Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][O:16]S(C)(=O)=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)OCc1ccc(Oc2ccc([N+](=O)[O-])cc2)nc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(COc3ccc(C(F)(F)F)cc3)cn2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 6-(4-nitrophenoxy)-pyridin-3-ylmethyl ester (4.86 g, 15 mmol) was dissolved in DMF (250 mL), and to the resulting solution were added 4-hydroxybenzotrifluoride (2.92 g, 18 mmol) and potassium carbonate (3.11 g, 22.5 mmol). The resulting solution was stirred under a nitrogen atmosphere for 1 hour at 50° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane methanol=80:1), to thereby yield 5.8 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[NH:12][C:11]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:10]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1.[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:3][O:4][C:5]1[C:13]2[N:12]([CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[OH:19])[C:11]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:10]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: c1cc(C2CO2)ccn1
Reactant: COc1cccc2c3c([nH]c12)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c3c(n(CC(O)c4ccncc4)c12)CCN(C)C3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.6 %

Procedure:
Sodium hydride (60%) (555 mg, 13.88 mmol) was added portionwise to a solution of 6-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.629 mmol) in DMF (10 mL) and stirred at RT for 15 min, the suspension was allowed to cool at 0° C. 4-(Oxiran-2-yl)pyridine (896 mg, 7.407 mmol) was added dropwise and reaction mixture was stirred at RT for 48 h. The reaction mixture was poured in to ice-cooled water and extracted with EtOAc (3×50 mL), and the organic layer was washed with water (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo, afforded crude was purified by reverse phase HPLC to afford 2-(6-methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol (165 mg) as the formate salt. 1H NMR (CDCl3, freebase) δ (ppm): 8.60 (d, 2H), 7.31 (d, 2H), 7.02 (m, 2H), 6.66 (d, 1H), 5.08 (dd, 1H), 4.66 (dd, 1H), 4.12 (dd, 1H), 3.99 (s, 3H), 3.60 (d, 1H), 3.56 (d, 1H), 2.9 (m, 1H), 2.81 (m, 1H), 2.72 (m, 1H), 2.64 (m, 1H), 2.55 (s, 3H). Separation by chiral HPLC provided enantiomers 44a and 44b.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:5][N:4]1[C@H:3]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:11][C:6]([C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:5]=[N:4][CH:3]=4)=[CH:7][C:19]=3[CH2:20][CH2:2]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: Brc1cncc2ccccc12
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cncc5ccccc45)cc3CC[C@@H]12
Yield: 47 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-bromoisoquinoline (135 mg, 0.65 mmol), 0.65 mL of sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. An additional 23 mg of the palladium reagent was added, and the mixture was heated an additional 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2 ×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 110 mg (47%) of the title compound as an amorphous foam. FDMS: m/e=356. α[D]589 =+67.82 (c=0.40, methanol).
Reaction SMILES: P(O[CH2:10][CH3:11])(OCC)(OCC)=O.Br[CH2:13][CH2:14][CH2:15][Si@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:27]=[C:26]([F:28])[C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([F:33])[CH:23]=2)[CH2:18][CH2:17]1>C1COCC1.[Cu]I>[F:33][C:24]1[CH:23]=[C:22]([C@H:19]2[CH2:20][CH2:21][Si@H:16]([CH2:15][CH2:14][CH2:13][CH2:19][C@H:22]3[CH2:27][CH2:26][C@H:25]([CH2:29][CH2:10][CH3:11])[CH2:24][CH2:23]3)[CH2:17][CH2:18]2)[CH:27]=[C:26]([F:28])[C:25]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CCOP(=O)(OCC)OCC
Reactant: Fc1cc([C@H]2CC[Si@H](CCCBr)CC2)cc(F)c1C(F)(F)F
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](CCCC[Si@H]2CC[C@H](c3cc(F)c(C(F)(F)F)c(F)c3)CC2)CC1

Procedure:
21.9 g (0.1 mol) of trans-4-bromomethyl-1-n-propyl-1-silacyclohexane was dropped in a mixture of 2.5 g (0.11 mols) of magnesium and 300 ml of THF to obtain a Grignard reagent. The resultant solution was then dropped in a solution, in 500 ml of THF, of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 40.1 g (0.1 mol) of 4-(trans-4-(3-bromopropyl)-4-silacyclohexyl) -2,6-difluoro-1-trifluormethylbenzene. The resultant product was subjected to ordinary aftertreatments to obtain trans-4-(4-(trans-4-(3,5-difluoro-4-trifluoromethylphenyl)-1-silacyclohexyl)butyl)-1 -n-propylcyclohexane, followed by isolation through chromatography to obtain 37.2 g (yield: 81%) of the intended trans isomer product.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][CH2:16][C:17]2[C:25]3[O:24][CH2:23][CH2:22][C:21]=3[CH:20]=[CH:19][CH:18]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[O:24]1[C:25]2[C:17]([CH2:16][NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:22][CH2:23]1
Reactant: CCOC(=O)C1(NCc2cccc3c2OCC3)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=C(O)C1(NCc2cccc3c2OCC3)Cc2ccccc2C1
Reaction time: 16 h
Yield: 96.6 %

Procedure:
A 100 mL round bottom flask containing 2-[(2,3-Dihydro-benzofuran-7-ylmethyl)-amino]-indan-2-carboxylic acid ethyl ester (367, 350 mg, 1.037 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (110 mg, 2.52 mmol). After 16 h, tlc analysis (silica, 50% EtOAc/Heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 6 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provided white solid (0.31 g, 99%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=[C:6]([F:32])[CH:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[F:32][C:6]1[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3nc4c(C(N)=O)cc(F)cc4[nH]3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(F)cc2[nH]c(-c3ccc(C4CCNCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
A mixture of EXAMPLE 88C (0.26 g, 0.6 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) and the mixture stirred at ambient temperature for 4 hours. The mixture was concentrated and purified by flash chromatography on silica gel using 0-10% methanol/dichloromethane/0.1% ammonium hydroxide, followed by HPLC on a C18 column using 0-100% acetonitrile/water/0.1% trifluoroacetic acid, to provide the title compound (0.131 g) as the trifluoroacetate salt. 1HNMR (DMSO-D6) δ 9.22 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 8.21 (d, J=8.3 Hz, 2H), 7.94 (s, 1H), 7.55-7.62 (m, 2H), 7.45 (t, J=7.7 Hz, 2H), 3.40 (s, 2H), 2.99-3.07 (m, 2H), 1.99 (s, 2H), 1.78-1.90 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:40])[C:36]([OH:39])([CH3:38])[CH3:37])[NH:30][C:29](=[O:41])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:40])[C:36]([OH:39])([CH3:38])[CH3:37])[NH:30][C:29](=[O:41])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 73.9 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol), N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide 11b (28.3 mg, 0.112 mmol) and piperidine (50 μL, 0.5 mmol) were dissolved in 2 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-N-{5-fluoro-3-[5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide 11 (46 mg, 74%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9](C(OC(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH2:21]([N:23]1[C:35]2[CH:34]=[CH:33][C:32]([NH2:36])=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][NH:9][C@H:8]([C:18]([NH:36][C:32]2[CH:33]=[CH:34][C:35]3[N:23]([CH2:21][CH3:22])[C:24]4[C:29]([C:30]=3[CH:31]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: C=CCON=C1CN[C@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=377.2.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[NH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:15]N(C=O)C.CI>O>[CH3:15][N:9]1[C:10]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8]1
Reactant: CN(C)C=O
Reactant: COC(=O)c1c[nH]c2c1CCCC2=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cn(C)c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of methyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (300 mg, 1.55 mmol) in dry DMF (5 mL) K2CO3 (429 mg, 3.10 mmol) and methyl iodide (0.193 mL, 3.10 mmol) were added. The reaction was stirred at room temperature for 3 h, then H2O was added (100 mL) and the product extracted with DCM (3×30 mL). The organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give 305 mg (yield: 95%) as light yellow solid.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1.O>[C:3]([C@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH3:6])(=[O:4])[NH2:5]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)C(N)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](OS(C)(=O)=O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71233.6 %

Procedure:
Alternatively, to a solution of (R)-2-hydroxy-propionamide (10 g, 0.11 mmol) and triethylamine (17.2 mL, 0.12 mmol) in THF (130 mL) at 0° C. was added dropwise, methanesulfonyl chloride (9.56 mL, 0.12 mmol) causing a thick white precipitate to form. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with TBME to yield methanesulfonic acid (R)-1-carbamoyl-ethyl ester as a white solid (13.1 g, 70%). 1H NMR (400 MHz, d6-DMSO) 7.56 (1H, br s), 7.41 (1H, br s), 4.91 (1H, t, J=6.6 Hz), 3.23 (3H, s), 1.44 (3H, d, J=6.6 Hz)
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([OH:9])(=O)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]([NH:22][CH:23]=[NH:24])[NH:20][N:21]=1.C(OC(=O)OCC)C>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]2[N:22]=[CH:23][NH:24][C:6](=[O:9])[N:20]2[N:21]=1
Reactant: N=CNc1cc(-c2ccccc2Cl)n[nH]1
Reactant: CC(=O)O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: O=c1[nH]cnc2cc(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To an ethanolic solution of sodium ethoxide, generated by portionwise addition of sodium metal (4.2 g, 185 mmol) to stirred ethanol (250 ml), was added N-[5-(2-chlorophenyl)-2H-pyrazol-3-yl]-formamidine, acetate salt (I-3A-9b; 5.2 g, 18.5 mmol) in one portion. Diethylcarbonate (17.8 ml, 148 mmol) was added, dropwise, and the mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction was concentrated, in vacuo, and then extracted with ethyl acetate from water after adjusting to pH 7 with 3 M aqueous HCL. The combined organic layers were washed with water and then brine, dried (MgSO4), filtered, and then concentrated, in vacuo, to one-third volume at which time a precipitate began to form. After stirring overnight, the product was collected by vacuum filtration and then dried, in vacuo, to afford I-3A-9c as a solid (2.61 g, 57%). A second crop of the intermediate was collected from the filtrate after standing an additional 24 hours (600 mg, 19%): +ESI MS (M+1) 247.1; 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.86-7.82 (m, 1H), 7.55-7.51 (m, 1H), 7.45-7.39 (m, 2H), 6.92 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17](O)=[CH:16][C:15]=1[CH3:22]>>[ClH:13].[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:10][CH:9]2[CH2:8][N:7]([CH3:11])[CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:16][C:15]=1[CH3:22]
Reactant: Cc1cc(O)cc(C)c1Cl
Reactant: Cc1cc2c(o1)CN(C)CC2O
Product: Cc1cc2c(o1)CN(C)CC2Oc1cc(C)c(Cl)c(C)c1
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 4-chloro-3,5-dimethylphenol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)[CH:9]=[C:10]2[NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:5][CH:4]=1.[Br:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2Cl)[NH:29][N:28]=1.C(OCC)(=O)C>O1CCCC1.C(N(CC)CC)C>[Br:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)[CH:9]=2)[NH:29][N:28]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: CNc1nccc(-c2cc(NCCCN)c3cc(OC)ccc3c2)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNc1nccc(-c2cc(NCCCNc3ncnc4[nH]nc(Br)c34)c3cc(OC)ccc3c2)n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a slurry of 182 in tetrahydrofuran (10 ml) and triethylamine (0.3 ml) was added 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (63 mg). The mixture was shaken at 50° C. for 24 hours. After cooling to room temperature the mixture was poured into ethyl acetate (150 ml) washed with water (2×200 ml) and the organic layer dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow solid which was purified by silica gel chromatography eluting with 60-100% ethyl acetate in hexanes to 1% methanol in ethyl acetate yielding N1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N3-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)propane-1,3-diamine 183 as a yellow powder (43 mg). M.p.=145-148° C. 1H NMR (DMSO-d6) 400 MHz δ 8.26 (s, 1H), 7.84-7.8 (m, 2H), 7.63-7.52 (m, 1H), 7.22-7.0 (m, 5H), 7.15-7.12 (m, 1H), 5.16 (m, 1H), 4.56-4.53 (m, 2H), 3.9 (s, 3H), 3.75 (m, 2H), 3.52-3.4 (m, 2H), 2.87-2.86 (m, 3H), 2.11 (m, 2H), LCMS m/e 534 and 536 (M+) Calculated for C24H24BrN9O 0.72 H2O-0.32 C4H8O2: C 52.75, H 4.9, N 21.9; found C, 52.76; H, 4.44; N, 21.92.
Reaction SMILES: C(OC([NH:8][C@:9]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][C:13](=[O:15])[NH:12][C:10]1=[O:11])=O)(C)(C)C.[ClH:21]>C(OCC)(=O)C>[ClH:21].[NH2:8][C@:9]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][C:13](=[O:15])[NH:12][C:10]1=[O:11]
Reactant: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)CC(=O)NC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(N)CC(=O)NC1=O
Reaction time: 1 h
Yield: 95 %

Procedure:
(R)-2-t-Butyloxycarbonylamino-2-ethoxycarbonylsuccinimide (243 mg) obtained in Example 21 was dissolved in a 4 mol/L solution of hydrochloric acid in ethyl acetate (5 mL), and the reaction mixture was stirred for 1 hour, and then concentrated under reduced pressure. The residue was suspended in ether, and filtered to obtain the title compound (179 mg, yield: 95%) as white crystals. Optical rotation [α]D25 was −14.2° (c 1.0, methanol). Optical purity was 71.6% ee.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[CH3:42][S:43]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1)(=[O:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a stirred solution of tert-butyl 4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazine-1-carboxylate (3.8 g, 10.4 mmol) in CH2Cl2 (35 mL) at 0° C. was added trifluoroacetic acid (17.2 mL). The reaction was brought to room temperature and stirred for 30 minutes. Volatiles were removed in vacuo, and the residue was azeotroped with toluene (2×10 mL). The residue was then dissolved in CH2Cl2 and washed with aqueous sodium hydroxide solution (2M, 2×20 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (3×10 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), and cooled to 0° C. and treated sequentially with triethylamine (1.5 mL, 16.7 mmol) and methanesulfonyl chloride (1.1 mL, 13.5 mmol). The reaction was brought to RT and stirred for 1 hour. The reaction was then quenched with water (50 mL). The layers were separated and the aqueous phase extracted with CH2Cl2 (3×20 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtoAc) to give 1-(methylsulfonyl)-4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazine as a brown solid (3.5 g, 10.2 mmol, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]([CH3:29])[CH3:28])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.O>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:27]([CH3:28])[CH3:29])[N:9]=2)=[CH:12][C:13]=1[O:25][CH3:26]
Reactant: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1N

Procedure:
A solution of tert-butyl 4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenylcarbamate (BA20) (20 mg, 0.05 mmol) in CH2Cl2, TFA, S(CH2)2, H2O (45:45:5:5) (1 ml) was stirred at room temperature for 15 minutes. NaHCO3 (2 ml) was added till reaction was alkaline. Reaction was extrated with H2O and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA20d.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=O)=O)=[CH:4][CH:3]=1.N(CC(O)C)N.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:25]([CH2:27][CH2:28][C:29](O)=O)=O.[NH:36]([CH2:38][CH:39]([OH:44])[CH2:40][CH2:41][CH2:42][CH3:43])[NH2:37].N(CC(O)CC)N>>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]2[CH2:8][CH2:9][CH:10]=[N:37][N:36]2[CH2:38][CH:39]([OH:44])[CH2:40][CH2:41][CH2:42][CH3:43])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]2[CH2:27][CH2:28][CH:29]=[N:37][N:36]2[CH2:38][CH:39]([OH:44])[CH2:40][CH2:41][CH2:42][CH3:43])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CCCCC(O)CNN
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: CC(O)CNN
Agent: CCC(O)CNN
Product: CCCCC(O)CN1N=CCCC1c1ccc(Cl)c(Cl)c1
Product: CCCCC(O)CN1N=CCCC1c1ccc(F)cc1

Procedure:
When the above procedure is carried out using equivalent amounts of 3-(p-fluorobenzoyl)-propionic acid and 1-hydrazino-2-hexanol,3-(3,4 dichlorobenzoyl)-propionic acid and 1-hydrazino-2-propanol or 3-(3,4-dichlorobenzoyl)-propionic acid and 1-hydrazino-2-hexanol in place of the 3-(p-chlorobenzoyl)-propionic acid and 1-hydrazino-2-butanol used therein, there is obtained 3-(p-fluorophenyl)-2-(2-hydroxyhexyl)-4,5-dihydropyridazin (2H)-3-one(m.p. 75°-77° C.) 3-(3,4-dichlorophenyl)-2-(2-hydroxypropyl)-4,5-dihydropyridazin(2H)-3-one (m.p. 108.5°-100° C.) or 3-(3,4-dichlorophenyl)-2-(2-hydroxyhexyl)-4,5-dihydropyridazin (2H)-3-one(m.p. 80°-81° C.) respectively.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:11](O)(=[O:14])[CH:12]=[CH2:13].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.F>>[N+:7]([C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:1]=1)[O:10][CH2:13][CH2:12][C:11]2=[O:14])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=CC(=O)O
Agent: F
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2ccc([N+](=O)[O-])cc21

Procedure:
Following the same procedure as Example 1, p-nitrophenol (34.8 grams), acrylic acid (27 grams), and an inhibitor, phenothiazine (0.02 grams) was added to the pressure reactor. The anhydrous hydrogen fluoride (110 grams) was added before the system was warmed. When the reaction temperature was attained, a pressure of 140 psig was noted, similar to previous reactions. Work-up was carried out as previous examples and the 6-Nitro-4-Chromanone was isolated and characterized.