Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH:5]([C:10]2[N:11]([CH3:29])[C:12](=[O:28])[C:13]([OH:27])=[C:14]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:17])[N:15]=2)[CH2:4]1)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][NH:18][C:16]([C:14]2[N:15]=[C:10]([CH:5]3[CH2:4][NH:3][CH2:8][CH2:7][N:6]3[CH3:9])[N:11]([CH3:29])[C:12](=[O:28])[C:13]=2[OH:27])=[O:17])=[CH:21][CH:22]=1
Reactant: CCN1CCN(C)C(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCNCC1c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C

Procedure:
The crude product from Step 3 was stirred in CH2Cl2/TFA (1:1) for 2 hours to remove the Boc protective group from the piperazinyl nitrogen.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[C:28]1([C:34]2[N:35]=[C:36]([CH2:39][CH:40]([C:44]3[CH:49]=[CH:48][C:47]([CH2:50]O)=[CH:46][CH:45]=3)[CH2:41][CH2:42][CH3:43])[S:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH2:50][C:47]2[CH:48]=[CH:49][C:44]([CH:40]([CH2:39][C:36]3[S:37][CH:38]=[C:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:35]=3)[CH2:41][CH2:42][CH3:43])=[CH:45][CH:46]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CO)cc1
Reactant: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CN(c2ccc(CCC(=O)OCC)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.686 g, 1.73 mmol), (4-{1-[(4-phenyl-1,3-thiazol-2-yl)methyl]butyl}phenyl)methanol (0.389 g, 1.15 mmol) and triphenylphosphine (0.603 g, 2.30 mmol) in tetrahydrofuran (15 mL) was stirred under ice-cooling, and diethyl azodicarboxylate (40% toluene solution, 1.05 mL, 2.3 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give ethyl 3-{2-fluoro-4-[[(2-nitrophenyl)sulfonyl](4-{1-[(4-phenyl-1,3-thiazol-2-yl)methyl]butyl}benzyl)amino]phenyl}propanoate as a yellow oil. To a solution of the obtained oil and mercaptoacetic acid (0.291 g, 3.16 mmol) in N,N-dimethylformamide (15 mL) was added lithium hydroxide monohydrate (0.265 g, 6.32 mmol), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (0.420 g, yield 69%, 2 steps) as a colorless oil.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[CH3:18][C:19]1([CH3:33])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[O:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][C:23]1([CH3:25])[C:19]([CH3:18])([CH3:33])[O:20][B:21]([C:26]2[CH:31]=[CH:30][C:29]([O:5][C@@H:6]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]3)=[CH:28][CH:27]=2)[O:22]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1

Procedure:
(S)-tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (0.53 g, 2.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.48 g, 2.2 mmol) and K2CO3 (0.33 g, 2.4 mmol) in DMF (5 mL) were heated at 85° C. for 1 d. The reaction mixture was concentrated in vacuo and Et2O and water were added. The aqueous phase was extracted with Et2O and the combined organics were washed with 1 M NaOH solution (aq), dried (MgSO4), filtered and concentrated in vacuo to give (R)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[O:15][N:14]=[C:13]([CH3:16])[N:12]=4)=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Cc1noc(-c2ccn3c(Br)cnc3n2)n1
Product: Cc1noc(-c2ccn3c(-c4ccc(F)c(-c5ccccc5C#N)c4)cnc3n2)n1

Procedure:
3-Bromo-7-(3-methyl-[1,2,4]oxadiazol-5-yl)imidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 2 to give 2′-fluoro-5′-[7-(3-methyl-[1,2,4]oxadiazol-5-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid: δH (400 MHz, CDCl3) 2.55 (3H, s), 7.46 (1H, t, J 9), 7.56-7.59 (1H, m), 7.64 (2H, dd, J 7 and 2), 7.69-7.73 (2H, m), 7.81-7.87 (2H, m), 8.16 (1H, s), 9.05 (1H, s); m/z (ES+) 397 (M++H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:31](=[O:33])[CH3:32])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC1(C)CC(OC(C)=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 6,36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol (prepared as described in GB 2335190, example 7, compound 102) and 2.02 g (2 mmol) of triethylamine in 50 ml toluene are added 1,57 g (2 mmol) acetyl chloride at 0-5° C. and the reaction mixture is stirred for 2 hours at 20° C. The reaction mixture is then several times extracted with water. The organic phase is dried over Na2SO4 and after removing the solvent 6.9 g (96%) acetic acid 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester are obtained as yellowish liquid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])[N:19]=1)[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:30]1[CH2:31][CH2:32][C:26]2([O:25][CH2:24][CH2:23][N:22]([C:20]([C:18]3[N:19]=[C:15]([CH2:13][CH3:14])[S:16][CH:17]=3)=[O:21])[CH2:27]2)[CH2:28][CH2:29]1
Reactant: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1cccc(CCO)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reaction time: 1.15 h
Yield: 107 %

Procedure:
To a solution of 2-chloro-3-(2-hydroxyethyl)benzaldehyde (1.1 molar equivalents) in DCM (12 volumes) was added to (2-ethylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone ((limiting reagent) (step b). Triethylamine (2 molar equivalents) was added and the mixture was stirred for 1.15 hr. Sodium triacetoxyborohydride (2.5 molar equivalents) was added portion-wise over 15 minutes maintaining the temperature below 25° C. The reaction mixture was stirred at ambient temperature for 22.5 hr. Saturated aq. sodium bicarbonate solution (8 volumes) was added slowly and the mixture was stirred vigorously for 1 hr; the aqueous was separated and extracted with DCM (5.3 volumes). The combined organics were washed with 20% brine solution (5.3 volumes), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. Yield 107% of theoretical.
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]([CH3:21])[C:3]1=[O:22].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]([CH3:21])[C:3]1=[O:22]
Reactant: CN1C(=O)C(O)N=C(c2ccccc2F)c2cc(Cl)ccc21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(F)N=C(c2ccccc2F)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
A solution of 1.4 g of 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 10 ml of methylene chloride was added dropwise to a stirred solution of 1.5 ml of diethylaminosulfur trifluoride in 50 ml methylene chloride cooled to -70°. The reaction mixture was allowed to warm slowly to 5° and then poured into 100 ml of ice water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was recrystallized from heptane to give 1.17 g of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one as cream-colored crystals: mp 91°-95°; Hu 1H nmr (CCl3D) δ 3.51 ppm (s, 3H), 5.66 ppm (d, J = 57 Hz, 1H) and 7.5 ppm (m, 7H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31][CH:32]=[CH2:33])[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH:45]O.[OH-].[Na+]>>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([C:24](=[O:34])[N:25]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:31][CH2:32][CH2:33][OH:45])[CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OO
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCO)C2CCCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.11 g) was added 9-BBN (0.5M in THF, 2.2 ml) and the resulting solution stirred at room temperature under nitrogen for 20 h. A mixture of 28% aqueous hydrogen peroxide solution (1.8 ml) and 2M aqueous sodium hydroxide (0.9 ml) was added and the reaction mixture stirred at reflux for 2 h. The solvent was removed in vacuo and the residue purified by preparative hplc and the title compound (0.064 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: FC1C=CC(C([N:8]2[CH2:12][CH2:11][C:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])=O)=CC=1.C(N)CCCCCCC>O1CCCC1>[CH:15]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][NH:8][C:9]1=[O:18])([CH3:17])[CH3:16]
Reactant: CC(C)C1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Solvent: C1CCOC1
Solvent: CCCCCCCCN
Product: CC(C)C1(C#N)CCNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of 1-(4-fluorobenzoyl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (280 mg) obtained in Step A in tetrahydrofuran (3 mL) was added n-octylamine (180 μL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added n-octylamine (168 μL) at room temperature, and the mixture was stirred at 50° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([O:28]C)[CH:16]=[CH:15][C:14]=3[N:13]([CH2:30][CH2:31][OH:32])[C:12]=2[CH:11]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].B(Br)(Br)Br.COC1C=CC2NC3C=C(C(OCC4C=CC=CC=4)=O)C4C(=O)NC(=O)C=4C=3C=2C=1>>[CH3:33][S:34]([O:32][CH2:31][CH2:30][N:13]1[C:12]2[CH:11]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:22]3[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=3[C:20]=2[C:19]2[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]1=2)(=[O:36])=[O:35]
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4OC)cc1n2CCO)C(=O)NC3=O
Reactant: CS(=O)(=O)Cl
Agent: BrB(Br)Br
Agent: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCOS(C)(=O)=O

Procedure:
Reaction of 4-(2-Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2OH) (111) prepared as described in example 63 with methanesulphonyl chloride, followed by reaction with BBr3 using the procedure described in example 170 of Scheme 3 gave 2-(4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-1,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol-6 (1H)-yl)ethyl methanesulfonate (VII; Ar=2-chloro-6-methoxyphenyl, n=2, mesylate) (114), as a yellow solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:19](=[O:22])[CH2:20][CH3:21])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: CCC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and propionyl chloride the title compound was obtained as a light yellow solid (5%), MS: m/e=322 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:12][C@H:11]2[N:28](C)[C@@H:7]1[CH2:8][N:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10]2)=[O:5])[CH3:2].Cl[C:38]([O:40][C:41]([CH3:47])([CH3:46])[C:42]([Cl:45])([Cl:44])[Cl:43])=[O:39]>ClCCCl>[Cl:43][C:42]([Cl:45])([Cl:44])[C:41]([O:40][C:38]([N:28]1[C@H:7]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])=[CH:18][CH:19]=3)[CH2:12][C@@H:11]1[CH2:10][N:9]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:8]2)=[O:39])([CH3:47])[CH3:46]
Reactant: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)=C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Solvent: ClCCCl
Product: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Temperature: 60 °C
Yield: 90.2 %

Procedure:
A mixture of compound B9 (6.16 g, 11.9 mmol) and 2,2,2-trichloro-1,1-dimethylethyl chloroformate (3.15 g, 13.1 mmol) in 1,2-dichloroethane (200 mL) was heated to 60° C. for 20 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 8:2) yielded the title compound (7.58 g, 90%). LC-MS: tR=1.29 min, ES+: 707.36.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29][CH3:30])=[O:28])[CH2:22]2)=[CH:3][CH:2]=1.[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:37]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:42]=[CH:41][C:40]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:3]=[CH:2][C:1]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:6][CH:5]=4)[C:9]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29][CH3:30])=[O:28])[CH2:22]4)=[N:10][C:11]=3[C:16]=2[F:17])=[CH:39][CH:38]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C1CCCC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Temperature: 120 °C

Procedure:
A 50 mL flask was charged with methyl 3-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.4 g, 0.664 mmol), 4-biphenylboronic acid (0.130 g, 0.664 mmol), Pd(PPh3)4 (0.038 g, 0.033 mmol), DMF (9 mL), and 1 M aqueous K2CO3 (1.3 ml, 1.30 mmol). The reaction was degassed with N2 and then heated at 120° C. for 1 h. Then the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H2O. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Chromatography of the resulting residue over silica (preparative TLC) eluting with 40% EtOAc/hexanes afforded the title compound. LC-MS: calculated for C40H34F2N2O3 628.25, observed m/e: 629.17 (M+H)+ (Rt 3.83/4 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.CN1C(=O)CCC1.[F:28][C:29]([F:37])([F:36])[C:30]([F:35])([F:34])C([O-])=O.[Na+].C(=O)([O-])O.[Na+]>[Cu](I)I.C1(C)C(C)=CC=CC=1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:30]([F:35])([F:34])[C:29]([F:37])([F:36])[F:28])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Temperature: 170 °C
Yield: 7.7 %

Procedure:
A mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (500 mg), NMP (24 ml), xylene (10 ml), copper iodide (1.1 g), and sodium pentafluoropropionate (1.1 g) was heated to 170° C., and stirred with heating for 3 days. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with tert-butyl methyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 43 mg of 2-(2-ethylsulfanylphenyl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 55).
Reaction SMILES: [C:1]1([C:7]2[C:11]([OH:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].CO.Br[CH2:25][CH2:26][CH3:27]>O>[CH2:25]([O:12][C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9][C:10]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:26][CH3:27]
Reactant: CCCBr
Reactant: Oc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 3,5-diphenyl-4-pyrazolol (10 g, 0.042 mole), sodium methoxide (2.27 g, 0.042 mole) and methanol (60 ml) is heated at 60° C for 2 hours. Then 1-bromopropane (5.17 g, 0.042 mole) is added slowly (5 minutes) at 60° C. The reaction mixture is then held at 60° C until the reaction is complete by tlc. The mixture is poured into water and the solid formed is isolated by filtration. Recrystallization of the solid from acetonitrile affords white crystals, 7.4 g (63%), melting point 142°-142.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(I)cc2)n1-c1ccc(Cl)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(-c3ccncc3)cc2)n1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A dry flask charged with 1-(4-chloro-phenyl)-2-(4-iodo-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (20 mg, 0.038 mmol), 4-tributylstannylpyridine (14 mg, 0.038 mmol) and tetrakis(triphenylphosphine) palladium (4.4 mg, 0.0038 mmol) is heated at 100° C. overnight. Filtration and concentration followed by purification gives the desired product. 1H NMR (methanol-d4) δ(ppm) 8.69 (d, 2H), 8.49 (s, 1H), 8.04 (d, 2H), 7.81 (m, 4H), 7.60 (m, 4H), 7.51 (m, 1H), 7.35 (m, 4H); HPLC-MS calculated for C28H18ClN5O (M+H+): 476.2. Found 476.2.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[OH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Oc1ccc(Nc2ncnc3c2ncn3C2CCCCO2)cc1
Yield: 90 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1309 mg) of 4-hydroxyphenylamine (4-hydroxyaniline) and 4 ml of N-ethyldiisopropylamine was refluxed in n-butanol for 3 hrs. After removal of the n-butanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield: 90%, white solid. TLC (CHCl3:CH3OH:NH3) (90:10:0.1) (v:v): single spot; HPLC: purity >98%. 1H NMR (400 MHz, DMSO): 1.56tt (2H, Ja=11.0 Hz, Jb=3.3 Hz); 1.72qq (1H, Ja=11.6 Hz, Jb=3.3 Hz); 1.94tt (2H, Ja=11.0 Hz, Jb=3.3 Hz); 2.28qq (1H, Ja=11.6 Hz, Jb=3.3 Hz); 3.66m (1H); 3.98dd (1H, Ja=11.0 Hz, Jb=2.1 Hz); 5.62dd (1H, Ja=11.0 Hz, Jb=2.1 Hz); 7.02d (2H, J=8.5 Hz); 8.19s (1H); 8.26d (2H, J=8.5 Hz); 8.29s (1H); 8.95s (1H). MS (ES+): [M+H]+=312 (100).