

Procedure:
To a solution of 7-chlorobenzo[b]thiophene (1.0 g, 5.92 mmol) in THF (25 mL) at −78° C. was added “butyllithium (7.41 mL, 11.8 mmol, 1.6 M solution). The reaction was allowed to warm to −30° C. then was cooled back to −78° C. and triisopropyl borate (2.23 g, 11.8 mmol) was added. The mixture was allowed to warm to 0° C., saturated ammonium chloride added and the organic phase separated off and concentrated in vacuo. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) and the mixture was washed with DCM. The aqueous phase was acidified with 2N sulfuric acid, and the resulting precipitate isolated by filtration and dried under vacuum to yield 7-chlorobenzo[b]thiophene-2-boronic acid (1.21 g, 96%) as white solid. 1H NMR (400 MHz, CDCl3) δ=7.41 (t, J=7.70 Hz, 1H), 7.50 (d, J=7.70 Hz, 1H), 7.91 (d, J=7.70 Hz, 1H), 8.03 (s, 1H), 8.63 (s, 2H); MS (ES+): m/z 211.86 [M+].
Reaction SMILES: [CH2:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=1)[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14].P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[S:13]([Cl:12])(=[O:15])=[O:14])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCc1cc2cccnc2s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1sc2ncccc2c1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.3 %

Procedure:
To a solution of 2-ethylthieno[2,3-b]pyridine (0.43 g, 2.6 mmoles) in CH2Cl2 (10 ml) at −78° C. was added chlorosulfonic acid (0.9 ml, 13 mmoles). The reaction was warmed to ambient temperature over a 1 hr. period, then stirred an additional 20 hrs., followed by the addition of phosphorus oxychloride (1.7 ml, 18 mmoles) and phosphorus pentachloride (0.82 g, 4.0 mmoles). One hour later the reaction mixture was added to ice (100 ml) and extracted with EtOAc (75 ml), then washed with sat. NaHCO3 (200 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect a brown oil. Flash chromatography (10% EtOAc/hexanes) provided 0.39 g (56%) of the title compound as a light yellow oil.