Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[S:22]([C:26]1[N:27]([CH2:31][C:32](Cl)=[O:33])[CH:28]=[CH:29][N:30]=1)([CH3:25])(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>O.[Na].CC(C)=O>[C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[CH2:14][S:15][C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1)[CH:2]([NH:1][C:32](=[O:33])[CH2:31][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[S:22]([CH3:25])(=[O:24])=[O:23])[C:9]2=[O:10])([OH:13])=[O:12]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CS(=O)(=O)c1nccn1CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3ccnc3S(C)(=O)=O)C2SC1
Temperature: 4 °C
Yield: 3.8 %

Procedure:
Acetone (200 cc.) is added to a solution of 7-amino-2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (18.4 g.) in water (110 cc.) and sodium bacarbonate (9.41 g). The mixture is cooled to about 4° C., and (2-mesyl-imidazol-1-yl)-acetyl chloride (12.4 g.) in acetone (50 cc.) is added dropwise while keeping the pH at 7 by adding a saturated aqueous solution of sodium bicarbonate. After having allowed reaction to take place for 1 hour, the acetone is removed under reduced pressure (20 mm.Hg). The pH is brought to 2.5 by adding 6 N hydrochloric acid; a solid precipitates. Ethyl acetate (100 cc.) is added, the mixture is stirred, and then the solid is filtered off and washed with ethyl acetate (500 cc.). The combined organic filtrates are dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm.Hg). A residue (8.7 g.) is obtained and is taken up in a saturated aqueous solution of sodium bicarbonate (100 cc.). The aqueous phase is washed with ethyl acetate (100 cc.) and then acidified to pH 5 by adding 6 N hydrochloric acid; a slight amount of insoluble matter is filtered off and then the filtrate is acidified to pH 2.5: a product precipitates. Extraction is effected using ethyl acetate (800 cc.), and the organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm.Hg). The residue is stirred with acetonitrile (40 cc.) and the solid formed is collected to yield 2-carboxy-7-[(2-mesyl-imidazol-1-yl)-acetamido] -3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene (1.08 g.), m.p. approx. 230° C., [α]D20 = -42°± 1 (c= 0.87, dimethylformamide).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1>CCOC(C)=O.CO.[Pd]>[N:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=[CH:12]3)=[N:7][CH:2]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc2cc(Oc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(2-chloropyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide (0.075 g, 0.17 mmol) in EtOAc (3 mL) and methanol (0.5 mL) was added 10% Pd/C (20 mg). The flask was capped with a septum, and H2 gas was introduced through a balloon/needle. Positive H2 pressure was continued as the reaction was stirred vigorously overnight at RT. The reaction was filtered through Celite, concentrated, and purified by chromatography on silica to afford the desired product as a white solid. MS (ESI, pos. ion) m/z: 410.1 (M+1). Mass Calc'd for C22H14F3N3O2: 409.36.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[F:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[CH2:14][CH2:15][C:16](=O)[CH3:17]>>[CH3:17][C:16](=[N:2][NH:1][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[CH2:15][CH2:14][C:13]1[CH:19]=[CH:20][CH:21]=[C:11]([F:10])[CH:12]=1
Reactant: NNc1cc[nH]c(=O)c1
Reactant: CC(=O)CCc1cccc(F)c1
Product: CC(CCc1cccc(F)c1)=NNc1cc[nH]c(=O)c1

Procedure:
In accordance with the same procedures as in Step 2 of Preparation 1, except for using 4-hydrazino-1H-pyridin-2-one (5.39 g, 43.1 mmol) prepared in Step 1 of Preparation 1 and 3-fluorobenzylacetone (9.82 ml, 65.1 mmol), the titled compound was obtained as a white solid. (Yield: 63.4%) The product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([OH:28])[CH2:4]1)[CH3:2].C([C@H]1[C@@H](C2N3C4C=CN(COCC[Si](C)(C)C)C=4N=CC3=NN=2)C[C@H](O)C1)C>>[CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](O)C[C@@H]1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: CC[C@@H]1C[C@@H](O)C[C@@H]1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Product: CCC1CC(=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12

Procedure:
A solution of 3-ethyl-4-((6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.296 g, 0.741 mmol) in THF (2.96 mL) was cooled to about 0° C. and to it was added DIBAL-H (1M in cyclohexane, 1.482 mL, 1.482 mmol). The reaction was stirred for about 45 min. The reaction was quenched with MeOH (3 mL). To the reaction mixture was added saturated aqueous NH4Cl (10 mL) and EtOAc (10 mL). The organic layer was collected and washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to provide the crude material. The crude material was purified by silica gel column chromatography using 0-5% MeOH/CH2Cl2 to provide a scalemic mixture enriched in (1S,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (148 mg, 0.369 mmol, 50%) and a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (60 mg, 0.149 mmol, 20%) both as amorphous solids. LC/MS (Table 1, Method a) Rt=2.37 min; MS m/z: 402 (M+H)+ and Rt=2.16 min; MS m/z: 402 (M+H)+ respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: Sc1ccc(Br)cn1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(SCC2CC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyridine-2-thiol (3.9 g) in THF (100 mL) was added NaH (1.24 g) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. Then (bromomethyl)cyclopropane (2.79 g) was added. The mixture was allowed to warm to r.t. and stirred for 6 hours. The mixture was poured into ice water (200 mL) and extracted with EA (100 mL×3). The combined organic phases were washed with brine (50 mL) and then dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by SGC (eluent: PE) to provide the subtitle compound. MS ESI+: m/z=244 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[F:21][C:22](I)([F:24])[F:23]>[Cu].CN(C)C=O>[F:21][C:22]([F:24])([F:23])[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(Br)c1
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 0.01 moles of ethyl 3-bromo-4-cyclohexylphenylglyoxylate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. The reaction is shaken in a sealed tube for 5 hours at 140°C, cooled, and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The ether extract is dried, evaporated to dryness and distilled to obtain ethyl 3-trifluoromethyl-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18]Cl.[C:21]1(=[O:27])[NH:25][C:24](=[O:26])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][N:25]1[C:21](=[O:27])[CH2:22][CH2:23][C:24]1=[O:26]
Reactant: O=C1CCC(=O)N1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN3C(=O)CCC3=O)c2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
The product from example 1 step (vii) (0.15 g) was dissolved in DMSO (2 mL) and succinimide (0.25 g) and potassium carbonate (0.07 g) was added. The reaction mixture stirred at 60° C. for 16 h. The reaction mixture was filtered through a filter disc and purified via RP-prep-HPLC to give title the compound (0.065 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)[O:10][C:9]2=[O:25])[CH:5]=[CH:6][CH:7]=1.O.NN>CCO>[NH2:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:25])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A solution of phthalimide 98 (3.0 g, 8.82 mmol) in EtOH (30 mL) was treated with hydrazine monohydrate (2.20 g, 2.2 mL, 44.12 mmol, 5.0 equiv) at 25° C., and the resulting reaction mixture was warmed to reflux for 2 h. White precipitates formed as the reaction mixture was refluxed. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (20 mL). The aqueous solution was then extracted with CH2Cl2 (3×40 mL), and the combined organic extracts were washed with H2O (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5S)-5-aminomethyl-3-(3-fluoro-phenyl)-oxazolidin-2-one (amine 99, 1.79 g, 96.6% yield) as a white powder. This product was directly used in the subsequent reactions without further purification. C10H11FN2O2, LCMS (EI) m/e 211 (M++H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][C:32](=[S:34])[CH3:33])[O:11][C@@H:10]1[O:35][CH2:36][CH2:37][CH2:38][OH:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40](Cl)(=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57].N1C=CC=CC=1.CO>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][C:32](=[S:34])[CH3:33])[O:11][C@@H:10]1[O:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(=S)C[C@H]1O[C@H](OCCCO)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCO[C@H]1O[C@H](CC(C)=S)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound (7) (21.9 g, 38.6 mmol) in anhydrous dichloromethane (200 ml), added were stearoyl chloride (15.2 g, 1.3 equivalents) and anhydrous pyridine (5 ml), and the mixture was stirred at room temperature for 2 hours. After the sufficient progress of the reaction was confirmed, methanol (5 ml) was added to stop the reaction, and the mixture was concentrated under reduced pressure. The residue was suspended in a minor amount of ethyl acetate, poured to water (200 ml), and extracted with ethyl acetate (3×100 ml). The organic layers were combined and washed with saturated saline (2×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified with silica gel chromatography (hexane-ethyl acetate, 10:1→8:1→6:1) to obtain the title compound (8) in the form of a colorless oily substance {31.3 g (37.6 mmol), 97.4%}.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[N:52]=[C:51]([CH3:59])[CH:50]=1.[H-].[Na+]>CN(C)C=O>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:49]5[C:58]6[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=6)[N:52]=[C:51]([CH3:59])[CH:50]=5)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2nc3c(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c3n2)c2ccccc2n1
Temperature: 160 °C

Procedure:
A mixture of Intermediate D (605 mg, 1.0 mmol), 4-chloroquinaldine (266 mg, 1.5 mmol), 60% NaH (60 mg, 1.5 mmol), and dimethylformamide (15 mL) was stirred under argon and heated at 160° C. for 4 days. The volatiles were removed under reduced pressure, and the residue was chromatographed using silica gel and hexane/ethyl acetate (2:1) as an eluent. The obtained product was recrystallized from ethanol to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(2-methylquinolin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 15) as orange crystals, 520 mg (70%). 1H NMR (400 MHz, CDCl3): δ 8.73 (d, J=8.4 Hz, 1H, quinaldine), 8.13 (d, J=8.4 Hz, 1H, quinaldine), 8.07 (d, J=8.8 Hz, 4H, p-phenylene), 7.98 (s, 1H, quinaldine), 7.77 (ddd, J=8.4, 7.0 and 1.1 Hz, 1H, quinaldine), 7.73 (s, 2H, benzotriazole), 7.60 (ddd, J=8.4, 7.3 and 1.1 Hz, 1H, quinaldine), 7.25-7.30 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.16-7.19 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph), 2.86 (s, 3H, quinaldine). UV-vis spectrum (dichloromethane): λmax=438 nm. Fluorimetry (dichloromethane): λmax=617 nm.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1)=[C:2]=[O:3].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[NH2:10][C:6]1[CH:5]=[C:4]([NH:1][C:2]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:3])[CH:9]=[CH:8][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: Nc1cccc(NC(=O)N2CC=CC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-isocyanato-3-nitrobenzene (1.125 g, 6.18 mmoles) and pyrrolidine (485 mg, 6.8 mmoles) in DCM (20 mL) was stirred at r.t. for 14 hrs. After concentrated, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and dried over MgSO4, followed by hydrogenation with Pd/C (wet, 10%, 0.15 g) under a hydrogen balloon overnight. After filtration and concentration, the reasonable pure N-(3-aminophenyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (3, 1.44 g) was used for the next reactions. MS+: 224.2, UV: λ=271.6 nm. 1H NMR: (DMSO) δ7.44 (s, 1H), δ6.78 (m, 1H), δ6.20 (m, 1H), δ3.32 (m, 4H), δ1.83 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1.O>ClCCl>[C:1]([O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
Acetyl chloride (10.2 mL, 144 mmol) was added in a dropwise manner over 1 h to a cold (ice bath) solution of 3-bromophenol (25 g, 144 mmol) and pyridine (10.8 mL, 144 mmol) in dichloromethane (100 mL), and the reaction was stirred 18 hr at room temperature. Water (150 mL) was added and the organic layer was extracted with dichloromethane. The combined organic layers were washed with 2.5N NaHSO4, 3N NaOH, water, brine, and dried over Na2SO4, and filtered. Concentration gave the 3-bromophenyl acetate as a pink liquid (28 g, 96%). GC-MS data: 214 (M+); 1H NMR (DMSO-d6): 7.37-7.39 (d, 1H), 7.26-7.30 (m, 2H), 7.04-7.07 (t, 1H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]1[CH2:21][N:16]3[CH2:17][CH2:18][NH:19][CH2:20][C@@H:15]3[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.Cl[C:23]1[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]1[CH2:21][N:16]3[CH2:17][CH2:18][N:19]([C:23]4[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=4)[CH2:20][C@@H:15]3[CH2:14][CH2:13]1)[CH:6]=[CH:5]2
Reactant: Fc1cnc(Cl)nc1
Reactant: Fc1ccc2c(ccn2C[C@@H]2CC[C@H]3CNCCN3C2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cnc(N2CCN3C[C@H](Cn4ccc5cc(F)ccc54)CC[C@H]3C2)nc1
Temperature: 95 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
A mixture of 2.20 g (7.67 mmol) of (7R,9aS)-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 1.02 g (7.67 mmol) of 2-chloro-5-fluoropyrimidine and 1.95 g (18.4 mmol) of sodium carbonate in 100 mL of water was stirred at 95° C. for 72 h. The mixture was cooled to room temperature, extracted with chloroform (3×), the combined organic phase was washed with brine, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 50:50 ethyl acetate:hexane gave 1.17 g (40%) of the title compound. mp (.HCl) 180–182° C. HRMS calc for HRMS calcd for C21H23F2N5: 383.1922, found: 383.1924.
Reaction SMILES: C(OC(N1CC(OC2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)C=CN=2)CC1C(O)=O)=O)(C)(C)C.C1([B:35]([OH:37])[OH:36])C=CC=CC=1.CC(C)([O-])C.[Na+]>C1COCC1>[CH3:25][O:24][C:20]1[CH:21]=[CH:22][C:23]([B:35]([OH:37])[OH:36])=[CH:18][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)nccc2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1
Yield: 236.9 %

Procedure:
A mixture of 4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (39 mg, 0.10 mmol), phenylboronic acid (14.6 mg, 0.12 mmol), sodium tert-butoxide (38 mg, 0.40 mmol) and ((t-Bu)2POH)2PdCl2 (POPd) (5 mg, 0.01 mmol) in THF (2 mL) was heated to reflux for 4 h. After cooling down, the formed mixture was quenched with 5% citric acid (aq) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over MgSO4, filtered, evaporated. The residue was purified by prep-HPLC to yield 36 mg (83%) of the desired product as an off-white foam.
Reaction SMILES: CC1C=CC(S(OCCC[N:15]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]4[C:35]5[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=5[N:37]=[C:33]4[N:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O)=CC=1.N1C2N(C3C=CC=CC=3N=2)C(C2C=CC(N)=CC=2)=CC=1.CC1C=CC(S(OCCCOS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>>[C:19]([O:18][C:16](=[O:17])[NH:15][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:34]3[C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=[C:33]3[N:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C(=O)OC(C)(C)C)c2ccc(-c3ccnc4nc5ccccc5n34)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Nc1ccc(-c2ccnc3nc4ccccc4n23)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccnc3nc4ccccc4n23)cc1

Procedure:
3-((4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-4-yl)phenyl)(tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate T544P The title compound was prepared using general procedure D from 4-(benzo[4,5]imidazo[1,2-a]pyrimidin-4-yl)aniline and propane-1,3-diyl bis(4-methylbenzenesulfonate). T554P was isolated as a solid (130 mg, 21%). 1H NMR (400 MHz, CDCl3): δ 1.51 (s, 9H), 2.09 (m, 2H), 2.46 (s, 3H), 3.87-3.90 (m, 2H), 4.12-4.15 (m, 2H), 6.94 (m, 1H), 7.04 (bs, 1H), 7.19 (m, 1H), 7.35 (m, 1H), 7.52-7.65 (m, 5H), 7.77-7.79 (m, 2H), 8.18 (m, 1H), 8.97 (d, J=4.4 Hz, 1H). MS (ESI): 573.1 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1.Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:31])[F:30])[CH:22]=4)=[CH:19][N:20]=3)[N:17]=2)[CH2:4][CH2:3]1
Reactant: NCC1CCC(F)(F)CC1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: FC1(F)CCC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 120 °C
Reaction time: 5 h
Yield: 0.8 %

Procedure:
To the solution of compound (4,4-difluorocyclohexyl)methanamine (100 mg, 6 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (190 mg, 6 mmol) in 3 mL DMSO was added DIEA (0.21 mL, 12 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound N-((4,4-difluorocyclohexyl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (21 mg, 10%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11](F)=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])[N:5]2[N:24]=[CH:25][N:26]=[C:4]2[N:3]=1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32].[H-].[Na+].O>CS(C)=O>[Br:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:20])[F:21])[N:5]2[N:24]=[CH:25][N:26]=[C:4]2[N:3]=1
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Br)nc2ncnn12)C(F)(F)F
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Nc1c(-c2c(F)cc(OCCCN(C)C)cc2F)c(Br)nc2ncnn12)C(F)(F)F
Temperature: 60 °C
Yield: 78.3 %

Procedure:
To a solution of 5-bromo-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (44 mg, 0.1 mmol) and 3-dimethylamino-1-propanol (51 m g, 0.5 mmol) in 1 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 20 mg, 0.5 mmol). The mixture is heated at 60° C. for 2 h, and cooled to room temperature. Water is added to quench the reaction, and the product is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride (x3), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 30% methyl alcohol in ethyl acetate. Concentration provides 5-bromo-6-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a light tan solid (41 mg, mp 40-42° C.). MS: m/z 523.1, 525.1 (M+H).