Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[N+:5]([O-:8])(O)=[O:6].[CH3:9][C:10]1([CH3:22])[CH2:14][C:13]2[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:12]=2[O:11]1>C(OC(=O)C)(=O)C>[CH3:9][C:10]1([CH3:22])[CH2:14][C:13]2[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]([CH3:19])=[C:18]([N+:5]([O-:8])=[O:6])[C:12]=2[O:11]1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2c(c(C)c1C)CC(C)(C)O2
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c([N+](=O)[O-])c1C)OC(C)(C)C2
Yield: 9.8 %

Procedure:
The mixed solution of acetic anhydride (5 ml) and acetic acid (5 ml) was cooled and nitric acid (5 ml) was added cautiously with stirring. Then, a solution of 2,2,4,5,6-pentamethyl-2,3-dihydrobenzofuran (2.9 g, 13.9 mmol) in acetic anhydride (5 ml) was added dropwise and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water and the product was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 9:1) and crystallized from methanol to obtain the desired compound (0.35 g, yield: 9.8% yield), m.p. 100°-101° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:19]([N:18]([C:26]1[N:31]=[CH:30][C:29]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][N:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCCCC2)cn1

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and piperidine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:14]=1[O:15]C1N=CC=C2C=CNC=12>>[Br:1][C:2]1[C:3]([O:15][C:14]2[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:13]=2[F:12])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2ccsc12
Reactant: O=[N+]([O-])c1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Yield: 61 %

Procedure:
Starting from the compound 271 and following the procedure described above for the synthesis of compound 260 (scheme 59, example 218, step 2), title compound 272 was obtained in 61% yield as an off-white solid. MS (m/z): 368.9(M+H).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:12][C:11]([C:13]2[C:14](=[O:24])[O:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([OH:23])[CH:17]=3)=[N:10][C:9]=1[CH3:25])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)C>ClCCl>[OH:23][C:18]1[CH:17]=[C:16]2[C:21]([CH:22]=[C:13]([C:11]3[S:12][C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH3:25])[N:10]=3)[C:14](=[O:24])[O:15]2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2cc3ccc(O)cc3oc2=O)sc1C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2cc3ccc(O)cc3oc2=O)sc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a suspension of 2-(7-hydroxy-2-oxo-2H-chromen-3-yl)-4-methyl-thiazole-5-carboxylic acid tert-butyl ester (387 mg, 1.08 mmol) and anisole (117 μL, 117 mg, 1.08 mmol) in anhydrous dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the obtained solution was stirred at room temperature for 6 h. Diethyl ether (30 mL) was added, the precipitate was collected, washed with diethyl ether and dried in air. In this manner the title compound (285 mg, 0.94 mmol, 87%) was obtained as a light brown solid.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:9](=[O:22])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:11]=[CH:12][C:13]=2Cl)=[CH:3][CH:2]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([C:13]1[CH:12]=[N:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9](=[O:22])[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:2][CH:3]=1)=[N+:30]=[N-:31]
Reactant: O=c1c(Oc2ccc(-c3ccccc3)cc2)c(Cl)cnn1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1cnn(-c2ccc(Cl)cc2)c(=O)c1Oc1ccc(-c2ccccc2)cc1

Procedure:
Obtainable by general method 13 from 2.05 g (5.0 mmol) of the compound from Example 9A with 1.63 g (25.0 mmol) of sodium azide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 263.2 %

Procedure:
To a solution of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.00053 mole), in DMF (5 mL) was added, NaH (60% w/w dispersion in oil) (0.0696 g, 0.0029 mole) and the resulting mixture was stirred at ambient temperature for 10 minutes under an atmosphere of nitrogen. Methyl iodide (0.617 g, 0.00435 mole) was then added, and stirring was continued for 30 minutes at ambient temperature. The reaction mixture was quenched with aqueous 10% NH4Cl solution and the product was extracted with ether. The organic layer was washed with aqueous NaHCO3 solution followed by brine solution. The ether layer was then collected, dried over sodium sulfate and concentrated under reduced pressure to afford 0.5 g of 4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester that which was used in the next step without further purification. 4-[Methyl-(2-trifluoromethyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester obtained (0.5 g) was stirred in dioxane.HCl (5 mL) for 30 minutes. The reaction mixture was concentrated under reduced pressure to afford 0.36 g (88%) of methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([S:22][C@H:23]1[N:26]([CH:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])Cl)[C:25](=[O:42])[C@@H:24]1[C@H:43]([O:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:47])[CH3:44])=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:59]1[CH:64]=[CH:63][C:62]([P:65]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:61][CH:60]=1>C1COCC1>[Si:1]([O:18][CH2:19][C:20]([S:22][C@H:23]1[N:26]([C:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])=[P:65]([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:62]2[CH:61]=[CH:60][CH:59]=[CH:64][CH:63]=2)[C:25](=[O:42])[C@@H:24]1[C@H:43]([O:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:47])[CH3:44])=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
A solution in THF of 4(R)-t-butyldiphenylsilyoxyacetylthio-3(S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl]-1-(1-p-nitrobenzyloxycarbonyl-1-chloromethyl)-azetidin-2-one, obtained from the previous example, was treated with Ph3P (2.2 g, 8.5 mmole) and silica gel (20 g).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[N:12]=[CH:11][C:10](O)=[CH:9][N:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:9][N:8]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: OCC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ncc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of cyclopropylmethanol (276 mg), 2-chloropyrimidin-5-ol (500 mg) and triphenylphosphine (1.51 g) in toluene (20 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (659 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.21-0.49 (2H, m), 0.49-0.69 (2H, m), 1.07-1.46 (1H, m), 4.00 (2H, d, J=7.2 Hz), 8.53 (2H, s).
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:21][C:22]1[C:23](Cl)=[C:24]([C:30](=[O:37])[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:25]([CH3:29])=[N:26][C:27]=1[CH3:28]>CC#N.CCOCC>[Br:21][C:22]1[C:23]([N:7]2[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]2)=[C:24]([C:30](=[O:37])[C:31]([O:33][CH:34]([CH3:35])[CH3:36])=[O:32])[C:25]([CH3:29])=[N:26][C:27]=1[CH3:28]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C(F)(F)F)CC2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.6 %

Procedure:
To a solution of 4-(trifluoromethyl)piperidine HCl (1.7 g, 8.97 mmol) and DIEA (3.13 mL, 17.9 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.0 g, 8.97 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.9 g (71%). 1H NMR (500 MHz, CDCl3) δ 5.25-5.20 (m, 1H), 3.54-3.51 (m, 2H), 3.15 (dt, J=12.5, 2.0 Hz, 2H), 2.87 (s, 3H), 2.57 (s, 3H), 2.30-2.23 (m, 1H), 2.02-1.99 (m, 2H), 1.79 (dq, J=12.4, 4.1 Hz, 2H) 1.43 (d, J=6.2 Hz, 6H). UPLC (M+H)=453.2.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[NH:18]1[CH2:19][CH2:20][CH2:21][C@H:16]([N:15]2[C:7]3=[C:8]4[S:14][CH:13]=[CH:12][C:9]4=[N:10][CH:11]=[C:6]3[N:5]=[C:4]2[C@H:2]([OH:1])[CH3:3])[CH2:17]1
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3S)-3-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate (0.25 g, 0.62 mmol) in methylene chloride (3.5 mL) was added 4.0 M hydrogen chloride in 1,4-dioxane (1.2 mL, 5.0 mmol). A precipitate immediately formed. The reaction was stirred at room temperature for 2 h. The solvents were evaporated and the solids dried in vacuo to give 0.21 g of the product as the HCl salt. LCMS calculated for C15H19N4OS (M+H)+: m/z=303.1. Found: 303.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[NH:8][N:7]=[C:6]2[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1n[nH]c2cc(F)ccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1n[nH]c2cc(F)c(Br)cc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
A mixture of 6-fluoro-1H-indazole-3-carboxylic acid (4.95 g, 23.8 mmol) and acetic acid (50 mL) was treated with bromine (2.0 mL, 38 mmol) dropwise at room temperature. The reaction mixture was heated to 90° C. and stirred for 16 hours under an atmosphere of nitrogen. The reaction mixture was then exposed to the atmosphere and stirred at 95° C. for 72 hours. The resulting solids were collected while the reaction mixture was still hot and rinsed with diethyl ether two times. The solids were dried at 50° C. under reduced pressure to give the title compound (2.89 g). 1H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J=6.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15]Br)[CH:5]=1.CC([O-])=[O:21].[K+].CO>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][OH:21])[CH:5]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cccc(-c2nc(C)sc2CBr)c1
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(C)sc2CO)c1
Reaction time: 0.5 h

Procedure:
3-(5-bromomethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester was stirred in DMF (16 mL) together with KOAc (2.35 g) at 20° C. for 20 min. MeOH (32 mL) and naOMe (0.86 g) were added and stirring was continued at 50° C. for 30 min. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt/hexane (1:1) as eluent to give 3-(5-hydroxymethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester (2.93 g) as a white solid.
Reaction SMILES: O=C1N2C[C@@H](CC[C@H]2C([NH:12][O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)=O)N1OS(O)(=O)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:12][O:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC[C@@H](ON)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a mixture of tert-butyl (3S)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 10 (0.11 g, 0.24 mmol) in DCM (4.0 mL) was added trifluoroacetic acid (0.20 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 2 (Table 1)(30.4 mg, 36%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[N:40]1[CH:45]=[CH:44][C:43]([C@@H:46]([NH2:48])[CH3:47])=[CH:42][CH:41]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Na+].[Cl-]>CN(C=O)C>[O:16]=[C:15]1[N:14]2[C@@H:10]([CH2:11][CH2:12][CH2:13]2)[C:9]2[N:17]=[C:18]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:31]3[CH:39]=[CH:38][C:34]([C:35]([NH:48][C@H:46]([C:43]4[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=4)[CH3:47])=[O:37])=[CH:33][CH:32]=3)[C:8]1=2
Reactant: C[C@H](N)c1ccncc1
Reactant: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1ccc(C(=O)N[C@@H](C)c3ccncc3)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 14 h
Yield: 48 %

Procedure:
4-((9aS)-3-(Ethoxycarbonyl)-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl)benzoic acid (0.264 g, 0.491 mmol) was dissolved in 1 mL DMF. (1S)-1-(4-Pyridinyl)ethylamine (0.090 g, 0.736 mmol; prepared identically to its enantiomer, but starting with (R) α-methyl-1(4-pyridyl)methanol) was added followed by PyBOP (0.383 mg, 0.736 mmol). After 14 h, the reaction mixture was added to half-saturated NaCl solution and extracted with EtOAc (3×). The combined organic layers were washed with pH 4.0 phosphate buffer (2×), 5% NaHCO3, and brine and dried over Na2SO4. Purification on SiO2 (hexanes:EtOAc 20:80 to 0:100 to) provided the title compound as a white solid (0.153 g, 0.238 mmol, 48%): mp=158–160° C. 1H NMR (300 MHz, CDCl3) δ 8.62 (d, J=5.7 Hz, 2H), 7.86 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.33 (d, J=5.5 Hz, 2H), 6.52 (d, J=7.5 Hz, 1H), 5.33 (m, 1H), 4.75 (dd, J=10.3, 6.3 Hz, 1H), 4.06 (m, 2H), 3.75 (m, 1H), 3.41 (m, 1H), 3.22 (m, 4H), 2.52 (m, 1H), 2.40 (m, 2H), 1.63 (d, J=7.0 Hz, 3H), 1.40 (m, 1H), 0.97 (t, J=7.1 Hz, 3H) ppm. ESMS m/z 643 (M+H)+. Anal. calcd. for C36H33F3N4O4.½H2O: C, 66.35; H, 5.26; N, 8.60; found: C, 66.35; H, 5.42; N, 8.79.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=5)[N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:31][S:32]([CH2:35][CH2:36][NH2:37])(=[O:34])=[O:33].Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][S:32]([CH2:35][CH2:36][NH:37][CH2:29][C:27]1[O:28][C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)=[N:16]3)=[CH:21][CH:22]=2)=[CH:25][CH:26]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)CCN
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(C=O)o5)n4n3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(CNCCS(C)(=O)=O)o5)n4n3)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Into an 8-dram vial, 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-furan-2-carbaldehyde (97.57 mg, 0.2424 mmol), 2-Methanesulfonyl-ethylamine; hydrochloride (0.2322 g, 1.454 mmol), 1,2-Dichloroethane (15.0 mL), and Acetic acid (100.0 uL, 1.759 mmol) were added and heated at 45° C. overnight. Sodium triacetoxyborohydride (0.1541 g, 0.7273 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded (7-{5-[(2-Methanesulfonyl-ethylamino)-methyl]-furan-2-yl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (45 mg, 36%). LCMS (E/I+) 510.08 (M+H). NMR 1H (DMSO-d6)-9.23 (s, 1H), 8.91 (s, 1H), 7.63 (d, 2H, J=8.69 Hz), 7.19 (d, 1H, J=3.02 Hz), 7.00 (d, 1H, J=4.57 Hz), 6.97 (d, 2H, J=9.42 Hz), 6.90 (d, 1H, J=5.03) Hz, 6.53 (d, 1H, J=3.66 Hz), 3.81 (s, 2H Hz) 3.25 (t, 2H, J=6.40 Hz), 3.10 (t, 4H, J=5.03 Hz), 3.02 (s, 3H), 2.97 (t, 2H, J=6.40 Hz), 2.49 (t, 4H, J=5.03), 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.BrC1C=CC([N+]([O-])=O)=CN=1.FC1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][N:44]1[C:52](=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]1=[O:54]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:42][CH2:43][N:44]2[C:45](=[O:54])[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]2=[O:53])=[CH:10][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Oc1ccc(-c2ccccc2F)nc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(Br)nc1
Agent: OB(O)c1ccccc1F
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg (2.64 mmol) of 6-(2-fluorophenyl)pyridin-3-ol (prepared from 2-bromo-5-nitropyridine and 2-fluorophenylboronic acid; the nitro group was converted into the hydroxy group according to the method described in WO 98/25920), 730.6 mg (5.28 mmol) of potassium carbonate and 738.6 mg (2.91 mmol) of 2-(2-bromoethyl)-isoindole-1,3-dione in 10 ml of DMF were stirred at room temperature for 4 h. The solvent was removed by evaporation and the residue treated with ethyl acetate and water. The organic layer was evaporated and the residue purified by chromatography. Yield: 189 mg.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:23])[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:24].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])[N:8]([CH3:23])[C:7]=2[C:2]=1[C:28]1[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1C
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(-c3ccncc3)c2n1C
Temperature: 140 °C
Yield: 18.8 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine, (0.10 g, 0.26 mmol), 4-pyridylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 45 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 433 as a white solid (0.019 g, 20%). LCMS (Method K): RT 2.10 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.70 (1H, s), 8.70 (2H, s), 8.25-8.13 (2H, m), 7.95 (1H, d), 7.71 (1H, dd, J=8.80, 4.80 Hz), 7.53 (2H, d, J=17.59 Hz), 7.17 (1H, dd, J=10.45, 8.79 Hz), 5.85-5.73 (1H, m), 3.30 (3H, s), 1.66 (3H, d, J=6.75 Hz). Signals split due to presence of tautomers