Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.C(=O)([O-])[O-].[Cs+].[Cs+].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[S:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Sc1ccccc1
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1ccc(Br)c(Sc2ccccc2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of 4-bromo-3-fluoro-N-methyl-2-nitroaniline (0.30 g, 1.20 mmol) in N,N-dimethylformamide (2.45 mL) was treated with cesium carbonate (0.472 g, 1.45 mmol) and benzenethiol (0.149 mL, 1.45 mmol). The resultant reaction mixture was warmed to 80° C. and stirred at 80° C. for 30 min, after which time the reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with 10% solution of K2CO3 and brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) gave the desired product (396 mg, 97%) as an orange solid. LCMS calculated for C13H12BrN2O2S (M+H)+: m/z=339.0, 341.0. found: 338.9, 340.9.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[C:16]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:15][C:14]([Cl:31])=[CH:13][N:12]=2)[CH:10]=1)=O)C.[OH-].[Na+].[CH3:34][NH:35][CH3:36].C(N(CC)CC)C>C(O)(=O)C.C1COCC1>[CH3:34][N:35]([CH3:36])[C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[C:16]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:25][CH:26]=3)(=[O:20])=[O:19])=[CH:15][C:14]([Cl:31])=[CH:13][N:12]=2)[CH:10]=1)=[O:3]
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cnn(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A 25 mL scintillation vial was charged with 1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (synthesized according to general procedure D, 93 mg, 0.2 mmol), NaOH (2 mL, 1.0 M solution in water), and THF (3 mL). The vial was sealed and stirred at 80° C. for 16 hours. The reaction solution was subsequently neutralized to pH=5 with glacial acetic acid. The mixture was extracted with ethyl acetate (2×10 mL) and the combined organics were concentrated in vacuo. The crude product was subsequently dissolved in 2 mL of THF in a 25 mL scintillation vial. To the resultant solution was added with dimethylamine (0.2 mL, 2.0 M in THF), 1-propanephosphonic anhydride solution (184 mg, 50% solution in ethyl acetate), and triethylamine (41 mg, 0.4 mmol). The vial was sealed and stirred at ambient temperature for 1 hour. The volatiles were then evacuated in vacuo and the residue was purified via preparative HPLC to afford 1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylic acid dimethylamide as a white powder: MS (ES) M+H expected 462.1, found 462.0.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][N:26]1[CH2:27][CH2:28][CH:24]([N:16]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]3[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[N:15]2)[CH2:25]1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ncc[nH]2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.4 %

Procedure:
3-(4-Phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 5.81 mmol), 1H-2-imidazolecarbaldehyde (77 mg, 0.806 mmol), sodium triacetoxyborohydride (113 mg, 0.537 mmol) and glacial acetic acid (48 mg, 0.806 mmol) were mixed with 1,2-dichloroethane (4 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (90:10) as mobile phase to give 1-[1-(1H-2-imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 83%). 1H NMR (DMSO-d6) δ 2.33 (m, 2H), 2.81 (m, 4H), 3.15 (m, 1H), 3.69 (s, 2H), 5.38 (m, 1H), 6.90 (s, 2H), 7.15 (m, 5H), 7.44 (m, 2H), 7.66 (m, 2H), 8.24 (s, 1H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+ 453.4, Rt=2.17 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:14][CH:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:36][CH2:37][C:38](Cl)=[O:39].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:36][CH2:37][C:38]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:14][CH:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=2)=[O:39]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of methyl 2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.48 g, 18.6 mmol), sodium acetate (1.68 g, 20.5 mmol) and acetic acid (1.17 ml, 20.5 mmol) in tetrahydrofuran (60 ml) was added dropwise chloroacetyl chloride (1.63 ml, 20.5 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was m washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-[2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate (7.90 g, yield 100%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][C:17](=[O:19])[CH3:18])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][C:12]1[C:11]([O:16][C:17](=[O:19])[CH3:18])=[CH:10][C:8]2[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[O:6][C:7]=2[C:13]=1[CH3:14]
Reactant: C1COCCN1
Reactant: CC(=O)Oc1cc2cc(C(=O)CBr)oc2c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1cc2cc(C(=O)CN3CCOCC3)oc2c(C)c1C
Yield: 89.8 %

Procedure:
A solution of 2-bromo-1-(5-acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone (47 mg) from Example 16, morpholine (15 mg), and potassium carbonate (25 mg) in acetone (10 mL) was stirred at room temperature for 30 min. It was then evaporated to dryness, and the residue was purified by silica gel column eluting with 5% MeOH in DCM to give 43 mg of acetic acid 6,7-dimethyl-2-(2-morpholin-4-yl-acetyl)-benzofuran-5-yl ester as an oil. Conversion into the HCl salt gave a yellow solid. 1H NMR (CDCl3, 300 MHz) δ: 7.60 (s, 1H), 7.20 (s, 1H), 3.78 (s+t, 6H), 2.64 (m, 4H), 2.50 (s, 3H), 2.40 (s, 3H), 2.20 (s, 3H) ppm. 13C NMR (CD3OD, 75 MHz) (as HCl salt) δ: 180.94, 170.31, 153.65, 150.33, 147.19, 131.94, 124.33, 122.34, 116.04, 113.59, 63.74, 60.89, 53.28, 19.64, 12.18, 12.22 ppm. M/S 332 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]2[N:6]=[C:5]([NH2:14])[CH:4]=[N:3][C:2]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:9]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Nc1cnc(Br)c(-c2cccnc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cnc(-c2ccncc2)c(-c2cccnc2)n1
Temperature: 150 °C
Yield: 93.4 %

Procedure:
A mixture of 5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6, 0.4 g, 1.59 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.424 g, 2.07 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1) (76 mg, 0.095 mmol) and cesium carbonate (1.55 g, 4.77 mmol) in dioxane (14 mL) and water (3.72 mL) was heated to 150° C. for 10 minutes in the microwave oven. The mixture was partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and evaporated. Silica gel flash chromatography (95:5 dichloromethane/methanol) gave the title compound (0.37 g, 74%) as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.[F:51][C:52]([F:56])([CH3:55])[CH2:53]O>>[F:51][C:52]([F:56])([CH3:55])[CH2:53][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][CH:15]=1)[NH:11][C:9]([C:6]1[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:10]
Reactant: CC(F)(F)CO
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCC(C)(F)F)[nH]n1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (15.0 mg, 32 μmol), HOBt (12.8 mg, 95 μmol) and EDC (16.8 μL, 95 μmol) were combined in DCM (121 μL, 1.9 mmol) and stirred for 10 minutes. 2,2-Difluoropropanol (24.3 mg, 253 μmol) was added and the resulting mixture was stirred at room temperature until the reaction was complete (≈48 hours). The mixture was evaporated under reduced pressure and the product was purified (reverse phase column) to yield the title compound (13.8 mg, purity 96%) as a TFA salt. MS m/z [M+H]+ calc'd for C25H24ClF3N4O5, 553.14. found 553.1.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:49][O:50][Si:51]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[CH:52]([CH3:54])[CH3:53])=[N:43][N:44]([CH2:46][CH2:47][OH:48])[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:70][S:71](Cl)(=[O:73])=[O:72]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:49][O:50][Si:51]([CH:55]([CH3:57])[CH3:56])([CH:58]([CH3:60])[CH3:59])[CH:52]([CH3:53])[CH3:54])=[N:43][N:44]([CH2:46][CH2:47][O:48][S:71]([CH3:70])(=[O:73])=[O:72])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[Si](OCc1nn(CCO)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCc1nn(CCOS(C)(=O)=O)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
A solution of Intermediate 74i (134 mg, 0.16 mmol) in DCM (1.6 mL) was treated with DIPEA (83 μL, 0.48 mmol) then cooled to 0° C. Methanesulfonyl chloride was added and the mixture was stirred at 0° C. for 5 min then at RT for 1 h. The mixture was diluted with DCM and a saturated aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM, to give the title compound (107 mg, 73%). LCMS (Method 3): Rt 5.06 min, m/z 917.4 [MH+].
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:38]2[CH2:37][CH2:36][N:35]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH2:34][CH2:33][C:32]=2[CH:31]=[CH:30][C:29]=1[Cl:45]>C(Cl)Cl.O>[Cl:45][C:29]1[CH:30]=[CH:31][C:32]2[CH2:33][CH2:34][N:35]([C:39](=[O:44])[C:40]([F:42])([F:41])[F:43])[CH2:36][CH2:37][C:38]=2[C:28]=1[NH:27][CH2:26][CH2:25][NH:24][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C(O)c1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: O=C(NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1cccnc1

Procedure:
Dissolve nicotinic acid (28.2 mg, 0.23 mmol) in DCM (3 mL). Add EDC (40 mg, 0.208 mmol), HOBT (28.1 mg, 0.2081 mmol) and stir at ambient temperature for 10 min. Add 6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.208 mmol) and stir at ambient temperature for 10 hr. Dilute with DCM, add water and extract the aqueous layer three times with DCM. Wash combined organic extracts with 1N aqueous NaOH, and brine. Dry the organic layer over MgSO4, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 1:1, 3:7 and 1:9) to obtain 7-chloro-6-{2-[(pyridine-3-carbonyl)-amino]-ethylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11]C(C)([O-])C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[N:3]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2ccccc21
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 85.7 %

Procedure:
In a 50 ml round-bottomed flask, 3-iodo-1H-indazole (1.0 g, 3.9 mmol) was dissolved in THF (12 ml) and the solution was cooled to 0° C. Potassium tert-butoxide (612 mg, 5.45 mmol) was added and the reaction mixture was stirred at 0° C. for 1.25 h. Methyl iodide (0.29 ml, 4.64 mmol) was added dropwise then the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/Hexanes (gradient 0-10% EtOAc) to afford 863 mg (86%) of 3-iodo-1-methyl-1H-indazole as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.42-7.53 (m, 2H), 7.33-7.40 (m, 1H), 7.22 (ddd, J=8.0, 6.9, 0.9 Hz, 1H), 4.11 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][CH:20]=O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:22]1[CH2:25][CH:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:19][CH2:20][N:22]2[CH2:25][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23]2)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:6][CH:7]=1
Reactant: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: C1CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CC(N2CCOCC2)C1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
tert-Butyl [(2S)-2-(4-fluorophenyl)-4-oxobutyl]methylcarbamate (1.57 g, 5.3 mmol) and 4-azetidin-3-ylmorpholine (0.83 g, 5.8 mmol) were dissolved in CH2Cl2 (60 mL) together with DIPEA (1.4 g, 10.6 mmol). The mixture was stirred for 20 min and then sodium triacetoxyborohydride (1.6 g, 7.4 mmol) was added. The mixture was stirred at room temperature for 6 h and then the solvent was removed by evaporation. The residue was partitioned between an aqueous solution of NaHCO3 and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the organic solution was dried over MgSO4 and then removed by evaporation. The product was chromatographed on a silica gel using a mixture of methanol and CH2Cl2 (5%-20% methanol) and there was obtained 440 mg (20%) tert-butyl [(2S)-2-(4-fluorophenyl)-4-(3-morpholin-4ylazetidin-1-yl)butyl]methylcarbamate as an oil. 1H NMR (400 MHz, CDCl3): 1.3 (s, 9H), 1.4-1.6 (m, 2H), 2.1-2.3 (b, 5H), 2.5-3.8 (cm, 16H), 6.9 (t, 2H), 7.0-7.1 (b, 2H); LCMS: m/z 422 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.CN(CCN(C)C)C.C([Li])CCC.CCCCCC.[CH3:34][C:35]([CH3:41])([CH2:38][CH:39]=[CH2:40])[CH:36]=[O:37]>C1COCC1>[CH3:34][C:35]([CH3:41])([CH2:38][CH:39]=[CH2:40])[CH:36]([OH:37])[CH:6]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[C:5]1[CH:12]=[CH:13][CH:14]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C=CCC(C)(C)C=O
Reactant: COc1cccc(Cn2ccnc2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC(C)(C)C(O)C(c1cccc(OC)c1)n1ccnc1
Yield: 6.4 %

Procedure:
7.52 g (40 mmol) of 1-(3-methoxybenzyl)-imidazole and 4.65 g (40 mmol) of TMEDA in 80 ml of absolute THF were metallized using 53.5 ml of 1.5 molar n-butyllithium/hexane solution according to the procedure described in Example 19, and the product was reacted with 5.00 g of 90% purity (≅40 mmol) 2,2-dimethyl-4-pentenaldehyde. Work-up was effected analogously to that in Example 19. The extract residue (12.2 g) was chromatographed as described in Example 19 on a silica gel S/CH2Cl2 column (φ 3.5 cm, height 40 cm), and the combined fractions which contained the compound desired (amount 6.3 g) were subsequently chromatographed a second time on a silica gel S/CH2Cl2 column (φ 2.4 cm, height 88 cm). A group of fractions (2.5 g) from the second chromatography crystallized from a hexane/diisopropyl ether 3:1 solution. After isolation of the substance, 0.77 g (≅6.3% yield) of pure 3,3-dimethyl-1-(1-imidazolyl)-1-(3-methoxyphenyl)5-hexen-2-ol of melting point 83° C. were obtained. C18H24N2O2 (300.41) calculated: C 71.97 H 8.05 N 9.33% found: C 68.9 H 8.0 N 8.6%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[N:12]1[C:20](=[O:21])[NH:19][C:18]2[C:13]1=[N:14][C:15]([N:22]1[C:26]3[CH:27]=[C:28]([C:31](F)(F)F)[CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]1)=[N:16][CH:17]=2.F[C:36]1C=CC=C2C=1OCC[C@H]2N1C(=O)NC2C1=NC(N1C3C=CC(C(F)(F)F)=CC=3N=C1)=NC=2.FC(F)(F)C1C=CC2N=CNC=2C=1>>[CH3:36][C:29]1[C:28]([CH3:31])=[CH:27][C:26]2[N:22]([C:15]3[N:14]=[C:13]4[C:18]([NH:19][C:20](=[O:21])[N:12]4[C@H:7]4[C:6]5[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=5)[O:10][CH2:9][CH2:8]4)=[CH:17][N:16]=3)[CH:23]=[N:24][C:25]=2[CH:30]=1
Reactant: O=c1[nH]c2cnc(-n3cnc4ccc(C(F)(F)F)cc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Reactant: O=c1[nH]c2cnc(-n3cnc4cc(C(F)(F)F)ccc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Agent: FC(F)(F)c1ccc2nc[nH]c2c1
Product: Cc1cc2ncn(-c3ncc4[nH]c(=O)n([C@@H]5CCOc6c(F)cccc65)c4n3)c2cc1C

Procedure:
9-((R)-8-Fluorochroman-4-yl)-2-(6-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-7H-purin-8(9H)-one and 9-((R)-8-fluorochroman-4-yl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-7H-purin-8(9H)-one. The title compound was synthesized from 5-trifluoromethylbenzimidazole (US 2004/0087601) via the procedures described in Example 25. Purification by column chromatography (2% MeOH/DCM) eluted the 6-trifluoromethyl isomer first (1H-NMR (300 MHz, CDCl3) δ 8.8 (d, 2H), 8.4 (s, 1H), 7.9 (d, 1H), 7.6 (d, 2H), 7.0 (t, 1H), 6.7 (m, 2H), 5.9 (t, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.0 (m, 1H), 2.4 (m, 1H).) followed by the 5-trifluoromethyl isomer (1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.4 (s, 1H), 8.1 (s, 1H), 8.0 (d, 1H), 7.6 (d, 2H), 7.0 (m, 1H), 6.8 (m, 2H), 5.9 (t, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 2.9 (m, 1H), 2.4 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>C(#N)C.CCOC(C)=O>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:8]=1)=[O:24])[CH3:21]
Reactant: CCN(CC)C(=O)Cl
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)C(=O)Oc1cccc(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-morpholinylphenol (0.34 g; 1.9 mmol) and powdered K2CO3 (0.576 g; 4.2 mmol) in dry acetonitrile (10 mL) was added diethyl carbamylchloride (0.26 mL; 2.0 mmol) via syringe at room temperature under nitrogen atmosphere. The resulting mixture was heated to reflux for 24 hours, then allowed to cool to room temperature. The reaction was diluted with EtOAc (60 mL), washed with water (2×20 mL) and brine, then dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified via radial chromatography (4 mm chromatotron plate with 2:1 hexanes/EtOAc) to provide the carbamate as a clear, colorless oil (0.39 g; 74%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>>[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:9]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: BrCc1cccc(Br)c1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: N#Cc1ccc(N(Cc2cccc(Br)c2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 3-bromobenzyl bromide
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:21])[CH3:20].C(Cl)Cl.C(N(CC)CC)C>>[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (3 g, 0.01 mol), 4-isopropoxyphenylboronic acid (5 g, 0.03 mol), and cupric acetate (2.55 g, 0.0140 mol) were placed in a vial followed by methylene chloride (100 mL, 2 mol) and finally triethylamine (9.78 mL, 0.0702 mol) at 23° C. The flask was then purged with nitrogen, sealed and stirred at room temperature overnight. The reaction was allowed to stir for 16 hours. Reaction was then heated to 50° C. for two hours. The reaction mixture was then cooled to RT and filtrated and the crude material was then purified via chromatography (SiO2, 40 g, 0-75% EtOAC/Hexane) to give 2.4 g of the desired product as a colorless solid. Material was used without additional purification. ESI-MS: 378 (M+H)+