Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[C@@H:12]2[C@@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@@H:13]2[O:20][CH3:21])(=O)=O)=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:21][O:20][C@@H:13]1[C@@H:12]2[C@H:16]([O:17]2)[C@@H:15]([CH2:18][OH:19])[O:14]1
Reactant: CO[C@H]1O[C@H](CO)[C@H](O)[C@H]1OS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CO[C@H]1O[C@H](CO)[C@H]2O[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Compound 35.5 (46.83 g, 147.26 mmol) was dissolved in anhydrous methanol 300 mL, cooled to 0° C. and treated with 25% NaOMe in MeOH. The mixture was allowed to rise to r.t. and stirred for 8 h. The mixture was then neutralized with acetic acid and the solvent was concentrated under reduced pressure. The residue was dissolved in EtOAc, filtered and the organic layer was washed with 200 mL water. The organic layer was collected and the aqueous layer was extracted with 4×100 mL ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a column chromatography to give compound 35.6 (18.18 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:23]4[NH:24][C:25]([CH3:36])=[C:26]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[C:22]=4[CH3:21])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)N(C)c3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
A mixture of 4(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol), 3,5dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (85 mg, 0.34 mmol) and piperidine (2 drops) in ethanol (3 mL) was stirred at 80° C. for 1 hour. The reaction was concentrated and column chromatographed to give 46 mg (26%) of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H, NH), 9.17 (s, 1H), 8.33 (s, 1H), 7.68 (m, 1H), 7.35 (s, 1H, H-vinyl), 7.32 (m, 2H), 3.55 (m, 4H, 2×CH2), 3.30 (s, 3H, CH3), 2.40 (m, 2H, CH2), 2.31 (s, 3H, CH3), 2.30 (m, 4H, 2×CH2), 2.20 (m, 2H, CH2), 2.10 (s, 3H, CH3), 1.55 (m, 2H, CH2).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:36])(=[O:35])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[S:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)(=[O:36])=[O:35])=[CH:33][CH:32]=1
Reactant: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{4-[(4-fluoro-benzyl)-isobutyl-sulfamoyl]-phenylamino}-piperidine-1-carboxylic acid tert-butyl ester (208 mg) in DCM (9 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and purified by SCX column eluting with 2 M NH3 in MeOH to give N-(4-fluoro-benzyl)-N-isobutyl-4-(piperidin-4-ylamino)-benzenesulfonamide. A solution of the crude product (149 mg) in DCM (5 mL) was added DIPEA (124 μL, 711 μmol) followed by methane sulfonylchloride (28 μL, 356 μmol) and the reaction stirred at room temperature for 30 minutes. Water was then added, passed through a phase separator, extracted once more through a phase separator, concentrated and purified by silica gel column chromatography (0-75% EtOAc in cyclohexane) to give the title compound (139 mg). 1H NMR (400 MHz, DMSO): δ 7.51 (d, J=8.7 Hz, 2H), 7.4 (dd, J=8.5, 5.6 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 6.71 (d, J=8.7 Hz, 2H), 6.55 (d, J=7.8 Hz, 1H), 4.15 (s, 2H), 3.48-3.53 (m, 3H), 2.93 (d, J=11.6 Hz, 2H), 2.89 (s, 3H), 2.76 (d, J=7.4 Hz, 2H), 1.99 (m, 2H), 1.44-1.49 (m, 3H), 0.65 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 498.0 [M+1]+.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([NH2:25])[C:17]=2[N:16]=[C:15]1[CH2:26][O:27][CH2:28][CH3:29]>>[NH2:25][C:18]1[C:17]2[N:16]=[C:15]([CH2:26][O:27][CH2:28][CH3:29])[N:14]([CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:22]=2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Reactant: O=C(Cl)N1CCOCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)N1CCOCC1

Procedure:
Using the method of Examples 94-105, 4-morpholinecarbonyl chloride was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 391.2465.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6](B(O)O)[CH:7]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1>O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 200 °C
Yield: 80 %

Procedure:
A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8](OS(C)(=O)=O)[CH2:9][CH:3]1[CH2:4][CH2:5]2.C([O:17][C:18]([S-:20])=[S:19])C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C@@H:3]2[CH2:9][CH:8]([S:19][C:18]([SH:20])=[O:17])[CH2:7][C@H:6]1[CH2:5][CH2:4]2
Reactant: CN1C2CCC1CC(OS(C)(=O)=O)C2
Reactant: CCOC(=S)[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC[C@H]1CC(SC(=O)S)C2
Reaction time: 2 h

Procedure:
Tropine-3-mesylate (243.6 g, 1.11 mol) and sodium ethylxanthate (245.1 g, 1.70 mol) were added to stirred toluene (1.25 L) at 36° C. under nitrogen. The mixture was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h). The oilbath was removed and water (500 mL) added. After 2 h stirring the mixture was filtered and the phases separated. The toluene phase was washed with deionised water (1×500 mL, 1×300 mL). The yield was found to be 192.36 g, 70.6%, based on 14.42% w/w in solution, by LC analysis against a reference standard. The solution was stored at 4° C. prior to use in Step 4a.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](N(OC)C)=[O:20]>C1COCC1>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9])=[O:20]
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CON(C)C(=O)CCCCl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(CCCCl)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF)(133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=1)=[O:19])C>>[Cl:30][C:25]1[CH:24]=[C:23]([CH:21]2[CH2:22][CH:20]2[C:18]([OH:19])=[O:17])[CH:28]=[CH:27][C:26]=1[O:29][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCCC3)n2)c(Cl)c1
Yield: 64.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (42 mg, 0.18 mmol) obtained in Step C of Preparation Example 27 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (49 mg, 0.20 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (47 mg, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:10]=1.[CH3:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH2:33]>C(OCC)(=O)C.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:32]([CH3:33])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:14]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reactant: C=C(C)c1ccccc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3cc(C(C)(C)c4ccccc4)c(O)cc3O)n2)c(C)c1
Temperature: 175 °C
Yield: 67.7 %

Procedure:
To a 1 L three-necked, round-bottomed flask equipped with a magnetic stirrer, condenser, dropping funnel, thermometer, and a nitrogen atmosphere are charged 15.0 g (37.8 mmol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-(2,4-dimethylphenyl)-s-triazine and 390 mg of aluminum isopropoxide. The mixture is heated to 175° C. and 4.47 g (37.9 mmol) of α-methylstyrene are added dropwise at a rate of one drop every two seconds. A total of six equivalents of a-methyl styrene are added in this fashion over a 4.5 hour period. After cooling to room temperature, the mixture is diluted with ethyl acetate, washed twice with water and once with brine, and is dried over anhydrous magnesium sulfate. Following filtration, the solvent is removed under reduced pressure to yield a yellow solid. The crude product is purified with medium pressure chromatography with 12% ethyl acetate/heptane to afford 13.2 g of the title compound as a yellow solid; mp 168°-170° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)Oc1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (171 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (278 mg, 61%).
Reaction SMILES: [C:1]([O:6][C@H:7]([C:9]1[N:14]=[C:13](O)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)Cl>[C:1]([O:6][C@H:7]([C:9]1[N:14]=[C:13]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C1CNCCN1
Reactant: CCCC(=O)O[C@@H](C)c1nccc(O)n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@@H](C)c1nccc(N2CCNCC2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To an ice cold solution of 1-(S)-(4-hydroxy-pyrimidin-2-yl)-ethyl butyrate (0.42 g, 2.0 mmol) and triethylamine (0.20 g, 2.2 mmol) in methylene chloride (10 mL) was added mesyl chloride (0.25 g, 2.1 mmol) dropwise and stirred for 1.5 h. The mixture was washed successively with saturated bicarbonate and water, and the organic layer dried over anhydrous magnesium sulfate. It was, filtered and evaporated to give 1-(S)-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl as an oil. The oil was dissolved in tetahydrofuran (10 mL), and to the solution was added piperazine (0.69 g, 8.0 mmol) and stirred at ambient temperature for 4 hr. The mixture was filtered and the filtrate was concentrated to obtain a crude product which was purified by flash chromatography (9:1 methylene chloride/methanol) to give the title compound as a oil 0.50 g (90%). 1H NMR (CDCl3, 300 MHz) δ0.95 (t, 3H), 1.51 (d, 3H) 1.68 (m, 2), 2.66 (t, 2H), 2.83 (m, 4H), 3.63 (m, 4H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (Cl) 251 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[Br:24][C:25]1[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=1>>[Br:24][C:25]1[N:30]=[C:29]([C:31]2[NH:21][C:3]3[C:2]([N:1]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:15])[CH2:9]2)=[CH:5][CH:4]=3)[CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Product: O=C([C@@H]1CCCN(c2ccc3[nH]c(-c4cccc(Br)n4)nc3n2)C1)N1CCCC1

Procedure:
(R)-(1-(2-(6-Bromopyridin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone was prepared using a method analogous to the one used for Example 112, but using (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone and 6-bromopicolinaldehyde as starting materials. MS (ES+APCI) (M+H) 455.0; LCMS retention time 3.238 min (Method C1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:45])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][S:41]([CH3:44])(=[O:43])=[O:42])OC5C=CC=CC=5)[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:47]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:45])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[NH:47])[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: CS(=O)(=O)NC(=N)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phenyl 4-[2-[4-(3-bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-(methylsulfonyl)-1-piperidinecarboximidate (Formula 22.0, prepare as described in Example 21 above) is dissolved in 2-propanol and concentrated ammonium hydroxide is added. The mixture is stirred at 25° C. for 24 h and then is evaporated to dryness. The residue is triturated with diethyl ether (2×250 ml) and the ether is discarded. The remaining product is chromatographed on a silica gel column to give the title compound (Formula 23.0).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]3[CH2:42][CH2:43]3)=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (311 mg, 77%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][NH:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:17][C:18]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CN1CCOCC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:11]3[C:24]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([Cl:17])[CH:25]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC1(C)CNC(c2ccc3c(c2)OCO3)C1
Solvent: CN1CCOCC1
Product: CC1(C)CC(c2ccc3c(c2)OCO3)N(c2ccc(C#N)c(Cl)c2)C1
Yield: 36.3 %

Procedure:
Combine 2-(1,3-benzodioxol-5-yl)-4,4-dimethylpyrrolidine (338 mg, 1.54 mmol) with 2-chloro-4-fluorobenzonitrile (216 mg, 1.39 mmol) and N-methylmorpholine (0.169 mL, 1.54 mmol) and then heat to 100° C. in a microwave for 1 h. Purify by flash chromatography (12 g RediSep silica gel columns, 0:100 to 90:10 gradient of [cyclohexane: ethylacetate] then repeat using (12 g RediSep silica gel columns, 0:100 to 97:3 gradient of [cyclohexane: ethylacetate] to provide 179 mg (36%) of the title compound. MS: 355 [M Cl35+H]+ and 377 [M Cl35+Na]+; 1H NMR (300 MHz, CDCl3): δ 7.28-7.30 (m, 1H), 6.72-6.76 (m, 1H), 6.61-6.67 (m, 1H), 6.58 (s, 1H), 6.51 (s, 1H), 6.28-6.31 (m, 1H), 5.92-5.95 (m, 2H), 4.68-4.72 (m, 1H), 3.48-3.50 (m, 1H), 3.30-3.35 (m, 1H), 2.20-2.30 (1H, m), 1.75-1.81 (1H, m), 1.18 (s, 3H) and 1.09 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][O:10][CH3:11])[N:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:23][C:22]=2[F:32])=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[F:32][C:22]1[CH:23]=[C:24]([C:28]([OH:31])([CH3:30])[CH3:29])[CH:25]=[C:26]([F:27])[C:21]=1[C:15]1[S:14][C:13]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][O:10][CH3:11])[N:3]=2)=[C:17]([C:18]([NH2:20])=[O:19])[CH:16]=1
Reactant: COCCc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: COCCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-bromo-6-(2-methoxyethyl)pyridine (42 mg, 0.19 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.19 mmol) as the starting materials.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:15][C:4]([C:5]=2[C:6]=34)=[CH:3][CH:2]=1.[Br:16]Br.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:16][C:2]1[CH:3]=[C:4]2[CH2:15][C:7]3[C:6]4[C:5]2=[C:14]([CH2:13][CH2:12][C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:1]=1
Reactant: BrBr
Reactant: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1cc2c3c(c1)Cc1cccc(c1-3)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
8.5 g (44.2 mmol) of 8,9-dihydro-4H-cyclopenta[def]phenanthrene was dissolved in 80 ml of CCl4, and 7.1 g (44.2 mmol) of Br2 was then slowly added thereto at 0° C. The reaction solution was stirred at room temperature for 4 hours and a 10% Na2SO3 solution was added thereto to separate the organic layer. The obtained organic layer was dried with magnesium sulfate, the solvent was evaporated therefrom, and the resultant product was recrystallized with n-hexane. As a result, 9.6 g of the target material was obtained (yield: 80%). The obtained compound was confirmed by LC-MS.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][C:7]1=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:25]1[N:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN1C(=O)CCC1.CO>[F:17][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:25]3[C:26]([C:27]#[N:28])=[CH:29][CH:30]=[CH:31][N:32]=3)=[CH:14][C:9]=2[S:8][C:7]1=[O:16]
Reactant: N#Cc1cccnc1F
Reactant: O=c1sc2cc(O)ccc2n1CC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: N#Cc1cccnc1Oc1ccc2c(c1)sc(=O)n2CC1CC1(F)F
Temperature: 100 °C

Procedure:
To a solution of 3-[(2,2-difluorocyclopropyl)methyl]-6-hydroxy-1,3-benzothiazol-2(3H)-one (18-2) (0.033 g, 0.13 mmol) in anhydrous NMP (1 mL) was added cesium carbonate (0.084 g, 0.26 mmol) and 2-fluoronicotinonitrile (0.024 g, 0.19 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol and NMP, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 2-[(3-{[2,2-difluorocyclopropyl]methyl}-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)oxy]pyridine-3-carbonitrile (18-3) as an off-white solid. HRMS (M+H)+: observed=360.0623, calculated=360.0613.