Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C@H]([N:9]2[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:13]3[CH2:20][C@H:10]2[CH:11]=[CH:12]3)C)C=CC=CC=1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C@H:10]12[CH2:20][C@H:13]([CH2:12][CH2:11]1)[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)[C@@H]1[C@H]2C=C[C@H](C2)N1[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1N[C@@H]2CC[C@H]1C2
Temperature: 45 °C
Reaction time: 60 h
Yield: 38.5 %

Procedure:
To a solution of ethyl (1S, 3S, 4R)-2-[(R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (3.01 g, 11.1 mmol) in ethyl acetate (22 ml) was added 20 wt % Pd(OH)2 (3.89 g) and the mixture was stirred under a hydrogen atmosphere at 45° C. for 60 hours. After a filtration through Celite, the solvent was concentrated. The residue was purified by silica gel column chromatography (1%–2.5% methanol/chloroform), to give ethyl (1R, 3S, 4S)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.724 g, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11][OH:12])=[O:5])[CH3:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[O:9][C:10]=1[CH2:11][O:12][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)=[O:5])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1COC1CCCCO1
Temperature: 25 °C

Procedure:
4.8 g 5-Hydroxymethyl-2-(4-methoxy-phenyl)-oxazole-4-carboxylic acid ethyl ester were dissolved in 75 ml dichloromethane. 1.9 ml 3,4-dihydro-2H-pyran and 870 mg pyridinium p-toluenesulfonate were added and the reaction mixture stirred at room temperature over night. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with n-heptane:ethyl acetate=3:1=>1:1) to obtain 5.3 g 2-(4-methoxy-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-oxazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.O>[Br:20][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[C:3]2([CH2:1][CH3:2])[CH2:13][CH3:14]
Reactant: BrBr
Reactant: CCC1(CC)C(=O)Nc2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1(CC)C(=O)Nc2ccc(Br)cc21

Procedure:
A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in aceticacid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, then brine, dried (MgSO4) and evaporated to afford the crude product (7.6 g, 75%). A sample was recrystallized from EtOAc/hexane to obtain the title compound, m.p. 164-165° C.; 1H-NMR (DMSO-d6) δ 10.45 (s, 1H), 7.41-7.40(d, 1H, J=2.2 Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d, 1H J=8.2 Hz), 1.78-1.65 (t, 4H), 0.50-0.46 (m, 6H); MS (−ESI) m/z 266/268 (M−H).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[N:16]1([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(CC)CC)C>ClCCl>[O:8]([C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:22][CH:23]=1)[S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(-n2ccnc2)cc1)C(F)(F)F
Reaction time: 18 h

Procedure:
Triflic anhydride (2.82 g) was added dropwise to a mixture of 4-(1-imidazolyl)phenol (Aldrich Chemical Company) and triethylamine (1.1 g) in dichloromethane (30 ml). The mixture was stirred for 18 hours. The mixture was evaporated and the residue partitioned between diethyl ether and water. The organic phase was separated, washed with water, dried (MgSO4) and evaported. The residue was triturated with cyclohexane to give crude 4-(1-imidazolyl)phenyl triflate (1.7 g) as a solid, which was used without further purification; m/Z 293 (M+H).
Reaction SMILES: [C:1]([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=2)[N:7]([C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)[C:6](=[O:29])[C:5]1=O)(=O)[CH3:2].Cl.[CH:32]1([NH:35][NH2:36])[CH2:34][CH2:33]1.CC(O)=O>O1CCOCC1>[CH:32]1([N:35]2[C:5]3[C:6](=[O:29])[N:7]([C:20]4[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=4)[CH:8]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=4)[C:4]=3[C:1]([CH3:2])=[N:36]2)[CH2:34][CH2:33]1
Reactant: NNC1CC1
Reactant: CC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1nn(C2CC2)c2c1C(c1cccc(OC(F)(F)F)c1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
To a solution of 4-acetyl-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(3-(trifluoromethoxy)-phenyl)pyrrolidine-2,3-dione (Step 91.1) (50 mg, 0.118 mmol) in Dioxane (1 mL) were added cyclopropylhydrazine hydrochloride (Step 17.2) (25.7 mg, 0.237 mmol) and TEA (0.082 mL, 0.592 mmol) and the resulting mixture was heated up and stirred at 120° C. for 2 hr. AcOH was added to acidify the reaction mixture and stirred at 100° C. for 30 min. The reaction was cooled down to RT and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with a saturated aq. NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (CH2Cl2/(CH2Cl2/MeOH 19:1 NH3) 0-100%) to afford the title product (10 mg, 0.021 mmol, 18.1% yield) as yellow foam. tR: 1.03 min (LC-MS 2); ESI-MS: 459 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.3 Hz, 2H) 1.24 (br. s., 3H) 1.93 (s, 6H) 3.37-3.39 (m, 1H) 3.81 (br. s., 1H) 6.13 (s, 1H) 7.22-7.57 (m, 5H) 7.76 (br. s., 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:74]([NH2:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1.C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:74]([NH:81][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2)[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1ccc2c(NCc3ccccc3)cccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A vial was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D, 0.100 g, 0.192 mmol), Pd2(dba)3 (0.018 g, 0.019 mmol), Xantphos (0.022 g, 0.038 mmol), and toluene (1.922 ml). Benzylamine (0.042 ml, 0.384 mmol) was added and the reaction was stirred for one hour at 100° C. The reaction was filtered through a plug of diatomaceous earth, which was then washed with ethyl acetate. The filtrate was concentrated, dissolved in 1 mL of DCM, and TFA (0.1 ml, 1.298 mmol) was added. The reaction was concentrated and purified via HPLC (50-95% MeCN:H2O with 0.1% TFA modifier) to afford 5-(benzylamino)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.48 (s, 1H), 8.42 (d, J=9.1 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 7.70 (dd, J=2.0, 9.0 Hz, 1H), 7.39 (d, J=7.6 Hz, 2H), 7.34-7.27 (m, 4H), 7.24-7.17 (m, 1H), 6.51 (dd, J=2.2, 6.6 Hz, 1H), 4.50 (s, 2H). m/z (ESI) 397.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B2OC(CC)(CC)C(CC)(CC)O2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCC1(CC)OB(c2cc(OC)cc(OC)c2)OC1(CC)CC
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)cc(OC)c3)cccc2c1N
Yield: 91 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetraethyl-(1,3,2)-dioxaborolane (256 mg, 0.97 mmol) were reacted to afford the title compound (110 mg, 93.9% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.57 (br, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.79 (dd, J=7.2 Hz, J′=1.3 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 6.79 (d, 3H), 3.83 (s, 6H), 3.47 (q, J=6.7 Hz, 2H), 1.67 (m, J=7.3 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.98 min.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:23])[CH2:19][CH2:20]2)=[CH:16][C:15]=1[C:24]([OH:26])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:2][N:3]([CH3:4])[C:24]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:14]=1[O:13][CH3:12])[CH2:20][CH2:19][C:18]2=[O:23])=[O:26]
Reactant: COc1cc2c(cc1C(=O)O)C(=O)CC2
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1C(=O)N(C)C)C(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of Dimethylamine hydrochloride (2.22 g, 27.24 mmol) and triethylamine (7 ml, 54.48 mmol) in CH2Cl2 (30 ml) was added 6-Methoxy-3-oxo-indan-5-carboxylic acid (2 g, 9.08 mmol), HOBt (2.45 g, 18.18 mmol), EDCI (3.48 g, 18.18 mmol) at 0° C. in order. The mixture was stirred at room temperature for 3 hrs and washed with 8% NaOH, water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product (1.69 g, 80% yield). LC-MS: m/e 234 (MH+)
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH2:1]([S:5]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
6.3 g of n-butanesulfonyl chloride was added under ice cooling to 5.61 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 4.1 g of triethyl amine suspended in 50 ml of chloroform, and the mixture was stirred for 1 hour. Diluted hydrochloric acid was added to the reaction mixture, the chloroform layer was collected by separation, washed and dried, and then the solvent was removed. The resulting crystals were recrystallized from tetrahydrofuran-isopropyl ether to obtain 6.40 g of 2-n-butylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:26])[CH2:11][N:12]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:8].I[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1>[CH2:7]([O:9][C:10](=[O:26])[C@H:11]([CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[NH2:12])[CH3:8]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: ICC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](N)CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of potassium tert-butoxide (25.7 g) in tetrahydrofuran (800 mL) was added N-(diphenylmethylidene)glycine ethyl ester (45.20 g) over 20 min at 0 to 8° C. The reaction mixture was stirred at 0° C. for 30 min, and 4-(iodomethyl)tetrahydro-2H-pyran (42.0 g) was added thereto. The reaction mixture was stirred overnight at room temperature, and the precipitate solid was filtrated. The filtrate was concentrated, the obtained residue was dissolved in ethanol (200 mL), and 2M hydrochloric acid (200 mL) was added thereto. The reaction mixture was stirred overnight at room temperature, and concentrated. The residue was diluted with water, and the mixture was washed with ethyl acetate (×4). The aqueous layer was adjusted to pH 11 with 8M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (23.00 g, yield 67%) as a yellow oil.
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1.Cl.[NH2:25][OH:26].C(O)C>O>[O:6]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[N:25][OH:26])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1
Reactant: NO
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 70 °C
Reaction time: 10 h
Yield: 118.7 %

Procedure:
A solution of sodium acetate (6.64 g, 60.72 mmol) in water (10 mL) was added into a mixture of 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde (5.0 g, 20.24 mmol) benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606), hydroxylamine hydrochloride (4.22 g, 60.72 mmol), ethyl alcohol (300 mL), and water (50 mL). The mixture: was stirred at 70° C. for 10 hours, then poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 2/1) gave a white solid (6.3 g, 90% yield); mp 151–152° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.63 (m, 4H), 3.35 (m, 4H), 3.90 (s, 4H), 6.96 (m, 2H), 7.40 (m, 2H), 7.96 (s, 1H), 10.75 (s, 1H); MS (ES) m/z: 263 (MH+); Anal. Calcd. for C14H18N2O3: C, 64.11; H, 6.92; N, 10.68. Found: C, 64.24; H, 6.81; N, 10.64.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.Cl.CN(C)CCCN=C=NCC.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:32]([NH:39][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 40 °C
Yield: 57.3 %

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (50 mg, 0.22 mmol) (from example 11), p-hydroxybenzotriazole hydrate (HOBt) (74 mg, 2.5 eq.), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDAC HCl) (105 mg, 2.5 eq.), benzylamine (94 mg, 4 eq.) and triethylamine (TEA) (0.5 mL) in DMF (1 mL) was heated at 40° C. for overnight. The reaction was concentrated and the residue was purified on a silica gel column to give 40 mg of the titled compound as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:30][NH2:31]>C(O)(=O)C>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:31][NH:30][C:4](=[O:3])[CH:5]=2)=[CH:14][CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1n[nH]c(=O)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (28.08 mmol, 10.8 g) and hydrazine hydrate (15 mL) in acetic acid (45 mL) was stirred at 120° C. for 4 h. The reaction mixture was concentrated under reduced pressure and to the residue was added water (200 mL). This was extracted with DCM (3×200 mL), and the combined organic layer was dried and concentrated under reduced pressure. The resultant residue was purified by flash silica gel column chromatography eluting with 50% ethyl acetate in hexanes to afford 5-(4-benzyloxy-phenyl)-6-butyl-2H-pyridazin-3-one.
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:51])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[C:25]4[N:27]([CH2:30][C:31]([F:34])([F:33])[F:32])[N:28]=[CH:29][C:24]4=[C:23]([N:35]4[CH:40]5[CH2:41][N:42](C(OC(C)(C)C)=O)[CH2:43][CH:36]4[CH2:37][O:38][CH2:39]5)[N:22]=3)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH:36]12[N:35]([C:23]3[N:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:15]([NH:14][C:13]([NH:12][C:9]5[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:52])[CH3:1])=[CH:11][CH:10]=5)=[O:51])=[CH:16][CH:17]=4)[N:26]=[C:25]4[N:27]([CH2:30][C:31]([F:34])([F:32])[F:33])[N:28]=[CH:29][C:24]=34)[CH:40]([CH2:41][NH:42][CH2:43]1)[CH2:39][O:38][CH2:37]2
Reactant: CN(C)CCOc1ccc(NC(=O)Nc2ccc(-c3nc(N4C5COCC4CN(C(=O)OC(C)(C)C)C5)c4cnn(CC(F)(F)F)c4n3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(-c3nc(N4C5CNCC4COC5)c4cnn(CC(F)(F)F)c4n3)cc2)cc1

Procedure:
A solution of tert-butyl 9-(6-(4-(3-(4-(2-(dimethylamino)ethoxy)phenyl)ureido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate.TFA (174 mg) in dichloromethane (5 mL) was treated with trifluoroacetic acid (1 mL). After concentration, the residue was purified by reverse-phase high performance liquid chromatography to provide, after concentration, the title compound. MS (ES+): 626.3 (M+H)+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=[O:12])=[O:6]>>[CH:5]([NH:7][C:8]1[C:9]([N+:1]([O-:4])=[O:2])=[C:10]([C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=[O:12])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Br)c(C(=O)O)cc1NC=O
Product: Cc1cc(Br)c(C(=O)O)c([N+](=O)[O-])c1NC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (120 mL, 2.8 mol) is cooled to about 0° C., whereupon 3-(Formylamino)-6-bromo-4-methylbenzoic Acid (20) (28.243 g, 109.5 mmol) is added in small portions over about 45 minutes, at such a rate to maintain the internal reaction temperature <5° C. The reaction mixture is then stirred at about 0° C. for about 1 hour. The reaction mixture is added to ice water (500 mL) and stirred for about 1 hour. The solids that form are filtered and dried to provide 3-(Formylamino)-6-bromo-4-methyl-2-nitrobenzoic Acid (21), as a beige powder (31.465 g, 95% yield).
Reaction SMILES: [Br:1][C:2]1[C:13]([F:14])=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:15]Br>ClCCl>[Br:15][CH:9]1[C:10](=[O:11])[C:4]2[CH:3]=[C:2]([Br:1])[C:13]([F:14])=[CH:12][C:5]=2[O:6][CH2:7][CH2:8]1
Reactant: O=C1CCCOc2cc(F)c(Br)cc21
Reactant: BrBr
Solvent: ClCCl
Product: O=C1c2cc(Br)c(F)cc2OCCC1Br
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed 7-Bromo-8-fluoro-3,4-dihydro-2H-benzo[b]oxepin-5-one (1168 g, 4.51 mol, 1.00 equiv) and dichloromethane (8 L), followed by the addition of Br2 (724.3 g, 4.53 mol, 1.00 equiv) dropwise with stirring at −20° C. over 90 min. The resulting solution was stirred at −20° C. for 30 min and at room temperature for 3 h. The reaction was then quenched by the addition of 6000 mL of saturated aqueous Na2SO3 at 0° C. and extracted with 4×2 L of dichloromethane. The combined organic layers were washed with 2×3000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1170 g (77%) of 4,7-dibromo-8-fluoro-2,3,4,5-tetrahydro-1-benzoxepin-5-one as a yellow solid.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[CH3:6][C:7]([OH:12])([CH:10]=[CH2:11])[C:8]#[CH:9]>>[CH2:1]([O:3][CH:4]([O:12][C:7]([CH3:6])([CH:10]=[CH2:11])[C:8]#[CH:9])[CH3:5])[CH3:2]
Reactant: C=COCC
Reactant: C#CC(C)(O)C=C
Product: C#CC(C)(C=C)OC(C)OCC

Procedure:
By reacting ethyl vinyl ether with 3-methyl-4-penten-1-yn-3-ol in the manner of Example 1, the compound 1-ethoxy-1-[3-methyl-4-penten-1-yn-3-oxy]ethane was produced.
Reaction SMILES: [CH2:1](I)[CH3:2].[Br:4][C:5]1[C:13]2[O:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[CH:8]=[C:7]([F:17])[CH:6]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:4][C:5]1[C:13]2[O:12][C:11]([C:14]([O:16][CH2:1][CH3:2])=[O:15])=[CH:10][C:9]=2[CH:8]=[C:7]([F:17])[CH:6]=1
Reactant: O=C(O)c1cc2cc(F)cc(Br)c2o1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)cc(Br)c2o1
Temperature: 55 °C
Yield: 90.1 %

Procedure:
Ethyl iodide (4.6 ml, 57.2 mmol) was added to a mixture of 7-bromo-5-fluoro-benzofuran-2-carboxylic acid (3.7 g, 14.3 mmol) and sodium bicarbonate (4.8 g, 57.2 mmol) in anhydrous dimethylformamide (40 mL). The mixture was heated at 55° C. for 18 h, cooled to rt, quenched with water (20 mL) and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2; hexane/DCM; 4/1) to give 3.7 g (90%) of the product.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].[H-].[Na+].C1COCC1.[F:18][C:19]([F:37])([F:36])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([NH:32][CH3:33])=[CH:25][C:24]=1F>CCOC(C)=O>[F:18][C:19]([F:36])([F:37])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([NH:32][CH3:33])=[CH:25][C:24]=1[N:8]1[CH2:9][CH2:10][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6][CH2:7]1
Reactant: CNc1cc(F)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(O)C1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1cc(N2CCC(C(C)(C)O)CC2)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1-hydroxy-1-methyl-ethyl)-piperidine (24 mg, 0.17 mmol), NaH-suspension (50% in mineral oil, 8 mg, ˜0.17 mmol) and THF (1 mL) is stirred for 10 min. Then, N-(2,2,2-trifluoro-ethyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide is added and it is stirred for 1.5 h. The mixture is diluted with EtOAc, washed with water, concentrated, dried and directly used in the next step.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([Br:24])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:27]N(C=O)C>>[CH3:27][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([Br:24])[CH:18]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: O=C(Nc1ccccc1)N1CCN(Cc2ccc(Br)c(Br)c2)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)N1CCN(Cc2ccc(Br)c(Br)c2)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3,4-dibromo-benzyl)-piperazine-1-carboxylic acid phenylamide (0.02 g) in DMF (0.6 mL) was added NaH (60% dispersion in oil; 3 mg) in one portion. The resulting mixture was allowed to stir for 30 min, then was treated with Mel (0.005 mL), and was stirred at rt for 12 h. The mixture was concentrated and the residue was purified by column chromatography (5% MeOH/DCM), giving the product as a white solid (0.015 g). 1H NMR (400 MHz, CDCl3): 7.54-7.50 (m, 2H), 7.33-7.31 (m, 2H), 7.12-7.05 (m, 4H), 3.34 (s, 2H), 3.22-3.20 (m, 6H), 2.23-2.21 (m, 4H), 1.63 (s, 3H).