Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([O:11][CH2:12][CH:13]3[O:24][C:16]4=[N:17][C:18](=[O:23])[C:19]([S:21][CH3:22])=[CH:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1([O-])O[O:28]1.O.O.O.O.[Na+].[OH-].[Na+]>CC(O)=O>[CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([O:11][CH2:12][C@H:13]3[O:24][C:16]4=[N:17][C:18](=[O:23])[C:19]([S:21]([CH3:22])=[O:28])=[CH:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [O-]B1OO1
Reactant: CSc1cn2c(nc1=O)OC(COc1ccc(C3CCCCC3)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1cn2c(nc1=O)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a solution of 2-(4-cyclohexyl-phenoxymethyl)-6-methylsulfanyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (0.284 g, 0.763 mmol), prepared in accordance with the procedures set forth in Example 98, in HOAc (6 mL) was added sodium perborate tetrahydrate (0.313 g, 2.04 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then neutralized with NaOH (2N) to PH˜9 after which it was extracted with EtOAc three times. The organic phase was washed with brine and dried (Na2SO4). Silica gel chromatography (0-8% EtOH/CH2Cl2) provided 0.03 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-6-methanesulfonyl-2,3-dihydro-oxazolo[3,2a]pyrimidin-7-one, 0.042 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-6-methanesulfinyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (Diastereomer 1) and 0.011 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-6-methanesulfinyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (Diastereomer 2).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:26]([O:30][CH2:31]Cl)(=[O:29])[CH2:27][CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:31][O:30][C:26]([CH2:27][CH3:28])=[O:29])=[O:24])(=[O:21])=[O:20]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1cc(C(=O)OCOC(=O)CC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
In a similar manner to Example 12, bumetanide can be reacted with chloromethyl propionate, triethylamine and sodium iodide in dimethylformamide (DMF) to yield ethylcarbonyloxymethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[S:12])([O-:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[N:13][C:14](=[O:16])[CH3:15])[S:12][CH3:17])([O-:3])=[O:2]
Reactant: CC(=O)NC(=S)Nc1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=NC(C)=O)Nc1ccccc1[N+](=O)[O-]
Yield: 42 %

Procedure:
6.5 g (0.026 M) of N-(o-nitrophenyl)-N'-acetyl-thiourea, 2.1 g (0.015 M) of potassium carbonate, 1.9 ml (0°-0.29 M) of methyl iodide and 70 ml of acetone are boiled in a reflux for four hours. The acetone is distilled off. Water is added to the residue and it is filtered. After drying 6.6 g (100% of the theoretical yield) of the product are obtained with a melting point of 118°-160°. After recrystallization twice from ethanol and isopropanol N-(o-nitrophenyl)-N'-acetyl-S-methylisothiourea with a melting point of 120°-122° C. and 42% yield of the theoretical one is obtained.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25]>CN(C)C=O>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[C:24]=1[CH3:25]
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Reactant: Cc1nc[nH]c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2nccc3[nH]c(=O)ccc23)c1C
Yield: 48 %

Procedure:
A mixture containing 12.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 300 ml of dimethylformamide, 13.8 g of anhydrous potassium carbonate, 10.8 g of 4,5-dimethylimidazole and 200 mg of cuprous bromide was refluxed with stirring for eight hours About 20 ml of the solvent was distilled off using a water separator to remove any moisture from the reaction mixture. The remaining reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in water, acidified with acetic acid and evaporated to dryness on a rotary evaporator. The residue was treated with 50 ml of water and the brown solid was collected, washed with water, recrystallized from ethanol in the presence of decolorizing charcoal. The resulting pale yellow solid was dried at 80°-85° C. to yield 6.4 g of 5-(4,5-dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 256°-258° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1>C(O)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:30]3[C:39]4[C:34](=[CH:35][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:12][CH2:13]1
Reactant: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Solvent: CCO
Solvent: CC(=O)Cl
Product: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.8 %

Procedure:
To 1.73 g (0.00498 n) of 1-[(p-aminophenyl)sulfonyl]-4-(o-methoxyphenyl)piperazine in absolute ethanol is added 0.35 ml acetyl chloride in 5 ml ethanol (source of hydrogen chloride). After stirring for 5 minutes, 1.15 g (0.00498 m) of 4-chloro-7-trifluoromethylquinoline is added. The reaction mixture is stirred at reflux for 3 hours and at room temperature overnight. The solvent is then removed in vacuo and the residue is extracted with methylene chloride/aqueous sodium bicarbonate. The organic layer is filtered through anhydrous sodium sulfate and taken to dryness and the product mixture is chromatographed on silica gel, once with 4% methanol: 96% methylene chloride as eluant, and a second time with methylene chloride as the eluant. Crystallization from methylene chloride/Skelly-solve® B hexanes gives 1.61 g (61%) of 1-(2-methoxyphenyl)-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine of melting point 146°-148° C.
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(OC([NH:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][N:23]=1)=S)=O)C>C(O)C>[Br:28][C:26]1[CH:25]=[CH:24][N:23]2[N:6]=[C:19]([NH2:18])[N:21]=[C:22]2[CH:27]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(Br)ccn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Product: Nc1nc2cc(Br)ccn2n1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A mixture of hydroxylamine hydrochloride (20.0 g, 288 mmol) and N-ethyldiisopropylamine (30.1 ml, 173 mmol) in ethanol (367 ml) is stirred for a few minutes at room temperature and the mixture is added to 1-ethoxycarbonyl-3-(4-bromo-pyridin-2-yl)-thiourea (17.5 g, 57.5 mmol). The resulting mixture is refluxed for 1 day. The solvent is evaporated and 100 ml water is added to the residue. The suspension is stirred for 10 minutes, the solid is collected by filtration, washed with water and dried affording 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (10.71 g, 87.4%) as a light yellow solid. Mp.: 190-2° C. MS: m/z=213.0, 215.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([N:11]=[N+]=[N-])[CH2:6]1)=[O:4]>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH2:11])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N)[C@@H](O)C1

Procedure:
To a stirred solution of (1R,3S,4S)-3-azido-4-hydroxy-cyclopentanecarboxylic acid methyl ester (2.73 g; CAS 213742-85-9; prepared as described in WO00/09463) at r.t. in methanol (30 ml) was added under an argon atmosphere Pt2O (140 mg). The reaction mixture was hydrogenated over night. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated to give (1R,3S,4S)-3-amino-4-hydroxy-cyclopentanecarboxylic acid methyl ester (2.29 g) as brown oil. MS: 160.3 ([M+H]+).
Reaction SMILES: [CH:1](=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[C:2]1([C@H:1]2[C@@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC/N=C/c1ccccc1
Agent: [Ti+4]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.7 %

Procedure:
To the imine 9A (0.31 g, 1.51 mmol) and triethylamine (0.42 mL, 3.02 mmol) in dichloromethane (15 mL) at 0° C. was added titanium chloride (1.51 mL, 1.0 M in dichloromethane) dropwise under argon. The reaction was stirred at rt for 3 h and then quenched with saturated potassium carbonate. The mixture was filtered through celite and the aqueous layer was extracted with dichloromethane (2×). The organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by preparative HPLC equipped with a YMC ODS S5 (30×100 mm) column. The separation was performed using a linear gradient (solvent A: 10% acetonitrile-90% water-0.1% TFA; solvent B: 90% acetonitrile-90% water-0.1% TFA; 0 to 100% B in 12 min with a flow rate of 40 mL/min to give 0.095 g of 9B as a solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 2.50 (m, 2H) 3.42 (s, 3H) 3.55 (m, 1H) 3.72 (m, 2H) 4.98 (d, J=7.09 Hz, 1H) 7.36 (m, 2H) 7.44 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][N:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN1CCCC1=O>[N:17]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[N:4][N:3]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Clc1nnc(-c2ccco2)c2ccccc12
Reactant: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: c1coc(-c2nnc(-n3ccnc3)c3ccccc23)c1
Temperature: 150 °C
Reaction time: 10 h
Yield: 4.3 %

Procedure:
300 mg of 1-chloro-4-(2-furyl)phthalazine and 707 mg of imidazol were dissolved in 2 ml of N-methylpyrrolidone, and the solution was stirred at 150° C. for 10 hours. After the solution was subjected to after-treatment, it was purified by column chromatography, thereby obtaining 14.5 mg of 1-(1-imidazolyl)-4-(2-furyl)phthalazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[Cl:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=C=O
Reactant: Clc1cc(Br)c2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1cc(Cl)cc2cc[nH]c12
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
1.15 g (5 mmol) of 7-bromo-5-chloro-1H-indole were dissolved in 30 ml THF. At a temperature of −75° C. under argon 9.4 ml (15 mmol) of a 1.6 M n-butyl lithium solution in hexane were added dropwise. After complete addition the reaction mixture was stirred at 5° C. for 30 min, cooled to −75° C. and 10 g dry ice was added. The reaction mixture was warmed to rt and stirred for 15 min. It was poured onto 100 ml of water and extracted twice with EtOAc. The aqueous layer was acidified with 1N aqueous HCl solution and extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated. The residue was treated with hexane and stirred for 10 min. The precipitate was filtered, washed with hexane and dried to yield 700 mg (72%) of 5-chloro-1H-indole-7-carboxylic acid as a white solid. MS (ISP) 194.0 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[Br:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Br:26][C:27]1[CH:28]=[C:29]([C:6]2[CH:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (1.0 g, 2.6 mmol) and commercially available 3-bromo-benzene-boronic acid (0.573 g, 2.85 mmol) according to the general procedure IVb. Obtained as an off-white solid (1.00 g, 98%). MS (ISP) 392.0 [(M+H)+] and 394.0 [(M+2+H)+].
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][C:22]2[N:23]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][N:26]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][CH:36]([O:40][CH3:41])N(C)C>>[CH3:34][O:35][CH:36]([O:40][CH3:41])[N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][CH2:30]1
Reactant: c1ccc(C(NCc2nccn2CC2CCNCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(Cn2ccnc2CNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]piperidine (1.45 g, 0.0033M) and dimethylformamide dimethylacetal was heated at 100° C. for 8 hrs. After this period, the reaction was stripped to dryness to give 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-piperidine carboxaldehyde dimethylacetal. The solution of the piperidinecarboxaldehydedimethylacetal in methylene chloride (5 ml) was added to the mixture of 6-aminopenicilanic acid (0.57 g, 0.0026M) and diisopropylethylamine (0.45 ml) in methylene chloride (5 ml) at 0° C. and stirred at room temperature for 3 hrs. The solvent was removed and the residue was stirred for 2 hrs in water (20 ml) which was maintained at pH 3 with 1NHCl. The mixture was filtered and the filtrate was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[[2-(aminomethyl)-1H-imidazol-1-yl]methyl]-1-piperidinyl] methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.27 g, 24% yield).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)#[N:2].C(Cl)Cl.C(N(CC)CC)C.Cl.[NH2:31][OH:32]>C(O)C.C(=O)(O)[O-].[Na+]>[OH:32][NH:31][C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[NH:2]
Reactant: NO
Reactant: COc1ccc(CC(=O)Nc2sccc2C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2sccc2C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide (234 mg, 0.859 mmol) in a mixture of ethanol (5 mL), methylene chloride (0.5 mL) and triethylamine (202 4, 1.46 mmol) was added hydroxylamine hydrochloride (90 mg, 1.29 mmol). The resulting solution was stirred at room temperature for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 7/3 to 2/8) to give N-(3-(N-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide. Retention time (min)=1.161, method [1], MS (ESI) 306.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[CH3:14][C@@H:10]1[NH:11][CH2:12][CH2:13][N:8]([C:5]2[N:6]=[N:7][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=3)=[C:3]3[CH:18]=[CH:17][N:16]=[CH:15][C:4]=23)[CH2:9]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1
Temperature: 100 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a round bottomed flask was added (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 (155 mg, 588 μmol), 4-trifluoromethylphenylboronic acid (167 mg, 882 μmol), tetrakis(triphenylphosphine)palladium (34 mg, 29 μmol), and 2 M aqueous sodium carbonate (588 μl, 1.18 mmol). Toluene (5.9 mL) was added and the reaction was heated to 100° C. After 16 h, the reaction was cooled to RT and diluted with ethyl acetate (70 mL). The organic layer was washed with 1×10 mL of sat. NaHCO3, 1×10 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (10:0.5:0.1) (CH2Cl2:MeOH:Et3N) afforded (S)-4-(3-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 47 (154 mg, 70% yield). 1H-NMR (400 MHz, CDCl3): δ 9.55 (d, J=0.8 Hz, 1H), 8.90 (d, J=5.5 Hz, 1H), 7.86 (m, 4H), 7.73 (dd, J=5.5, 0.8 Hz, 1H), 4.09 (m, 2H), 3.37 (ddd, J=12.5, 11.0, 3.5 Hz, 1H), 2.23 (m, 3H), 2.99 (dd, J=12.5, 10.2 Hz, 1H), 2.85 (br s, 1H), 1.17 (d, J=6.3 Hz, 1H). MS 373.1 (calc'd) 374.0 (M+H, found).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Li+].C([O-])(O)=O.[Na+].Cl[CH2:25][C:26](=[O:28])[CH3:27]>C(O)C.O>[CH2:1]([N:8]([CH2:25][C:26](=[O:28])[CH3:27])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc(NCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N(CC(C)=O)Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
To a solution of N-benzyl-p-anisidine (2.00 g, 9.38 mmol) in 19 mL of ethanol was added lithium bromide (1.22 g, 14.0 mmol), NaHCO3 (1.58 g, 18.8 mmol), chloroacetone (0.87 mL, 10.8 mmol) at room temperature, successively. After the reaction mixture was stirred at 80° C. for 3 h, the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound (2.09 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[OH:8].I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=3)[C:21]=12
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(O)c(F)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 27.4 %

Procedure:
A solution of 3-fluoro-4-hydroxyphenylboronic acid (103 mg, 0.66 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.33 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP using silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA59 (26 mg, 27% yield). ESI-MS (M+H)+ m/z calcd 288, found 288.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Yield: 110.6 %

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (632 mg, 2.07 mmol, Eq: 1.00) in EtOH (25.0 ml) and ethyl acetate (10 ml) was combined with palladium on carbon (66.1 mg, 62.1 μmol, Eq: 0.03). The mixture was evacuated twice with hydrogen and then stirred with a hydrogen-filled balloon for 22 h. The hydrogen was replaced with nitrogen. The solution was filtered through celite. The celite was washed several times with EtOAc. Concentrated in vacuo to give tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (635 mg, quantitative yield). LC/MS-ESI observed [M+H]+ 278.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:21])[CH3:20])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[F:28][C@H:29]1[C@@H:34]([CH2:35][OH:36])[CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30]1>CN(C)C=O>[F:28][C@H:29]1[C@@H:34]([CH2:35][O:36][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:20])[CH3:21])=[CH:14][N:13]=3)=[CH:4][CH:3]=2)[CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](F)C1
Reactant: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
4-fluoro-N-isobutyl-N-(5-isopropyl-3-methylpyridin-2-yl)benzenesulfonamide (35 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (DMF) (3 mL) and to this solution was added sodium hydride (2 mg, 0.10 mmol, 60% wt in mineral oil) followed by tert-butyl cis-3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (22 mg, 0.10 mmol). The reaction was stirred overnight at room temperature, under nitrogen, then quenched with water and concentrated in vacuo. The crude product was extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was then passed through a hydrophobic frit and concentrated in vacuo to give the title compound (53 mg). LCMS (2 min, formic) Rt 1.53 min, m/z (ES+) 578 (M+H).