Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C@@H:26]5[CH2:30][CH2:31][CH2:32][N:25]5[CH3:24])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (200 mg, 0.65 mmol) in N,N-dimethylformamide (4.0 mL) were added 1-methyl-L-proline (167 mg, 1.29 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (736 mg, 1.94 mmol), hydroxybenzotriazole (262 mg, 1.94 mmol) and N,N-diisopropylethylamine (338 μL, 1.94 mmol), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol=8/1), and the obtained residue was recrystallized from ethyl acetate to give the title compound (86 mg, 32%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl.[CH:19]([N:32]1[CH2:35][CH:34]([CH2:36]Cl)[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH:19]([N:32]1[CH2:35][CH:34]([CH2:36][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][CH:13]=2)[CH2:33]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CC1(c2ccc(OCC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)CCOCC1
Yield: 75.4 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.15 g, 5.65 mmol), 1-benzhydryl-3-chloromethyl-azetidine hydrochloride (1.58 g, 5.13 mmol), N,N-dimethylformamide (32 ml) and potassium carbonate (2.84 g, 20.52 mmol) were reacted together according to general procedure B. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 2M sodium hydroxide (3×50 ml), brine (3×50 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to provide 1-[4-(4-{[1-benzhydrylazetidin-3-yl]methoxy}phenyl)tetrahydro-2H-pyran-4-yl]-N,N-dimethylmethanamine (1.82 g, 81%) as an off-white solid.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[CH3:33][CH:34]([NH2:47])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1>C(Cl)Cl.O>[CH3:33][CH:34]([NH:47][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:16])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][CH:38]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CC(N)COc1ccc(C(F)(F)F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(COc1ccc(C(F)(F)F)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
1.6 g of N-methylpiperidine was added to a solution containing 4.0 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 15 minutes at the same temperature, 2.2 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 3.5 g of 1-methyl-2-(4-trifluoromethylphenoxy)ethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 2.8 g of the desired product in the form of a white crystal (yield: 40%).
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[C:12]2[C:17]([C:18](Br)=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2>CC(N(C)C)=O>[S:9]([C:11]1[C:12]2[C:17]([C:18]([S:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: c1ccc(Sc2c3ccccc3c(Sc3ccccc3)c3ccccc23)cc1
Temperature: 170 °C

Procedure:
Potassium hydroxide (19.6 g) and thiophenol (35.5 ml) were heated at 170 degrees C. in dimethylacetamide for two hours. 9,10-dibromoanthracene (37.5 g) was added and the mixture heated at 170 degrees C. an additional two hours. (The corresponding dichloro compound has also been used successfully.) The mixture was quenched with water and the precipitate recrystallized from chloroform/ethanol to give DTPA.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCC(C(=O)c2ccccc2F)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCC(Cc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
In an 18 mL vial with stir bar and 4-(2-fluorobenzoyl)cyclohexanecarboxylic acid methyl ester (333 mg; 1.2 mmol), trifluoroacetic acid (4 mL) was chilled to 0° C. and triethylsilane (700 mg; 6.0 mmol) was added over 1 minute. Mixture was allowed to warm to room temperature. After 48 hours, mixture was concentrated in vacuo and reduced by half volume. Mixture was poured into cold KOH solution and pH adjust further to pH 6. Aqueous mixture was extracted 3×5 mL ethyl acetate. Combined ethyl acetate was washed with brine and dried over MgSO4. Crude oil was purified via (20:1) flash chromatography 0-10% ethyl acetate in hexanes to give 250 mg of title compound. (83% yield).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C@H:21]([C@@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[CH2:20][C:19]1=[O:29].[CH:36](=[O:38])[CH3:37]>CCCCCC.O1CCCC1>[CH3:13][O:14][C:15]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C@H:21]([C@@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[C@@H:20]([C@H:36]([OH:38])[CH3:37])[C:19]1=[O:29]
Reactant: CC=O
Reactant: COc1ccc(CN2C(=O)C[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(CN2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Reaction time: 0.75 h

Procedure:
0.65 ml of a 1.7M solution of butyl lithium in hexane is added to a solution, cooled to -65°, of 111 mg (1.1 mmol) of diisopropylamine in 4 ml of tetrahydrofuran. The mixture is cooled to -78° and treated after 15 minutes with a solution of 321 mg (1 mmol) of (S)-1-(2,4-dimethoxy-benzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone in 1 ml of tetrahydrofuran. The mixture is stirred at -78° for 45 minutes and then a solution of 100 mg (2,27 mmol) of acetaldehyde in 0.5 ml of tetrahydrofuran is added dropwise within 3 minutes thereto, whereby the temperature rises to -70°. The mixture is stirred for 10 minutes, the cooling bath is removed, the reaction solution is treated with 2 ml of 14 percent aqueous ammonium chloride solution and extracted with 30 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on 10 g of silica gel with ethyl acetate/hexane (2:1) as the eluent. There is obtained (3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-[(R)-1-hydroxyethyl]-2-azetidinone which is obtained as fine needles of melting point 145°-146° after crystallization from ethyl acetate/hexane.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=1)C.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:13]([S:12][C:7]1[N:6]=[C:5]([CH:4]=[O:3])[CH:10]=[C:9]([CH3:11])[N:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCSc1nc(C)cc(C(OCC)OCC)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCSc1nc(C)cc(C=O)n1
Yield: 73.8 %

Procedure:
4-Diethoxymethyl-2-hexylsulfanyl-6-methyl-pyrimidine(19 g, 60.8 mmol) was dissolved in THF (100 mL) and 4 N aqueous H2SO4 (100 mL) and heated at 50° C. for 33 h. Poured in cold 10% Na2CO3 solution (400 mL) and extracted with ethyl acetate and a sat. solution of NaCl. The crude oil was purified by silica gel chromatography with a heptane/DCM gradient of 100:0 to 67:33. One obtained 10.7 g (74%) of a yellow oil.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9].C(N(CC)C(C)C)(C)C.[CH2:36]([O:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([O:43][C:44]([S:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]([OH:10])=[O:9])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(CCS)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)SCCN(CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 69 %

Procedure:
(2S)-2-[3-(2-Mercaptoethyl)-3-phenethylureido]-3-phenylpropionic acid (Compound No. 11-1, 108 mg) is dissolved in anhydrous methylene chloride (1.5 ml) under a nitrogen atmosphere, and the solution is stirred. To the solution are added N,N-diisopropylethylamine (0.07 ml) and benzyloxycarbonyl chloride (0.05 ml) successively under ice cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the whole is extracted with ethyl acetate. The organic layer is washed with a 10% aqueous citric acid solution, water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 102 mg (69%) of the titled compound (Compound No. 12-1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=2[N:7]=[C:6]1[C:17]1[C:22](F)=[CH:21][CH:20]=[CH:19][C:18]=1[F:24].FC1C=CC=C(F)C=1CBr.[H-].[Na+].[CH2:42]([O:44]C(=O)C)C.CCCCCC>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=2[N:7]=[C:6]1[C:17]1[C:22]([O:44][CH3:42])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: Fc1cccc(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(F)c1-c1nc2c([N+](=O)[O-])cccc2n1Cc1c(F)cccc1F
Reaction time: 8 h

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (2.00 g, 8 mmol)was added 2,6-difluorobenzylbromide (2.0.2 g, 9.76 mmol, 130 M %) dissolved in THF (20 mL) was added NaH (0.84 g, 21 mmol, 290 M %). After 8 h, the reaction was quenched with m ethanol and concentrated. The residue was dissolved in CH2Cl2, and washed with water and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, concentrated. The crude product was purified by flash chromatography eluting with ethylacetate:hexane (1:1) (2.33 g, 5.64 mmol, 78%). M.p. 189-192° C. 1H-NMR (200 MHz, CD2Cl2) δ 8.11 (dd, J=8.1, 1.0 Hz, 1H, H5), 7.84 (dd, J=8.1, 1.0 Hz, 1H, H7), 7.52 (m, 1H, H4′), 7.40 (dd, J=8.1 Hz, 1H, H6), 7.26 (m, 1H, H4″), 6.89-6.74 (m, 4H, H3′,5′,3″,5″), 5.36 (d, J=3.4 Hz, 2H, CH2PhF2 (rotamers)), 3.73 (s, 3H, OCH3).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O>O>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NC(=O)CC(N)C(=O)O
Solvent: O
Product: NC(=O)C[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
H2O: A slurry of D,L-Asn.H2O (500 mg) and poly-(Nε -methacryloyl-L-lysine) in water (5 ml) was heated to about 80° C. until complete dissolution occurred. The warm solution was filtered and cooled to room temperature without agitation. After 20 h the separated crystals were recovered by filtration and the enantiomeric excess was determined. The conditions and results are summarized in Table III.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][N:11]([CH3:17])[C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([N:14]2[CH2:15][CH2:16][C@@H:12]([N:11]([CH3:17])[CH3:10])[CH2:13]2)=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: CN(C)[C@@H]1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cnc1N1CC[C@@H](N(C)C)C1
Yield: 92.3 %

Procedure:
Combine 2,5-dibromo-3-methyl-pyridine (2.00 g, 7.97 mmol) with dimethyl-(R)-pyrrolidin-3-yl-amine (2.40 g, 20.72 mmol) and p-toluenesulfonic acid monohydrate (0.39 g, 2.07 mmol) in a sealed tube and heat at 100° C. overnight. Dilute with EtOAc (100 mL), wash with saturated NaHCO3 (3×40 mL), dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography, eluting with 2% NH3H2O in 1:1 CH3OH:EtOAc to give 2.09 g (99%) of the title compound. LC-MS/ES m/z (79Br) 284.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][CH:51]([OH:54])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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]>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:47]=[CH:46][C:45]([N:48]5[CH2:53][CH2:52][CH:51]([OH:54])[CH2:50][CH2:49]5)=[CH:44][CH:43]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2ccc(N3CCC(O)CC3)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCC(O)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.28 mmol) was coupled with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol (130 mg, 0.428 mmol) using sodium carbonate (89 mg, 0.84 mmol) and Pd(dppf)Cl2 (10 mg, 0.14 mmol) in DME/water (10/1 mL). This afforded 130 mg (crude). MS: m/z=622.5 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[C:8]([C:13]3([OH:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[N:9]2[CH3:12])=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:4]=1.[CH:26](I)([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[C:8]([C:13]3([OH:19])[CH2:18][CH2:17][CH2:16][N:15]([CH:26]([CH3:28])[CH3:27])[CH2:14]3)[N:9]2[CH3:12])=[C:5]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:4]=1
Reactant: CC(C)I
Reactant: Cn1c(C2(O)CCCNC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCCC(O)(c2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C1
Temperature: 50 °C

Procedure:
The HCl salt of 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)piperidin-3-ol (70 mg) was reacted with isopropyl iodide (1.5 eq), cesium carbonate (2 eq) and DIPEA (3 eq) in DMF (1 mL). The reaction was heated at 50° C. for several hours until complete. The reaction mixture was diluted with Ethyl acetate and extracted with a saturated ammonium chloride solution. The organic layer was dried, filtered and concentrated to give 70 mg of crude 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-1-isopropylpiperidin-3-ol which was reacted with 2-ethyl benzimidazole via General Procedure I for Buchwald coupling to give 515 [7.6 mg; MS (Q1) 505.3 (M)+] and 518 [7.7 mg; MS (Q1) 505.2 (M)+] following reverse phase purification and subsequent chiral separation.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O>[C:1]([N:9]1[CH2:12][C:11](=[O:13])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CC(O)C1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccccc2)C1

Procedure:
To a stirred mixture of 2.5 g. of N-benzoyl-3-azetidinol, 21 g. of triethylamine in 35 ml. of DMSO, add rapidly, in a dropwise manner, a suspension of 7.0 g. of pyridine sulfur trioxide in 35 ml. of DMSO and stir for 15 minutes. Remove most of the DMSO in vacuo at 60° C and chromatograph the residue on 100 g. of silica gel. Elute with chlorform and collect 2.4 g. of the crude compound of this example from the front running yellow band. Recrystallize from isopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:18])[CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:17][CH2:16][CH2:15][CH:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)[CH3:18])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CCO)N1CCN(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CCOS(C)(=O)=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(4-(4-fluorophenyl) piperazin-1-yl) butan-1-ol (prepared according to procedure reported in U.S. Pat. No. 5,021,420, 3.5 g, 13.87 mmol) in dichloromethane (30 ml) was added triethylamine (4.2 g, 41.61 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0-5° C. Methane sulfonyl chloride (1.58 g, 13.87 mmol) was added at 0-5° C. dropwise in 20 mins. The reaction mixture was stirred at same temp for 1 h. Progress of reaction was monitored by TLC. The reaction mixture was diluted with dichloromethane (20 ml) and washed with water (3×20 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain title compound (4.2 g) which was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9](O)=[O:10].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9]([Cl:15])=[O:10]
Reactant: Cc1cc(/C=C/C(=O)O)c(C)s1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc(/C=C/C(=O)Cl)c(C)s1

Procedure:
To a solution of (E)-3-(2,5-dimethylthiophene-3-yl)acrylic acid (328 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10]C)=[O:9])[C:5]2[CH:12]=[C:13]([Cl:17])[C:14]([Br:16])=[CH:15][C:4]=2[S:3]1.CO.[OH-].[Na+]>O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5]2[CH:12]=[C:13]([Cl:17])[C:14]([Br:16])=[CH:15][C:4]=2[S:3]1
Reactant: COC(=O)Cn1c(=O)sc2cc(Br)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1c(=O)sc2cc(Br)c(Cl)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
A mixture of methyl 2-oxo-5-chloro-6-bromo-3-benzothiazolineacetate (2.0 g), methanol (250 ml) and 10% sodium hydroxide aqueous solution (2.5 ml) was refluxed with stirring for 1.5 hours and then cooled with ice-water to give crystals, which were separated by filtration. The filtrate was concentrated under reduced pressure to give crystals. The combined crystals were dissolved in water (80 ml) under heating and then insoluble materials were removed by filtration. The filtrate was adjusted at pH 2-3 with 10% hydrochloric acid and cooled to give crystals, which were separated by filtration, washed with water and dried to give crystalline 2-oxo-5-chloro-6-bromo-3-benzothiazolineacetic acid (1.5 g).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1.[CH3:18][CH:19]([SH:23])[CH:20]([SH:22])[CH3:21].[C:24]1([CH2:30][CH:31]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:30]([CH:31]1[S:23][CH:19]([CH3:18])[CH:20]([CH3:21])[S:22]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CCc1ccccc1
Reactant: CC(S)C(C)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CC1SC(Cc2ccccc2)SC1C
Reaction time: 0.5 h

Procedure:
Into a 100 ml flask equipped with reflux condenser and magnetic stirring bar and hot plate equipped with magnetic stirring apparatus is placed 0.2 grams of para-toluenesulfonic acid, 5 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. With stirring, over a period of 30 minutes, 6.0 grams (0.05 moles) of phenylacetaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and refluxed for a period of 10 hours during which time water of formation is removed. After the 10 hour period, the reaction mass is cooled and transferred to a separatory funnel. The reaction mass is washed with one 50 ml portion of saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. The resulting filtrate is then distilled on a Microvigreux column yielding the following four fractions: