Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[N:41]1([C:1]([O:2][C@@H:3]2[CH2:19][C@@H:18]3[C@@:6]([CH3:29])([C@@H:7]4[C@@H:15]([CH2:16][CH2:17]3)[C@:14]3([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]5[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=5)[CH2:12][CH2:13]3)[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)=[O:30])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: C1CNCCN1
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)N3CCNCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 69.1 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CH2Cl2 was added piperazine (46.4 mg, 0.54 mmol). The resultant mixture was stirred at rt for 16 h and then purified via preparative TLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (18.6 mg, 69.2%) as a white solid. LRMS (M+H+) m/z 499.5. 1H NMR (CD3OD, 400 MHz) δ 7.90 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.89 (m, 1H), 3.41 (m, 4H), 2.77-2.80 (m, 4H), 2.44-2.48 (m, 1H), 1.08-2.15 (m, 21H), 0.88 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:44])[CH3:43].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:42](=[O:44])[CH3:43])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: CC(=O)Cl
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(N)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(NC(C)=O)c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-amine (115 mg, 0.261 mmol) was taken up in THF (2.6 ml) and cooled to 0° C. DIPEA (228 μl, 1.304 mmol) followed by acetyl chloride (93 μl, 1.304 mmol) was added. The mixture was allowed to stir, reaching room temperature overnight. EtOAc and saturated NH4Cl were added. The products were extracted into EtOAc (3×). The combined organic layers were washed with brine, dried over Mg SO4, and concentrated in vacuo to give N-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)acetamide (48B). Reaction products were carrried forward without purification. MS: [M+H]+ m/z 483.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12]([C:13]2([CH3:17])[CH3:16])=[CH:11][C:10](=[O:18])[CH:9]=[CH:8]3)=[CH:4][CH:3]=1.[S:19]([NH:29][C@H:30]([C:32](Cl)=[O:33])[CH3:31])([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].N1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[S:19]([NH:29][C@H:30]([C:32]([O:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12]([C:13]2([CH3:16])[CH3:17])=[CH:11][C:10](=[O:18])[CH:9]=[CH:8]3)=[CH:4][CH:3]=1)=[O:33])[CH3:31])([C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=1)(=[O:20])=[O:21]
Reactant: CC1(C)C2=CC(=O)C=CC2=Nc2ccc(O)cc21
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Oc2ccc3c(c2)C(C)(C)C2=CC(=O)C=CC2=N3)cc1
Temperature: 25 °C

Procedure:
A solution of the dimethyl chromogen (20) prepared according to Example 2 (38 mg; 0.16 mmol) in anhydrous tetrahydrofuran (3.2 mL) was stirred at ambient temperature and treated portionwise, over 1.5 hours, with N-tosyl-L-alaninyl chloride (35) from step (a) of the present example (243 mg; 0.93 mmol) and anhydrous pyridine (280 μL) while maintaining an inert gas atmosphere over the reaction. Once the addition was complete, the reaction was stirred for an additional hour then blended into ethyl acetate (50 mL) and then extracted twice with aqueous 1 N citric acid (10 mL @). The combined aqueous extracts were washed once with ethyl acetate (10 mL) and the combined ethyl acetate layers were extracted thrice with 5% aqueous NaHCO3 (10 mL each). The combined NaHCO3 extracts were washed once with ethyl acetate (10 mL) then the combined ethyl acetate layers were washed once with brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness in vacuo to give an orange viscous oil (110 mg). This was chromatographed on silica gel (50 g) using acetone/CHCl3 (9) solvent. The yellow major product band (Rf =0.32) was collected and evaporated to dryness in vacuo to obtain 7-(N-tosyl-L-alaninyloxy)-9,9-dimethyl-9H-acridin-2-one (36) (40 mg; 54%) in the form of a yellow glass.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.CN([CH:38]=[O:39])C.[BH4-].[Na+]>C1COCC1.CO.C(Cl)Cl>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[O:18])=[CH:3][C:2]=1[CH2:38][OH:39]
Reactant: CN(C)C=O
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2D, 100 mg, 0.210 mmol) in THF (2 ml) at −78° C. under argon was treated drop wise with n-BuLi (1.5 M in hexane, 0.309 ml, 0.463 mmol). The resulting brown solution was stirred for 2 min and then DMF (0.1 ml, 1.29 mmol) was added. The resulting yellow solution was stirred at −78° C. for 15 min. The reaction mixture was quenched by addition of sat. aq. NH4Cl, warmed to room temperature and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the 7-(dimethoxymethyl)-6-formyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated to give a white solid. This material was dissolved in MeOH (2 ml) and DCM (1 ml), treated at room temperature with NaBH4 (6.36 mg, 0.168 mmol) and stirred for 0.5 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 1) tR 1.10 min; ESI-MS 421.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:24])=O>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2[Cl:24])([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(O)c2c1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(Cl)c2c1
Temperature: 110 °C
Yield: 84 %

Procedure:
6-Nitro-2-(3-fluoro-phenyl)-quinolin-4-ol, 5.2 g (16.3 mmoles), was placed in a 500 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet. To this was added 15.2 mL (25.0 g, 163 mmoles, 10 equiv.) of phosphorus oxychloride with stirring. The mixture was heated to 110° C. for 4 hr. At the end of this time the reaction was cooled to room temperature and water was cautiously added dropwise until all of the POCl3 was consumed. The product crystallised from the water and solids were collected by filtration. The solids were washed with water, placed in a 250 mL Erlenmeyer and triturated with water. After collection by filtration, washing with water, and drying in a vacuum oven, 4.6 g (84%) of the product was obtained.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Temperature: 80 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of intermediate 47, 2-azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (660 mg, 2.6 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was added triphenylphosphine (740 mg, 2.8 mmol), and the mixture stirred under nitrogen for 1 hr. The tetrahydrofuran was evaporated in vacuo and a mixture of the residue and 6N HCl (3 mL) in MeOH (5 mL) was heated at 80° C. for 20 hrs. This was washed with CH2Cl2, and the aqueous phase basified with dilute NH4OH and extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered and concentrated to provide 210 mg (0.91 mmol, Yield 35%) of the title compound; 1H NMR (500 MHz, CDCl3) δ ppm: 2.84 (6 H, s) 4.10 (2 H, s) 7.23-7.29 (1 H, m) 7.53-7.60 (2 H, m); LC/MS m/z 233 (M+H).
Reaction SMILES: I[C:2]1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=C[CH:3]=1.C(OC(=O)N[C@H](C1NC(C2C=CC=CC=2F)=CN=1)[C@H](C1C=CC=CC=1)C)(C)(C)C.C(OC(N[C@H](C1C=CC(OCC(=O)N(C)C)=CC=1)C(O)=O)=O)(C)(C)C.ClN1C(=O)CCC1=O.BrC1C=CC(C(=O)C)=C(Cl)C=1.[Br:102][C:103]1[CH:111]=[CH:110][C:106]([C:107]([OH:109])=O)=[CH:105][C:104]=1[F:112]>>[Br:102][C:103]1[CH:111]=[CH:110][C:106]([C:107](=[O:109])[CH2:2][CH3:3])=[CH:105][C:104]=1[F:112]
Reactant: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CC(=O)c1ccc(Br)cc1Cl
Agent: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccccc2F)[nH]1
Product: CCC(=O)c1ccc(Br)c(F)c1

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) 1-(4-bromo-3-fluoro-phenyl)-propan-1-one was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 21-D; (iii) (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 21-E; and (iv) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 21-F was omitted. 1-(4-Bromo-3-fluoro-phenyl)-propan-1-one was prepared as described in example 6 for the preparation of 1-(4-bromo-2-chloro-phenyl)-ethanone except that 4-bromo-3-fluorobenzoic acid was used in place of 4-bromo-2-chlorobenzoic acid in step 21-I. HR-MS: calcd for C28H24BrFN4O4 [M+H+] 579.1038. Found 579.1038.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH:11](=[O:13])[CH3:12].[OH-].[K+].C(OC(=O)C)(=O)C.Cl.O>CO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:12]/[CH:11]=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC=O
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 5 °C
Yield: 48 %

Procedure:
A mixture of 3,4-dichlorobenzaldehyde (140.0 g, 0.8 mol) and acetaldehyde (300 mL) was cooled to 5° C. Potassium hydroxide (5.1 g, 0.091 mol) was dissolved in hot MeOH (40 mL), and the resulting solution was added to the above cooled mixture while maintaining the internal temperature at 25° C. to 30° C. The mixture was allowed to stir in ice-H2O bath for 40 minutes and then treated with acetic anhydride (400 mL). After the addition, the mixture was heated to 100° C. with string for 30 minutes and then cooled to 30° C. To this mixture, 12N HCl/H2O (102 mL/1.2 L) was added, and the resulting mixture was heated to reflux for 30 minutes and then cooled to room temperature. This heterogeneous mixture was filtered and washed with H2O to afford a brown solid. The crude product was dissolved in EtOAc and washed with H2O, dried Na2SO4), and concentrated to dryness. Recrystallization from hexane/EtOAc (9:1) yielded 76.5 g (0.38 mol, 48%) of the title compound. mp: 91-93° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][C:6]1[N:7]([CH3:16])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])C.S(=O)(=O)(O)O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.ClC(Cl)C.O1CCOCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C.O.ClCCl.C([O-])(O)=O.[Na+]>[CH3:16][N:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]1[CH2:5][CH2:4][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccn(C)c1CC(OCC)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1ccn(C)c1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.8 g of the compound obtained in Step C (14.05 mmol) in 28 mL of tetrahydrofuran there are added 58 mL of aqueous 10% sulphuric acid solution. The reaction mixture is stirred at ambient temperature for 2 hours and then diluted with a mixture of ethyl acetate and water. After separation, the organic phase is washed with brine, dried over MgSO4 and concentrated to dryness. To a solution of the residue thereby obtained in 70 mL of dichloroethane there are added a solution of 13.5 mL of morpholine (14.5 mmol) in a mixture composed of 30 mL of dichloroethane and 3.6 mL of 4N aqueous HCL solution in dioxane (14.5 mmol), and then 7.4 g of sodium triacetoxyborohydride (NaBH(OAc)3) (35.13 mmol). The reaction mixture is stirred at ambient temperature for 3 hours and then diluted with a mixture of dichloromethane and saturated aqueous NaHCO3 solution. After separation of the phases and extraction of the aqueous phase with dichloromethane, the organic phases are dried over MgSO4 and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel using dichloromethane and methanol as eluants. The title product is isolated in the form of an oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:25]4[CH2:26][CH2:27][CH2:28][C:23](=[O:29])[CH2:24]4)[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: O=C1C=CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCCC(=O)C4)c3)ncnc21
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (309 mg, 0.980 mmol) in ACN (6 mL) was added 2-cyclohexen-1-one (190 μL, 01.96 mmol), followed by DBU (40 μL, 0.3 mmol). The resulting mixture was stirred for one hour at which point LCMS indicated complete addition. The mixture was reduced in vacuo and the crude product was purified by column chromatography to obtain the product (397 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.45 (d, 1H), 6.79 (d, 1H), 5.67 (s, 2H), 4.61 (m, 1H), 3.55 (m, 2H), 3.05-2.90 (m, 2H), 2.45-2.30 (m, 4H), 2.05 (m, 1H), 1.90 (m, 1H), 0.92 (m, 2H), −0.06 (s, 9H). MS (EI) m/z=412.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([CH:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:33][CH:34]=4)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(NCc5cccnc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-[3-({2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyridin-2-yl]-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (47.0 mg, 0.247 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.061 g, 57%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (dd, J=4.7, 1.5 Hz, 1H), 7.87-7.80 (m, 2H), 7.50 (d, J=8.5 Hz, 2H), 7.29-7.25 (m, 1H), 7.20 (d, J=8.5 Hz, 2H), 6.69-6.62 (m, 2H), 6.30 (d, J=7.6 Hz, 1H), 5.29 (t, 5.8 Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 3.32 (s, 3H), 3.09 (s, 3H), 3.01-2.94 (m, 2H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 3.10-2.00 (m, 2H), 1.87-1.73 (m, 4H). MS=521 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: N#Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccsc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
A mixture of bis(benzonitrile)palladium(II) chloride (30 mg, 0.079 mmol) and 1,4-bis(diphenylphosphino)butane (33.6 mg, 0.079 mmol) in toluene (3 mL) was stirred at room temperature for 20 min. To this mixture was added 6-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (300 mg, 0.79 mmol, Synth. Commun. 1995, 25, 3255), thiophene-3-boronic acid (131 mg, 1.02 mmol), 1 M aqueous sodium carbonate (1.57 mL, 1.57 mmol), and ethanol (2 mL). This dark mixture was heated to reflux with stirring under nitrogen overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered through Celite, evaporated, and purified by flash column chromatography (hexanes→5% ethyl acetate/hexanes) to give 252 mg (100%) of the title compound of Example 248, Step A as a pale yellow waxy solid. 1H NMR (CDCl3, 250 MHz) δ 7.47-7.38 (c, 5H), 7.14 (d, 1H), 4.60 (s, 2H), 3.72-3.64 (c, 2H), 2.95-2.82 (c, 2H), 1.52 (s, 9H); MS (TS) 316 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8](OCC)=[O:9].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][OH:9]
Reactant: CCOC(=O)c1cnn(C)c1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1ncc(CO)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (2.00 g, 8.58 mmol) in tetrahydrofuran (30 mL) at 0° C. was treated with diisobutylaluminum hydride (1 M solution in tetrahydrofuran, 18.9 mL, 18.9 mmol), and the mixture was allowed to warm to room temperature and stir for 18 hours. Saturated aqueous sodium potassium tartrate solution was added, and stirring was continued for 4 hours. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Eluent: 100:1 ethyl acetate/methanol) afforded the product. Yield: 1.63 g, 8.53 mmol, 99%. LCMS m/z 192.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 1H), 3.84 (s, 3H), 4.48 (s, 2H), 7.51 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1.N1CCCCC1.CC(O)=O>C(Cl)Cl>[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(Cc1ccncc1)C(C)=O
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Ethyl acetoacetate (5.20 g), piridine-4-aldehyde (4.28 g), piperidine (0.4 ml) and AcOH (0.24 ml) are mixed in CH2Cl2 (150 ml) at room temperature under nitrogen atmosphere. The reaction mixture is stirred overnight and the solvent is removed. The residue is dissolved in EtOH (150 ml). 10% Pd/C (1.0 g) is added and reaction mixture is stirred at room temperature under hydrogen for 7 hours. Concentration under reduced pressure after Celite® filtration afford Ethyl 2-(4-piridylmethyl)acetoacetate (8.0 g) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].F[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=1[N+:33]([O-:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(Cl)(Cl)Cl.O>[Br:1][C:2]1[C:3]([O:18][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[CH:22][C:21]=2[N+:33]([O-:35])=[O:34])=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(O)c2Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a stirred solution of ethyl 8-bromo-6-chloro-7-hydroxychroman-4-carboxylate (4.00 g, 11.9 mmol) and tert-butyl 4-fluoro-3-nitrobenzoate (3.16 g, 13.1 mmol) in N,N-dimethylformamide (66 mL) at ambient temperature was added solid potassium carbonate (2.64 g, 19.1 mmol). The resulting mixture was stirred in an oil bath set to 90° C. for 30 minutes. The mixture was cooled to ambient temperature and poured into a separatory funnel containing water (600 mL). Chloroform (300 mL) was added, followed by 1M hydrochloric acid (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 hexanes/ethyl acetate to afford ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate as a light yellow glass (4.33 g, 65% yield).