Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:13]=1.C[O:31][B:32](OC)[O:33]C.Cl>C1COCC1>[B:32]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:13]=1)([OH:33])[OH:31]
Reactant: COB(OC)OC
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
A 1.7 M solution of tert-butyl lithium (t-BuLi) in pentane (3.8 ml; 6.45 mmol) was added over ~5 minutes, to a solution of the title product of Step (B) (1 g; 3 mmol) in THF at -100° C. The temperature was kept below -84° C. during the addition. After stirring 5 minutes at -100° C., trimethylborate was added in one portion and the reaction mixture was allowed to warm to room temperature over 4 hours. At this time, 10 ml of 10% HCl was added and the mixture was extracted with methylene chloride (3×30 ml). The combined organic layers were washed with water (3×30 ml) and brine (30 ml). Drying (MgSO4), decolorizing (Darco) and concentration afforded a tan foam. Due to apparent decomposition at room temperature, the foam was stored at -80° C. overnight. The residue was then partitioned between ether (20 ml) and 0.5 N NaOH (20 ml). The purple ether layer was extracted with 10 ml of 0.5N NaOH. The combined green basic layer was washed with ether (20 ml), acidified to pH 2 with saturated KHSO4 solution to afford a purple mixture, which was extracted with methylene chloride (2×30 ml). Drying (MgSO4) and concentration afforded 623 mg (69%) of the title product of this step as a purple foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[N:23]([C:24]([C:26]4[C:27]([CH3:31])=[N:28][O:29][CH:30]=4)=[O:25])[CH2:22][CH2:21][N:10]2[C:11](=[O:20])[C:12]2[N:13]([CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[CH2:14]3)=[CH:5][CH:4]=1.Cl>CO.[Pd]>[NH2:19][CH2:18][C:16]1[CH:17]=[C:12]2[C:11](=[O:20])[N:10]3[CH2:21][CH2:22][N:23]([C:24]([C:26]4[C:27]([CH3:31])=[N:28][O:29][CH:30]=4)=[O:25])[C:9]3([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:14][N:13]2[CH:15]=1
Reactant: COc1ccc(C23Cn4cc(C#N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C23Cn4cc(CN)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 25 °C

Procedure:
To a stirred suspension of 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carbonitrile (89) (220 mg, 0.53 mmol) in methanol (22 mL) was added Pd/C and conc. HCl (1.1 mL). The reaction was placed under an atmosphere of hydrogen and stirred at room temperature. Analysis by tlc and LCMS indicated a new product was forming. The crude material was purified by preparative HPLC to give 7-(aminomethyl)-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]-pyrazin-5-one; trifluoroacetate salt (147) as an oil (44 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.Br[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: BrC1CCCC1
Reactant: Clc1nc(NC2CCCCC2)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc(NC2CCCCC2)c2ncn(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
2-Chloro-6-cyclohexylamino-purine (10 mmol), bromocyclopentane (20 mmol) and potassium carbonate (20 mmol, water free) in DMF (70 ml) are heated up to 50° C. and the mixture is stirred at this temperature for 10 hours. After cooling to RT the mixture is poured on water and extracted 3 times with ethyl acetate. The combined organic phases are washed twice with brine and the extract is dried over sodium sulfate and evaporated. A pale oil with Rf=0.36 (CH2Cl2/MeOH=20:1) is obtained.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([C:24]#[N:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH2:15][CH2:14][O:13][CH:12]2[CH2:11][N:9]2[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:17][C:18]=1[C:24]#[N:25]
Reactant: COc1cc2c(cc1C#N)CCOC2CN1CCN(C(=O)[O-])C(C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C#N)CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl-4-{[6-cyano-7-(methyloxy)-3,4-dihydro-1H-isochromen-1-yl]methyl}piperazine-1-carboxylate (270 mg, 0.697 mmol) in 5 mL of DCM was added 5 mL of TFA and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford 7-(methyloxy)-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-6-carbonitrile. The residue was directly used in next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH2:18][C:19]([O:21]CC)=[O:20])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A mixture of ethyl 3-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoate obtained in Example 8 (300 mg), lithium hydroxide monohydrate (840 mg), water (10 mL), and tetrahydrofuran (10 mL) was stirred at room temperature for 3 h. 6 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (199 mg, 73%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[OH:26])=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=C(O)Cc2ccc(Cl)cc2)C(=O)O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (52.7 g, 366 mmol) in DCM (205 mL) at −10° C. in an ice/methanol bath was added pyridine (72.5 mL, 897 mmol) over 10 minutes. To the resulting solution at −10° C. was added a solution of 2-(4-chlorophenyl)acetyl chloride (69.1 g, 366 mmol) in DCM (144 mL) dropwise over 1 hour. The mixture was stirred at −10° C. for 1 hour, then at room temperature for 1 hour. The mixture was poured into a mixture of 2 M HCl (820 mL) and ice (400 mL) and the aqueous layer was extracted with DCM (2×200 mL). The combined DCM layers were washed with 1 N HCl (100 mL) and brine (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 103 g of title compound. (95% yield). LC/MS (FA) ES− 295. 1H NMR (400 MHz, CDCl3) δ: 15.25 (br s, 1H), 7.34-7.26 (m, 4H), 4.37 (s, 2H), 1.72 (s, 6H).
Reaction SMILES: [C:1]([NH:10][C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19](Br)[CH:20]=[CH2:21].[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH2:21]([N:10]([C@@H:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: CCCCCCCC(=O)N[C@H](C)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCN(C(=O)CCCCCCC)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.8 %

Procedure:
A solution of 10.0 g (40.0 mmol) of (R)-N-octanoyl-1-phenylethylamine in 20 ml of toluene, and 9.90 g (80.0 mmol) of allyl bromide were added to a suspension of 3.20 g (80.0 mmol) of sodium hydride (60%) in 74 ml of toluene, and the reaction was allowed to proceed at 100° C. for 6 hours. The reaction mixture was cooled to room temperature and added dropwise to 80 ml of ice-cooled 1 N hydrochloric acid to thereby terminate the reaction. The resulting mixture was extracted with three 30-ml portions of hexane. The organic phase was washed with 50 ml of water and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was quantitated by HPLC. Thus was obtained 9.87 g (86%) of the title compound.
Reaction SMILES: C1C=CN=CC=1.F.[Si]([O:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[N:25][C:26]=1[CH:27]([O:30][CH3:31])[O:28][CH3:29])[N:23]([C:32]([NH:34][C:35]1[CH:40]=[C:39]([NH:41][CH2:42][CH2:43][O:44][CH3:45])[C:38]([C:46]#[N:47])=[CH:37][N:36]=1)=[O:33])[CH2:22][CH2:21][CH2:20]2)(C(C)(C)C)(C)C>C1COCC1>[C:46]([C:38]1[C:39]([NH:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:40][C:35]([NH:34][C:32]([N:23]2[C:24]3[C:19](=[CH:18][C:17]([CH2:16][OH:15])=[C:26]([CH:27]([O:30][CH3:31])[O:28][CH3:29])[N:25]=3)[CH2:20][CH2:21][CH2:22]2)=[O:33])=[N:36][CH:37]=1)#[N:47]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CO)c(C(OC)OC)nc32)ncc1C#N
Reaction time: 2 h

Procedure:
HF-Pyridine (426 μL, 3.31 mmol) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 74, 900 mg, 1.577 mmol) in THF (7 ml) at room temperature. The reaction mixture was stirred for approximately 2 h, quenched with saturated aqueous NaHCO3 and partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried using Na2SO4, filtered and concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 0.85 min; ESI-MS 457.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 13.71 (s, 1H), 8.21 (s, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 5.49 (s, 1H), 5.28 (s, 1H), 4.71 (d, 2H), 4.07-3.99 (m, 2H), 3.67-3.59 (m, 2H), 3.55 (s, 6H), 3.51-3.45 (m, 2H), 3.41 (s, 3H), 2.85 (t, 2H), 2.05-1.96 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:16][CH3:17])[C:10]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:16][CH3:17])[C:10]([N:11]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[CH2:24][CH:21]3[CH2:22][CH2:23][O:18][CH2:19][CH2:20]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1NCC1CC1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nn2c(Br)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylamine (106 mg) in tetrahydrofuran (3 mL) was added tetrahydropyran-4-carbaldehyde (123 mg) at room temperature, and then sodium triacetoxyborohydride (229 mg) was gradually added. After stirring the reaction mixture for 1 hour, saturated aqueous sodium bicarbonate was added thereto. The obtained mixture was extracted with ethyl acetate, and organic extract was washed with brine and then dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (10 g) and the title compound (120 mg) was obtained as a yellow oil from the ethyl acetate:n-hexane (1:6) fraction.
Reaction SMILES: CC([O:4][C:5]([C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:18])=[CH:15][CH:16]=1)([CH3:9])[CH3:8])=[O:6])C.[OH-].[Na+].Cl>C(O)(C)C.O>[CH3:9][C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:16]=1)([C:5]([OH:6])=[O:4])[CH3:8]
Reactant: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 75 °C
Yield: 96.6 %

Procedure:
Fenofibrate (200.0 g, 0.5543 mol) was suspended in 900 mL of isopropanol. A solution of NaOH (33.0 g NaOH, 0.825 mol, 1.49 eq) in 400 mL of water was added and the mixture heated to reflux for 2 hours. The solution was cooled to approximately 75° C. A solution of hydrochloric acid (652 g of a 5.0% solution, 32.8 g of HCl, 0.894 mol, 1.6 eq) was added maintaining the temperature above 55° C., and the product crystallized from solution. The slurry was cooled to 28° C. over 3.5 hours. The product was filtered and rinsed twice with 500 mL of water. The product was dried in a vacuum oven at 60° C. with a nitrogen purge for approximately 16 hours. The dry weight was 170.7 g, or 96.6% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:27])[CH3:26])=[CH:3][CH:4]=4)=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(N)cc3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nc3c(C)nn(C4CCCCC4)c3c(=O)[nH]2)cc1
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a 4 ml pyridine solution of 110 mg (0.34 mmol) of the compound obtained in Example 3, 39 μl (0.41 mmol) of acetic anhydride was added with ice cooling. The mixture was stirred at the same temperature for 30 minutes. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. Then, the washed layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization (ethanol) to obtain 43.7 mg (35%) of the captioned compound.
Reaction SMILES: [CH:1]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(=O)(O)[O-].[Na+]>CO>[CH:1]1([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCCCC1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: c1cn(C2CCCCCC2)cn1

Procedure:
Cycloheptyl bromide (10.0 g, 0.0565 mole) was added dropwise to a refluxing mixture of imidazole (385 g, 0.0565 mole) and sodium bicarbonate (4.75 g, 0.0565 mole) im methanol (100 ml). After addition was complete the mixture was heated under reflux for a further 24 hours.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][N:43]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 67.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (644 mg, 1.24 mmol, 68%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][N:16]3[CH:21]=[CH:20][C:19]([N:22]4[C@@H:26]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=5)[CH2:25][O:24][C:23]4=[O:34])=[N:18][C:17]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[P:41]([O:53][CH2:54]Cl)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C.CCOC(C)=O>[P:41]([O:53][CH2:54][N:10]1[CH:11]=[N:12][C:8]([C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:14]=[N:15][N:16]4[CH:21]=[CH:20][C:19]([N:22]5[C@@H:26]([C:27]6[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=6)[CH2:25][O:24][C:23]5=[O:34])=[N:18][C:17]=34)=[CH:3][C:2]=2[F:1])=[N:9]1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:42]
Reactant: O=C1OC[C@H](c2ccc(F)cn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OP(=O)(OCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cn5)nc34)cc2F)n1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (S)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (0.66 g, 1.4 mmol) in DMF (10 mL) was added cesium carbonate (0.47 g, 1.4 mmol) followed by di-tert-butyl chloromethyl phosphate (1.1 g, 4.3 mmol) and the reaction mixture was stirred overnight at ambient temperature, then diluted with EtOAc (100 mL). The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was chromatographed twice on silica gel using EtOAc as eluent to yield (S)-di-tert-butyl (3-(2-fluoro-4-(5-(4-(5-fluoropyridin-2-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)methyl phosphate (0.27 g, 0.40 mmol, 28% yield).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[Br:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:19][CH3:20]
Reactant: COc1c(Br)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(Br)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.7 %

Procedure:
To 220 mg of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 10 h. When the reaction was done, the solvents were removed by vacuum and the residue was triturated with hexane/dichloromethane. Filtration of the suspension gave 141 mg (77% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:46][C:45]2[CH:47]=[CH:48][CH:49]=[C:43]([O:42][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:44]=2)=[O:21])[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 16 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate from the previous step (0.186 g, 0.5 mmol) was reacted with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]urea as solid (0.037 g, 16%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.54 (s, 2H), 7.56 (m, 7H), 7.50 (d, 1H), 7.38 (s, 1H), 7.22 (m, 2H), 6.54 (s, 1H), 4.73 (m, 2H), 4.58 (m, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 1.33 (s, 3H); LC-MS (ESI) m/z 575 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:7])=[N:5][N:6]=1.[CH2:8]([CH2:10][NH2:11])[OH:9]>CN1CCCC1=O>[CH3:1][C:2]1[N:11]([CH2:10][CH2:8][OH:9])[C:4]([CH3:7])=[N:5][N:6]=1
Reactant: NCCO
Reactant: Cc1nnc(C)o1
Solvent: CN1CCCC1=O
Product: Cc1nnc(C)n1CCO
Temperature: 160 °C
Yield: 49585.2 %

Procedure:
2,5-Dimethyl-1,3,4-oxadiazole (19.7 g, 0.2 mmole) and ethanolamine (18.3 g, 0.3 mole) were dissolved in 1-methyl-2-pyrrolidinone (20 ml) and the stirred reaction mixture heated at 160° C. for 24 hours, then cooled to ambient temperature. The residual gum was chromatographed on silica eluting with ethyl acetate containing from 20% to 50% methanol. Evaporation of the appropriate fractions and trituration of the residual foam with ethyl acetate gave the title product (14 g, 50%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:22])(=[O:21])[N:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:14](=[O:15])[C:4]1=2)[CH3:2].C[O-].[Na+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:22])(=[O:21])[NH:13][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:14]([OH:15])[C:4]1=2)[CH3:2]
Reactant: CCn1c2c(c3ccccc31)S(=O)(=O)N(CC(=O)OC)C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCn1c2c(c3ccccc31)S(=O)(=O)NC(C(=O)OC)=C2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
19.3 gm (60 millimols) of methyl 4-ethyl-3,4-dihydro-3-oxo-2H-isothiazolo[4,5-b]indole-2-acetate-1,1-dioxide and a suspension of 9.7 gm (180 millimols) of sodium methylate in 150 ml of toluene were admixed, while vigorously stirring, with 30 ml of dry tert. butanol, and the mixture was stirred for 30 minutes at room temperature and then for 90 minutes at 60° C. Subsequently, the reaction mixture was cooled on an ice bath and admixed with 120 ml of ice water. The organic phase was extracted with water, and the aqueous phase was extracted with ether. The combined aqueous phases were then acidified with hydrochloric acid to pH 3. The precipitate formed thereby was washed with water, methanol and ether, and after recrystallization from ethylene chloride yielded 8.3 gm (43% of theory) of methyl 5-ethyl-2,5-dihydro-4-hydroxy-1,2-thiazino-[5,6-b]indole-3-carboxylate 1.1-dioxide; M.p.: 216° C. (decomposition).