Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([C:26]2[C:27]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:23]1.Cl[C:44]1[N:53]=[CH:52][C:51]2[C:46](=[CH:47][C:48]([Cl:54])=[CH:49][CH:50]=2)[N:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[Cl:54][C:48]1[CH:47]=[C:46]2[C:51]([CH:52]=[N:53][C:44]([N:22]3[CH2:23][CH:24]([C:26]4[C:27]([C:32]5[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=5)=[N:28][CH:29]=[CH:30][N:31]=4)[CH2:25]3)=[N:45]2)=[CH:50][CH:49]=1
Reactant: Clc1ccc2cnc(Cl)nc2c1
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CNC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Solvent: O
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(c3ncc4ccc(Cl)cc4n3)C2)cc1F
Temperature: 110 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
4-(3-(Azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate) (0.150 g, 0.239 mmol), 2,7-dichloroquinazoline (0.062 g, 0.310 mmol), and potassium carbonate (0.165 g, 1.19 mmol, Aldrich) were mixed in butan-1-ol (2 mL) in a sealed tube. The reaction mixture was stirred at 110° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude mixture was purified via silica gel flash column chromatography eluting with 50% to 100% EtOAc in hexanes to yield give 99 mg (92%) of a light yellow solid. 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.09 (d, J=4.50 Hz, 3 H) 4.29-4.38 (m, 1 H) 4.46-4.58 (m, 4 H) 6.75-6.85 (br. m., 1 H) 7.18 (dd, J=8.61, 1.56 Hz, 1 H) 7.36 (d, J=12.32 Hz, 1 H) 7.40 (dd, J=8.12, 1.27 Hz, 1 H) 7.60 (d, J=8.41 Hz, 1 H) 7.63 (br. s., 1 H) 8.27 (t, J=8.02 Hz, 1 H) 8.57 (d, J=2.15 Hz, 1 H) 8.65 (d, J=2.15 Hz, 1 H) 8.97 (s, 1 H). m/z=449 (M+1).
Reaction SMILES: [C:1]1([OH:9])[C:2](C)=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].[C:10]([C:14]1[CH:19]=[CH:18][C:17](C)=[CH:16][C:15]=1[OH:21])(C)(C)C.ClCC=O>>[C:1]1([OH:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:15]1([OH:21])[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1.[C:14]1([CH:10]=[CH:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(C)c1O
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Agent: O=CCCl
Product: C(=Cc1ccccc1)c1ccccc1
Product: Oc1ccccc1
Yield: 705.6 %

Procedure:
An amount of 195.5 g (0.16 mol) 2,6-xylenol (hereinafter referred to "26XY"), 65.7 g (0.4 mol) of 2-t-butyl-5-methylphenol and 174.4 g (1.0 mol) of an aqueous 45% chloroacetoaldehyde solution were charged in a flask and stilbene bisphenol (yellow crystal 208 g) was obtained according to the method described in R. H. Siebe, Liebigs, Ann. Chem., 730, 31 (1969).
Reaction SMILES: C(N(CC)CC)C.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][N:33]=1.[NH2:41][C:42]1([CH2:48][OH:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:41][C:42]2([CH2:48][OH:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:38])=[CH:34][N:33]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NC1(CO)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NC1(CO)CCCCC1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.6 %

Procedure:
Triethylamine (2.2 ml, 16.12 mmol, 2 eq), hydroxybenzotriazole hydrate (0.217 g, 1.61 mmol, 0.2 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 g, 8.87 mmol, 1.1 eq) are added to a cold (ice bath) solution of 6-chloronicotinic acid (1.27 g, 8.06 mmol, 1 eq) and (1-aminocyclohexyl)methanol (1.04 g, 8.06 mmol, 1 eq) in dichloromethane (80 ml), stirred 30 min at 0° C. and then at room temperature for 1 h. The organic layer is then washed with water, with a saturated solution of aqueous sodium hydrogenocarbonate and dried over magnesium sulfate. The solvent is finally removed to give 2.46 g of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1.O1CCOCC1.N#N>O=[Mn]=O.C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: O=[Mn]=O
Agent: N#N
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 80 °C

Procedure:
(4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (0.552 g, 1.158 mmol, Intermediate 45: step e), 1,4-dioxane (25 mL), dry THF (3 mL) and activated MnO2 (0.503 g, 5.788 mmol) were combined in a round-bottom flask and the mixture was heated at 80° C. under a condenser and a positive pressure of N2 overnight. The reaction was allowed to cool to ambient temperature and was filtered through Celite®, rinsing with THF. The filtrate was concentrated to provide the title compound which was used without further purification.
Reaction SMILES: [C:1]1([SeH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[Se:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1I
Reactant: [SeH]c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1ccccc1[Se]c1ccccc1
Yield: 60 %

Procedure:
Using this protocol (see example 4 below), phenyl selenol was coupled with electron-rich aryl iodides in very good yields (Table 5). Sterically hindered iodides such as those with ortho-functionalities (entries 3, 5, 7 and 11), were coupled, as well as aryl iodides containing heteroatoms (entry 8 and 10). When o-iodoaniline was used as the aryl halide, in addition to the desired selenide, products were observed arising from the self-coupling of o-iodoaniline. This problem also persisted with K3PO4. However, when K2CO3 was used as the base, 1-amino-2-phenylselanyl-benzene was isolated in 60% yield (entry 12). With electron-poor aryl iodides, in addition to the desired diaryl selenides, diaryl diselenides were observed if NaOt-Bu or K3PO4 was used. In addition, with NaOt-Bu, transesterifcation products were observed when aryl halides with ester groups were used. Such complications can be avoided if K2CO3 is used instead of NaOt-Bu or K3PO4. Using this modified protocol a variety of diaryl selenides were obtained from electron-poor aryl halides (Table 6). The protocol tolerates even base sensitive groups such as esters and ketones (entries 3, 4, and 6).
Reaction SMILES: C(O)C(C)(C)C.[H-].[Na+].C(OC([N:16]1[CH2:22][CH2:21][C:20]2[C:23](SCC3N=NC(Cl)=CC=3)=[C:24](Cl)[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=O)(C)(C)C>C1COCC1.O>[CH2:21]1[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17][NH:16][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nn3)c2CC1
Agent: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a stirred solution of neopentyl alcohol (105 mg, 1.19 mmol) in THF (5 mL) at ambient temperature add sodium hydride (31 mg, 95%, 1.19 mmol) and continue stirring for 3 h at ambient temperature. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (315 mg, 0.59 mmol) in THF (1 mL) and continue stirring overnight at ambient temperature and then at 60° C. for 1 h. Dilute with water, extract the reaction mixture three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give 3-tert-butoxycarbonyl-7-chloro-6,6-(2,2-dimethyl-propoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (81 mg, 28%). MS (APCI+) m/z: 492 (M+H)+, 392 (M+H-Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white powder. MS (APCI+) m/z: 392 (M+H)+, m/z: 322 (M+H—C5H11)+.
Reaction SMILES: [I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C=O)C.O>[I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: O=C(O)c1ccc2[nH]cc(I)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid (0.549 g, 1.906 mmol) in DMF (9.5 mL) at 0° C. was added NaH (60% in mineral oil, 0.191 g, 4.76 mmol). After 30 min at 0° C., p-toluenesulfonyl chloride (0.436 g, 2.287 mmol) was added and the reaction was warmed to RT. After 1 h at RT, the mixture was poured into H2O and the mixture was acidified with 5 M HCl (aq.). The precipitate was collected by filtration, washed with H2O and dried in a vacuum oven overnight to afford 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid. (0.663 g, 1.499 mmol, 79%) as a tan solid. MS (ESI, pos. ion) m/z: 442.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (3H, br s), 7.44 (2H, d, J=8.22 Hz), 7.96-8.01 (2H, m), 8.10 (1H, d, J=8.80 Hz), 8.47 (1H, d, J=8.80 Hz), 8.54 (1H, s).
Reaction SMILES: [CH3:1][CH:2]([S:4]([Cl:7])(=[O:6])=[O:5])[CH3:3].[NH2:8][CH2:9][CH:10]([CH:12]([NH:34]C(=O)OC(C)(C)C)[CH2:13][CH:14]([CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]2[CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:15]([CH3:17])[CH3:16])[OH:11].C(N(CC)CC)C>ClCCl>[ClH:7].[NH2:34][CH:12]([CH2:13][CH:14]([CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]2[CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:15]([CH3:16])[CH3:17])[CH:10]([OH:11])[CH2:9][NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN)C(C)C)cc12
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCc1cn(C)c2ccc(CC(CC(N)C(O)CNS(=O)(=O)C(C)C)C(C)C)cc12
Product: Cl
Reaction time: 6 h

Procedure:
0.007 ml of propane-2-sulphonyl chloride is added to a solution of 0.026 g of tert-butyl {1-(2-amino -1-hydroxyethyl)-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate (Example 3Kb), and 0.007 ml of triethylamine in 1 ml of dichloromethane is added at 0° C. After 6 hours, the reaction mixture is concentrated by evaporation—the N-Boc intermediate is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F). The N-Boc intermediate is dissolved in 0.82 ml of 4N HCl/dioxane—after 4 hours, the reaction mixture is concentrated by evaporation, and the residue is dissolved in 0.5 ml of tert-butanol, frozen in liquid nitrogen and lyophilized under high vacuum overnight. The title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].C(N(C(C)C)CC)(C)C.[CH:44]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45]1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:48]([CH:44]3[CH2:47][CH2:46][CH2:45]3)=[O:49])[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: O=C(Cl)C1CCC1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing Example 22) (100 mg, 0.2 mmol) in dry THF (1 ml) is treated with diisopropylethylamine (0.17 ml, mmol) and cyclobutanecarboxylic acid chloride (0.023 ml, 0.2 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure. The residue is purified by reverse-phase chromatography eluting with a gradient system of acetonitrile (0.1% TFA): water (0.1% TFA) (0:100 by volume) gradually changing to acetonitrile (0.1% TFA) water (0.1% TFA) (100:0 by volume) to afford the title compound (Slmg). LCMS (electrospray): m/z [MH+] 547.26. 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.25(m, 8H), 7.20-7.15(m, 2H), 4.70(m, 1H), 4.50(m, 2H), 4.20(m, 2H), 3.95(m, 1H), 2.85(m, 1H), 2.30(m, 2H), 2.20(m, 2H), 2.05(m, 2H), 1.90(m, 1H)
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([CH:14]=[O:15])[CH:3]=1.[Na].OO.Cl([O-])=[O:20].[Na+]>C(#N)C.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([OH:20])=[O:15])[CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1c(C=O)cc(F)c2ccccc12
Agent: OO
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: COc1c(C(=O)O)cc(F)c2ccccc12
Reaction time: 2.5 h
Yield: 93.7 %

Procedure:
9.3 g of 4-fluoro-1-methoxynaphthalene-2-carbaldehyde were dissolved in 100 ml of acetonitrile. 2.1 g sodium dihydrogenphsophate monohydrate in 10 ml of water were added, followed by the addition of 9.5 ml hydrogen peroxide (30%). 8.9 g sodium chlorite, dissolved in 20 ml water were added drop wise while maintaining an internal temperature between 5° C. and 15° C. The reaction was then allowed to come to room temp over 2.5 h. The precipitated solid was filtered with suction, and the solid was washed with water, and dried in vacuo at 40° C. to yield 9.4 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid. The filtrate was treated with 60 ml of cold 10% aqueous sodium bisulfite solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was washed with 0.2 N NaOH twice. The washes were acidified with 6 N HCl to pH 3, whereupon crystallization occurred. The precipitating product was filtered, washed with water and dried in vacuo at 40° C. to yield a second batch of 1.0 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[H][H].[Cl:10][C:11]([Cl:15])=[CH:12][CH2:13]Cl>O>[Cl:10][C:11]([Cl:15])=[CH:12][CH2:13][O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: OCCCO
Reactant: [H][H]
Reactant: ClCC=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: OCCCOCC=C(Cl)Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
In a reaction vessel containing 7.61 g of 1,3-propanediol was put 2.20 g of 60% sodium hydride (in oil), and the mixture was stirred until the evolution of hydrogen gas ceased, to which 7.28 g of 1,1,3-trichloro-1-propene was added dropwise under ice cooling. The reaction mixture was slowly warmed and stirred at 60° C. for 3 hours, which was then poured into water and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 5.48 g of 3-(3,3-dichloro-2-propenyloxy)propanol (yield, 60%).
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][C:18]([I:22])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][OH:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C=O)C>[F:1][C:2]1[C:20]([F:21])=[CH:19][C:18]([I:22])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][O:16][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(=CNCCO)C(=O)c1cc(I)cc(F)c1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-(2-hydroxyethylamino)acrylate (2.0 g, 4.7 mmol) obtained in Step 2 was dissolved in DMF (10 ml), imidazole (705 mg, 10.4 mmol) and tert-butyldimethylsilyl chloride (1.49 g, 9.9 mmol) were added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4) to give the object product (2.3 g, yield 91%) as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[Cl:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24]C(Cl)=O)=[CH:21][CH:20]=1.[Cl:30][C:31]1[CH:32]=[C:33]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:14][CH:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:29][CH:28]=2)[C@H:9]([C:15]([N:41]2[CH2:40][CH2:39][N:38]([C:33]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:31]([Cl:30])[CH:32]=3)[CH2:43][CH2:42]2)=[O:17])[CH2:10]1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: O=C([C@@H]1CC(=CCl)CN1C(=O)COc1ccc(Cl)cc1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, (4-chlorophenoxy)acetyl chloride, and 1-(3,4-dichlorophenyl)piperazine the title compound was obtained in 64% purity by LC/MS. MS(ESI+): m/z=543.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([CH3:22])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17]([O:20][NH2:21])(=[O:19])=[O:18]>ClCCl>[CH3:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:22])[C:10]=1[S:17]([O-:20])(=[O:19])=[O:18].[NH2:21][N+:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Clc1ccnc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
To a cooled solution (0° C., ice bath) containing 2,4-dichloropyridine (4.0 g, 27.0 mmol) and dichloromethane (60 mL) was added O-(mesitylsulfonyl)hydroxylamine (10.2 g, 27.0 mmol) in dichloromethane (75 mL) quickly, dropwise. The solution was maintained at 0° C. for 15 min, removed from the cooling bath and maintained at ambient temperature for 20 h. The solution was concentrated to afford 1-amino-2,4-dichloropyridinium 2,4,6-trimethylbenzenesulfonate as a light yellow foam (165 MH+). The product thus obtained was combined with tert-butyl 3-(4-fluorophenyl)propioloyl(methyl)carbamate (6.6 g, 24.0 mmol) and THF (100 mL). The resultant solution was cooled to −78° C. (dry ice, acetone bath) and DBU (7.2 mL, 48.0 mmol) was added dropwise over 10 min with rapid stirring. The mixture was kept in the cooling bath with stirring and allowed to proceed for 15 h at ambient temperature. The mixture was then filtered and concentrated. Purification on silica gel (0-80% ethyl acetate/hexanes, 60 min gradient) afforded an off white residue. The residue thus obtained was further purified using preparative HPLC (Phenomonex-Luna, 50×100 mm, 5 micron, C18 column; 0.1M TFA, 0-100% B (B=10% H2O/CH3OH)/A (A=90% H2O/CH3OH), 15 min. gradient) to afford tert-butyl 5,7-dichloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a white solid. Preparative HPLC retention time: 14.0 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (d, J=2.26 Hz, 1H), 7.71 (dd, J=8.91, 5.40 Hz, 2H), 7.16 (t, J=8.66 Hz, 2H), 7.03 (d, J=2.26 Hz, 1H), 3.26 (s, 3H), 1.12 (s, 9H). LCMS retention time: 2.810 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 460 (MNa+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13](C(C4C=CC=CC=4)=O)[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:24]=1.C(OCC)(=O)C.[ClH:31]>C(O)(=O)C>[ClH:31].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)=[CH:8][S:7][C:6]=2[CH:24]=1
Reactant: O=C(c1ccccc1)N1CCC(c2csc3cc(F)ccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1ccc2c(C3CCNCC3)csc2c1
Yield: 89 %

Procedure:
A solution of (4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl) phenylmethanone (6.5 g, 19 mmol) in acetic acid (100 mL) and concentrated hydrochloric acid (100 mL) was stirred at 90° C. for 10 h. To a solution of reaction mixture was added ethyl acetate. The precipitated crystals were collected by filtration and washed with ethyl acetate to give 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride (4.8 g, 89%) as yellow crystals.
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>C1COCC1>[F:30][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:24][CH2:25]3)[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A solution of 100 mg (0.24 mmol) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (WO 2006/095906) and 0.51 g (50 mmol) of Et3N in 20 mL of THF was cooled to 0° C. and 41 mg (0.36 mmol) of methanesulfonyl chloride was added. The mixture was allowed to warm to room temperature, and after 1 hr water was added. The precipitate was collected, washed with water, and dried to give 110 mg (93% yield) of 2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (MeOH) 248-250° C.; 1H NMR (CDCl3) δ 8.30 (br d, J=8.3 Hz, 1H), 7.90 (br d, J=7.3 Hz, 1H), 7.52 (t, JHF=53.6 Hz, 1H), 7.46-7.40 (m, 2H), 4.03 (m, 4H), 3.89 (m, 4H), 3.80 (m, 4H), 3.34 (m, 4H), 2.82 (s, 3H); Anal. Calcd. for C20H24F2N8O4S: C, 48.6; H, 4.9; N, 22.7. Found: C, 48.8; H, 4.9; N, 22.85%.