Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:28]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1OCCOCCOCCOCCOCCOC1>CC#N.O>[C:28]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[CH:21]=[N:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH:7]=3)=[O:4])[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCN(c2ccccc2)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (1.64 g, 5.5 mmol), K2CO3 (0.92 g, 6.87 mmol), 1-phenylpiperazine (1.05 mL, 5.5 mmol) and a catalytical amount of 18-crown-6 in MeCN (20 mL) was refluxed for 7 hrs, cooled to room temperature, and diluted with water. The resulting solid was filtered, washed with water, and dried to afford 2-(4-phenylpiperazin-1-yl)-N-[3-(quinoxalin-2-yl)phenyl]acetamide (2.1 g, 90% yield). LCMS calculated for C26H25N50 (M+H): 424.52. found 424. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.5 (1H, br. s), 9.52 (1H, s), 8.58 (1H, br. s), 8.20-7.80 (6H, m), 7.55 (1H, m), 7.25-7.15 (2H, m), 6.98-6.90 (2H, m), 6.80-6.72 (1H, m), 3.28-3.25 (6H, m), 2.75-2.65 (4H, m).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)C.[OH-].[Na+]>C1COCC1.C(O)C.OS([O-])(=O)=O.[K+].OS(O)(=O)=O>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH3:18])([C:4]([OH:19])=[O:3])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Yield: 26.5 %

Procedure:
To a stirring solution of N-tert-butoxycarbonyl-4-methylisonipecotic acid ethyl ester (17.4 mmol, 4.73 g) in THF (50 mL) and ethanol (50 mL) was added 50% NaOH (50 mL) and the mixture heated to reflux overnight. The reaction was diluted with 10% KHSO4 (600 mL) and conc. H2SO4 (5 mL) and extracted with ethyl acetate (2×250 mL). The organic layers were combined, washed with water (500 mL) and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was triturated with diethyl ether:hexanes and filtered to give 1.12 g of an orange solid. The filtrates were evaporated to give 2.71 g of the title compound as an orange solid.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[C:38]1([OH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O1CCOCC1>CN(C=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([O:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[N:4]=[C:5]2[N:6]([CH2:14][C:15]([CH3:18])([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: Oc1ccccc1
Reactant: Cn1c(=O)c2c(Cl)n(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(Oc3ccccc3)n(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 150 °C
Yield: 67.3 %

Procedure:
3-chloro-5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (30 mg, 0.069 mmol), potassium carbonate (29 mg, 0.2 mmol) and phenol (20 mg, 0.20 mmol) are placed in a Biotage microwave vial, and then 0.3 mL of dioxane is added. The vial is sealed, and then heated in a Biotage microwave instrument at 150° C. for 3 h. The reaction mixture is diluted with DMF, and then filtered. The filtrate is purified with a semi-preparative HPLC to give 23 mg of pure product as pale yellow solids. MS (ESI) m/z 496.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29])[CH2:12][CH2:11][CH:10]=[C:9]3[C:21]1[O:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C([O-])=O.[NH4+]>[Pd].CCO>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29])[CH2:12][CH2:11][CH2:10][CH:9]3[C:21]1[O:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C2=CCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(C2CCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1,3-Dimethyl-10-(5-methylfuran-2-yl)-5-phenyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (step 1) (411 mg, 1.061 mmol), 10% wt. palladium on activated carbon (113 mg, 0.106 mmol) and ammonium formate (669 mg, 10.61 mmol) were suspended in EtOH (30 mL) and the mixture stirred at 50° C. for 1 h. A further portion of 10% wt. palladium on activated carbon (113 mg, 0.106 mmol) was added and heating continued at 50° C. for a further 1 hour. The reaction mixture was cooled to RT and filtered through a Celite® (filter material) cartridge (10 g), rinsing the residue with MeOH. The filtrates were evaporated under reduced pressure. The residue was taken up in a small volume of MeOH and solids precipitated by addition of diethyl ether. The salts were removed by filtration and rinsing with diethyl ether. The solvent was evaporated and the residue was purified by chromatography on silica, eluting with 20% EtOAc in iso-hexane. Precipitation from EtOAc/iso-hexane afforded the title compound as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.4 %

Procedure:
To an ice-cold solution of N-Boc-4-piperidine-ethanol (5.0 g, 21.8 mmol) and Et3N (4.6 mL, 33.0 mmol) in dry DCM (10 mL) was added p-toluenesulfonyl chloride (6.25 g, 32.8 mmol) slowly. Upon addition, the reaction was warmed to room temperature and stirred for 20 h. The reaction mixture was washed with water (40 mL), 10% (wt/v) citric acid(aq) (40 mL), and saturated NaHCO3(aq) (40 mL). The DCM layer was dried with MgSO4, filtered and concentrated in vacuo to give a pale yellow oil, which was chromatographed to give the title compound (7.47 g, 89% yield) as a clear and colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][N:16]1[CH:20]=[C:19]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[CH:18]=[N:17]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cn1
Temperature: 100 °C
Yield: 29.9 %

Procedure:
A suspension of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (1 g, 3.70 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was added to a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.771 g, 3.70 mmol) in 1,4-dioxane (12 mL) and water (4 mL). PdCl2(dppf) (0.271 g, 0.370 mmol) and Cs2CO3 (2.413 g, 7.41 mmol) were added and the mixture was heated at 100° C. for 20 min. The mixture was then cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=1:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.3) were combined and concentrated to yield a light yellow solid of 1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (300 mg, 1.106 mmol, 29.9% yield): 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 4.01 (s, 3H). ES-LCMS m/z 272 (M+H).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH2:2][C:3](CNCCCNCCCNCC(C)C)([CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:4]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:6]=1.[ClH:55]>>[ClH:55].[C:1]1([C:1]2[CH:2]=[CH:3][CH:4]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:6]=2)[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:4]=[C:3]([CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:2]=1
Reactant: CC(C)CNCCCNCCCNCC1=CC(CNCCCNCCCNCC(C)C)(CNCCCNCCCNCC(C)C)CC(c2ccccc2)=C1
Agent: Cl
Product: CC(C)CNCCCNCCCNCc1cccc(-c2cc(CNCCCNCCCNCC(C)C)cc(CNCCCNCCCNCC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
N1,N1′,N1″-([1,1′-biphenyl]-3,3′,5-triyltris(methylene))tris(N3-(3-(isobutylamino)propyl)propane-1,3-diamine) from step 2 was subjected to acidification with methanolic HCl (100 mL, 1.0M). The reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the solid was collected by vacuum filtration and washed with Et2O (50 mL) and hot MeOH (50 mL) to afford the desired product (0.58 g, 52%) as a white solid. 1H NMR (500 MHz, D2O) δ ppm 7.91 (s, 1H), 7.85-7.82 (m, 3H), 7.65-7.56 (m, 3H), 4.42 (s, 4H), 4.39 (s, 2H), 3.29-3.16 (m, 24H), 2.93 (d, J=6.0 Hz, 6H), 2.20-2.13 (m, 12H), 2.07-2.00 (m, 3H), 0.99 (d, J=6.0 Hz, 18H). 13CNMR (125 MHz, D2O) δ ppm 141.6, 139.8, 132.2, 131.3, 130.4, 130.3, 129.7, 129.5, 128.6, 128.4, 54.8, 54.8, 51.1, 50.8, 44.7, 44.6, 44.2, 44.0, 25.5, 22.7, 22.5, 19.0. LRMS [M+2H+]2+376.8.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(C)cc1C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCc1ccc(C)cc1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoate (690 mg, 1.54 mmol) was treated with trifluoroacetic acid to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the above product was treated with oxalyl chloride and N,N-dimethylformamide to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoyl chloride as a crude product. According to a similar procedure to that described in Example 1-(12), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (670 mg, 1.23 mmol) described in Reference example 1 was treated with sodium hydride and then reacted with the crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoyl chloride (the whole amount) obtained above to afford, after purification by column chromatography, the title compound (448 mg, 43% yield) as a pale yellow, candy-like material.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].[C:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>CN(C)C=O>[C:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 79 %

Procedure:
Using 0.3 g of (3,3,3-trifluoropropyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.08 g of sodium hydride (60% in oil), and 0.4 g of 4-acetylbenzyl bromide, and according to the process described in the Production Example 1, there was obtained 0.43 g of 2-(4-acetylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (6)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[C:40]([F:46])[C:41]=1[C:42]([OH:45])([CH3:44])[CH3:43].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:46][C:40]1[CH:39]=[N:38][CH:37]=[C:36]([C:2]2[CH:11]=[N:10][C:9]3[NH:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:3]=2)[C:41]=1[C:42]([OH:45])([CH3:43])[CH3:44]
Reactant: Brc1cnc2c(c1)CCCN2
Reactant: CC(C)(O)c1c(F)cncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(O)c1c(F)cncc1-c1cnc2c(c1)CCCN2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a vial is added 6-bromo-1,2,3,4-tetrahydro-[1,8]naphthyridine, Intermediate A (144 mg, 0.68 mmol), bis(pinacolato)diboron (223 mg, 0.88 mmol), potassium acetate (200 mg, 2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (50 mg, 0.07 mmol) in 5 ml of 1,4-dioxane. The reaction mixture is stirred at 120° C. under Ar for 2 hours. The reaction mixture is cooled down to room temperature, followed by the addition of 2-(3-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (190 mg, 0.81 mmol), 2M Na2CO3 (0.67 ml, 1.35 mmol) and [1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (25 mg, 0.034 mmol). The reaction mixture is stirred under Ar at 120° C. for 3 hours. The reaction mixture is concentrated. The residue is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 72 mg of 2-[3-fluoro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-propan-2-ol.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:34])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:34][C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:9]=2[C:10]([O:15][CH3:16])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)c2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (72.4 mg) obtained in Step A of Example 92 in DMF (5 mL) was added NBS (38.1 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (67.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([CH3:14])[S:13][C:9]=2[CH:8]=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([CH3:14])[S:13][C:9]=2[CH:8]=1
Reactant: COC(=O)C/C=C/c1ccc2nc(C)sc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccc2nc(C)sc2c1

Procedure:
Next, a solution of (E)-4-(2-methyl-benzothiazol-6-yl)-but-3-enoic acid methyl ester in THF (10 mL) is hydrogenated over 10% Pd/C (22 mg, 10% wet) at 1 atm for 48 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by flash chromatography (heptane:EtOAc, 2:1) to give 4-(2-methyl-benzothiazol-6-yl)-butyric acid methyl ester. MS 250.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH3:24])[CH:6]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH3:24])[CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(2-methylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.OP(O)(O)=O.[OH-].[NH4+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH:24]=1
Reactant: O=S(=O)(Oc1cc(Br)c2[nH]ccc2c1)c1ccccc1
Reactant: CN1CCC(=O)CC1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3c(Br)cc(OS(=O)(=O)c4ccccc4)cc23)CC1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
Combine benzenesulfonic acid 7-bromo-1H-indole-5-yl ester and 1-methyl-4-piperidone (4 eq.) in acetic acid. Heat to about 75° C. before adding 2.0 N H3PO4 (3 eq.). After about 6 hours, cool to room temperature and pour into a mixture of ammonium hydroxide in ice water. Separate the organic layer and dry over Na2SO4 and concentrated. Purify to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:11]([CH3:24])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:33]>CN(C)C=O>[CH2:25]([N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C@H:11]([CH3:24])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CI
Reactant: C[C@H](Cc1c[nH]c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Cc1cn(C)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
NaH (180 mg of 60% oil dispersion, 4.5 mmol) is added to a solution of dibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (1.4 g, 3.6 mmol) in 20 ml dimethylformamide under N2 at 0° C. The resulting mixture is stirred for 20 minutes, then is allowed to warm to room temperature over 20 minutes. A 5 ml solution of iodomethane in dimethylformamide (7.2 mmol) is added dropwise and the reaction mixture is stirred for 1 hour. The reaction is quenched with cold aqueous NaHCO3, xtracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 1.3 g of dibenzyl-[2-(5,7-difluoro-1-methyl-1H-indol-3-yl)-1 (R)-methyl-ethyl]-amine (89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH:22]3[CH2:24][CH2:23]3)[CH2:20][CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH:22]1([N:21]2[C:14]3[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:10][CH2:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[CH:13]=3)[CH2:19][CH2:20]2)[CH2:24][CH2:23]1
Reactant: OCc1ccc(F)c(F)c1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,4-difluorophenyl)methanol and 7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(C)(C)C)cc1Oc1cccc(C(F)(F)F)n1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
A mixture of methyl 4-tert-butyl-2-hydroxybenzoate (0.70 g, 3.4 mmol), 2-fluoro-6-(trifluoromethyl)pyridine (0.55 g, 3.4 mmol), and Cs2CO3 (1.1 g, 3.4 mmol) in DMF (15 mL) was heated at 70° C. for 19 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with 0-15% ethyl acetate in hexanes to give methyl 4-tert-butyl-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzoate (0.49 g, 41% yield). LC/MS: m/z 354.3 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [H-].[Na+].C(COC)OC.COP([CH2:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=O)OC.[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)([O:25][CH3:26])=[O:24]>C(O)(=O)C>[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1/[CH:35]=[CH:15]/[C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CCCCCCc1ccccc1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCCCCC(=O)/C=C/c1ccccc1CCCCCCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.25 g. of this benzyl alcohol in 75 ml. of chloroform is added to a slurry of 12.5 g. of activated manganese dioxide in 75 ml. of chloroform. The mixture is stirred for one hour, filtered and the solvent is evaporated to leave 2-(6-carbomethoxyhexyl)benzaldehyde as a clear oil. To a slurry of 260 ml. of a dispersion of sodium hydride in mineral oil in 40 ml. of dimethoxyethane is added a solution of 1.31 g. of dimethyl(2-oxoheptyl)phosphonate in 25 ml. of dimethoxyethane. The slurry is stirred for one hour, cooled to 0° C. and 1.22 g. of the benzaldehyde in 20 ml. of dimethoxyethane is added. The mixture is stirred at 0° for 30 minutes and at room temperature for three hours. It is then neutralized with acetic acid and the solvent removed in vacuo. The residue is chromatographed on silica gel to yield 1-(6-carbomethoxyhexyl)-2-(3-oxo-trans-1-octenyl)benzene as a pale yellow oil.