Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C[Sn](C)(C)[C:28]1[CH:29]=[N:30][CH:31]=[N:32][CH:33]=1.C(N(CC)CC)C.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:28]4[CH:29]=[N:30][CH:31]=[N:32][CH:33]=4)[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Sn](C)(C)c1cncnc1
Reactant: CN1CCC(c2cccc3ccc(OS(=O)(=O)C(F)(F)F)cc23)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCC(c2cccc3ccc(-c4cncnc4)cc23)CC1
Temperature: 115 °C

Procedure:
A mixture of 1-(1-methylpiperidin-4-yl)-7-trifluoromethanesulfonyloxynaphthalene (0.304 g, 0.819 mmol), 5-trimethylstannylpyrimidine (0.220 g, 0.905 mmol), triethylamine (0.55 mL, 3.95 mmol), lithium chloride (0.107 g, 2.53 mmol), bis(triphenylphosphine)palladium chloride (0.029 g, 0.041 mmol), and butylated hydroxytoluene (BHT, approx. 0.01 g, antioxidant) in dimethylformamide (15 mL) was heated to 115° C. for 1 hour. The reaction was cooled and diluted with ethyl acetate. The mixture was extracted with a mixture of 1N lithium chloride (25 mL) and 1N sodium hydroxide (3 mL), 1N lithium chloride and brine. The organic phase was dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (1×2.5 inches packed with 75% ethyl acetate/hexane). Elution proceeded as follows: 75% ethyl acetate/hexane, 225 mL, nil; ethyl acetate, 200 mL, nil; 1% methanol/ethyl acetate, 200 mL, nil; 5% methanol/ethyl acetate, 300 mL, nil; and 7% methanol/1% triethylamine/ethyl acetate, 250 mL, 0.130 g (52%) of 1-(1-methylpiperidin-4-yl)-7-pyrimid-5-yl-naphthalene as a tan foam. A sample triturated with ether afforded white crystals which had: Mp 121.5°-123° C.; 1H NMR (250 MHz, CDCl3) δ 9.27 (s, 1H), 9.08 (s, 2H), 8.26 (s, 1 H), 8.03 (d, J=8.5 Hz, 1H), 7.78 (dd, J=3, 6.5 Hz, 1H), 7.69 (dd, J=1.5, 8.5 Hz, 1H), 7.57-7.50 (m, 2H), 3.36 (sym m, 1H), 3.09 (br d, J=12 Hz, 2H), 2.40 (s, 3H), 2.28 (sym m, 2H), 2.06-1.90 (m, 4H). Analysis calculated for C20H21N3 : C, 79.17; H, 6.98;N, 13.85. Found: C, 78.46; H, 7.14; N, 13.89. HRMS m/e 303.1731. Observed m/e 303.1700.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][S:22](=[O:25])(=[O:24])[N:21]([C:26]3[C:35]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][C:29]([C:30](OC)=[O:31])=[C:28]([CH3:40])[CH:27]=3)[CH2:20]2)=[CH:15][CH:14]=1.Cl>CN(C=O)C.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][S:22](=[O:24])(=[O:25])[N:21]([C:26]3[C:35]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][C:29]([C:30]([NH:10][C:9]([NH2:11])=[NH:8])=[O:31])=[C:28]([CH3:40])[CH:27]=3)[CH2:20]2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N2CC(c3ccc(F)cc3)CS2(=O)=O)cc1C
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CC(c3ccc(F)cc3)CS2(=O)=O)c(S(C)(=O)=O)cc1C(=O)NC(=N)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
44.48 g of KOtBu were dissolved in 800 ml of anhydrous DMF and, at RT, 45.44 g of guanidinium chloride were added. After stirring at RT for 1 hour, the solution was poured into a solution of 35.00 g of methyl 4-[4-(4-fluoro-phenyl)-1,1-dioxoisothiazolidin-2-yl]-5-methanesulfonyl-2-methylbenzoate in 300 ml of anhydrous DMF. The mixture was then stirred at RT for 5 hours. It was then poured into 2 l of water, adjusted to pH=8 with aqueous HCl solution and extracted 5 times with 300 ml of EA each time. After drying over MgSO4, the solvent was removed in vacuo.
Reaction SMILES: CS(O)(=O)=O.C([O:13][C:14]1[CH:39]=[CH:38][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][C:22]=2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:19])=[CH:16][CH:15]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[BrH:48].C(OCC)C>C(O)(=O)C>[BrH:48].[OH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][C:22]=2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:19])=[CH:38][CH:39]=1
Reactant: N=C(N)c1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)c(C(=O)c2ccccc2)c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OC(=O)c2ccc(O)cc2)c(C(=O)c2ccccc2)c1
Reaction time: 5 h

Procedure:
To 25 ml of acetic acid, was added 2.7 g of 4-amidino-2-benzoylphenyl 4-benzyloxybenzoate methanesulfonate followed by 1 ml of anisole. To the mixture cooled in ice, was added 13.5 g of a 30% solution of hydrogen bromide in acetic acid. The mixture was stirred for 5 hours and mixed with ethyl ether. The precipitate was collected by filtration and recrystallized from a methanol-ethyl ether mixture to obtain 1.4 g of 4-amidino-2-benzoylphenyl 4-hydroxybenzoate hydrobromide.
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].Cl[C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1.O>O1CCCC1>[CH2:1]([O:5][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: Clc1nsnc1-c1cccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-butyn-1-ol (530 mg, 7.5 mmol) and sodium-hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH:17]([OH:23])[C:18]([O:20]CC)=[O:19].[OH-].[K+].C(OCC)(=O)C.S([O-])(O)(=O)=O.[K+]>C(O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH:17]([OH:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(O)C(Sc1cc(Oc2ccccc2)ccc1N)c1ccc(OC)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(Sc2cc(Oc3ccccc3)ccc2N)C(O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
3.28 g of ethyl 3-(2-amino-5-phenoxyphenyl)thio-2-hydroxy-3-(4-methoxyphenyl)propionate [prepared as described in step (a) above] were dissolved in 20 ml of ethanol, and a solution of 615 mg of 85% (by weight purity) caustic potash dissolved in 5 ml of water were added to the resulting solution. The solution was then stirred at room temperature for 2 hours, after which 50 ml of water and 70 ml of ethyl acetate Were added thereto, followed by an aqueous solution of potassium hydrogen sulfate sufficient to adjust the pH to a value of 3. The precipitate which formed was collected by filtration, to give 1.44 g of the title compound. The filtrate was separated, and the ethyl acetate layer was recovered, washed, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was triturated in diethyl ether and then filtered to give a further 0.76 9 of the title compound. This substance was used in the subsequent step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:19]=[N+:20]=[O:21]>S1(CCCC1)(=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]2)=[CH:6][C:7]=1[N+:20]([O-:21])=[O:19]
Reactant: Cc1ccc(C2(C(=O)O)CC2)cc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc(C2(C(=O)O)CC2)cc1[N+](=O)[O-]

Procedure:
Commercially available 1-(4-methylphenyl)-1-cyclopropane carboxylic acid is treated with nitronium tetrafluoroborate in sulfolane to afford 1-(4-methyl-3-nitrophenyl)-1-cyclopropane carboxylic acid. This is converted to 1-(4-methyl-3-nitrophenyl)-1-bromocyclopropane by treatment with mercuric oxide and bromine in methylene chloride. Reduction with zinc dust in the presence of calcium chloride in aqueous ethanol affords 5-cyciopropyl-2-methylaniline. Conversion to 4-cyclopropyl-5-(2-imidazolinylamino)-7-methylbenzimidazole is completed in the same manner as 4-ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole (see Example 2).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6]1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccccn2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: c1ccc(-c2cc[nH]c2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyridine (1 g, 3.2 mmol) in anhydrous THF (15 mL) was added TBAF (3.84 mL of a 1M solution in THF, 3.84 mmol). After stirring for 10 min. at rt, the reaction was complete. The reaction mixture quenched with H2O (40 mL), extracted with EtOAc (3×25 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and chromatographed on silica gel eluting with EtOAc:hexane (1:1) to afford 2-(1H-pyrrol-3-yl)pyridine as a solid. 1H NMR (CD3Cl, 300 MHz) δ 8.55 (ddd, 1H), 7.65 (dt, 1H), 7.54 (dd, 1H), 7.46˜7.43 (d, 1H), 7.07 (ddd, 1H), 6.85 (dd, 1H), 6.74 (dd, 1H). MS (ESI) 145.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@H:19]5[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].N>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)c(Cl)c3)cc3c1N2CCC3
Agent: N
Product: Clc1ccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)cc1Cl
Yield: 101 %

Procedure:
The title compound (72.6 mg, 100%) was prepared by the method of Example 112 from tert-butyl (±)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (90 mg, 0.20 mmol) as pale yellow amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.58 (d, 1H, J=2.2 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.32 (dd, 1H, J=2.2, 8.4 Hz), 7.09 (s, 1H), 7.07 (s, 1H), 3.34-3.46 (m, 1H), 3.31 (dt, 1H, J=4.4, 10.7 Hz), 3.03-3.13 (m, 2H), 2.83-2.92 (m, 2H), 2.61-2.78 (m, 4H), 2.10-2.19 (m, 2H), 1.74-1.91 (m, 2H) ppm. MS (CI, NH3): 359 (base, M+H).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:18]2)[CH:12]=3)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH:25]([OH:27])[CH3:26])[CH2:19][CH2:18]2)[CH:12]=3)[CH2:5][CH2:4]1
Reactant: CC(=O)CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (0.306 g) was added to a solution of 4-{trans-4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]cyclohexyl}butan-2-one (2.75 g) in ethanol (100 mL) under ice-cooling in small portions. The reaction mixture was stirred at room temperature for 1 hr, and the mixture was concentrated under reduced pressure. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.46 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:36])([F:35])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[N:28][C:27]([O:30][CH2:31][C:32]#[CH:33])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:34])([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C:11]([F:35])([F:36])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[N:28][C:27]([O:30][CH2:31][C:32]#[CH:33])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:34])([CH3:14])[N:13]=1
Reactant: C#CCOc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(NC(=O)OC(C)(C)C)OCC3(F)F)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCOc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)cn1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
((R)-5,5-Difluoro-4-{2-fluoro-5-[(5-prop-2-ynyloxy-pyrazine-2-carbonyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-carbamic acid tert-butyl ester (350 mg, 674 μmol) was combined with DCM (5.2 ml) to give a light yellow solution. The solution was cooled to 0° C. and TFA (768 mg, 519 μl, 6.74 mmol) was added. After stirring 30 min at 0° C. the ice bath was removed and the reaction was allowed to warm up and was stirred at RT for 6 h. The pH of the reaction mixture was adjusted to 8 by dropwise addition of sat. aq. NaHCO3 and the product was extracted with DCM. The organic layers were dried over Na2SO4 and concentrated under vacuum. A colorless foam was obtained that was purified by flash chromatography (SiO2, 10 g, 0 to 80% EtOAc in heptane). Colorless foam (230 mg, 81%). MS (ISP): m/z=420.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH2:22][C:23]#[N:24])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:22](/[C:21]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=1)=[O:25])\[C:23]#[N:24]
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Product: Cc1n[nH]c2cc(F)c(/C=C(\C#N)C(=O)c3ccc(F)cc3)cc12

Procedure:
Following the procedure described for Example 2A, the title compound was prepared using 500 mg (2.81 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 504 mg (3.09 mmol) 3-(4-fluorophenyl)-3-oxopropanenitrile to yield 768 mg (69% of th.) of the crude product (81% purity) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([CH:11]=[N:12]O)=[CH:9][CH:8]=2)=[C:4]([Cl:18])[CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)=[C:4]([Cl:18])[CH:3]=1
Reactant: ON=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCc1ccc(Oc2ccc(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18 mg (0.06 mmol) of 4-(4-bromo-2-chloro-phenoxy)-benzaldehyde-oxime was dissolved in 2 mL methanol, then 37 mg (0.15 mmol) of nickel(II)chloride hexahydrate and 21 mg (0.56 mmol) of sodium borohydride were slowly added. The reaction mixture was stirred overnight at RT and then purified by chromatography (reversed phase).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:47]([NH:55][C:56]1[CH:68]=[C:67](Br)[CH:66]=[CH:65][C:57]=1[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:47]([NH:55][C:56]1[CH:68]=[C:67]([O:7][C:6]2[CH:1]=[CH:2][C:3]([CH3:8])=[CH:4][CH:5]=2)[CH:66]=[CH:65][C:57]=1[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C

Procedure:
0.023 mL of p-cresol, 79 mg of tripotassium phosphate, 2.4 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 0.8 mg of palladium acetate were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1]to obtain tert-butyl 2-(benzamido)-4-(4-methylphenoxy)benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CC(N(C)C)=O>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: Nc1cc(Cl)ccn1
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCOCC2)ccn1
Temperature: 200 °C

Procedure:
A mixture of 4-chloropyridin-2-amine (400 mg, 3.1 mmol) and morpholine (2 mL) in 2 mL of DMA was heated at 200° C. for 5 min in a microwave reactor. LCMS analysis indicated completion of the reaction. The mixture was partitioned between EtOAc and brine, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude 4-morpholinopyridin-2-amine as a yellow solid (350 mg). LCMS (ESI) m/z 180 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCN(c4ccccn4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(N3CCN(c4ccccn4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-fluorophenyl)-2-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (157.4 mg, 0.36 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (71.1 mg, 1.78 mmol, 5.00 equiv) in water (2 mL) dropwise with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 36 mg (23%) of 3-(4-fluorophenyl)-2-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][C:25]([NH2:32])=[N:26][C:27]=2Cl)[C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=[O:34]>O>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][N:22]1[CH:30]=[N:29][C:28]2[C:27](=[O:34])[NH:26][C:25]([NH2:32])=[N:24][C:23]1=2)[C@H:11]([OH:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1cnc2c(Cl)nc(N)nc21
Solvent: O
Product: C[C@@H](O)[C@@H](COCc1ccccc1)Cn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 48 h

Procedure:
A solution of 24 (4.3 g, 9.03 mmol) in a mixture of TFA (60 ml) and water (20 ml) was kept at room temperature for 2 days until almost no starting 24 was seen by HPLC analysis. The reaction was concentrated, co-evaporated with acetionitrile (3×100 ml) to remove most of TFA and water and re-dissolved in THF (100 ml), triethylamine (2 ml) was added to neutralize residual TFA followed by 12 ml of 1 M tetrabutylammonium fluoride in THF. The reaction was allowed to proceed for 2 hrs (monitored by HPLC), concentrated and treated with water (70 ml) and ethyl acetate. At this point crystallization of 25 started as a gelatinous solid. After being allowed the solid to form for several hours the mixture was filtered to collect the solid, which was washed with 33% ethyl acetate in hexane and dried to afford 1.65 g of 25. The aqueous phase was extracted with ethyl acetate. All ethyl acetate extracts, including the very first one, were combined, concentrated and chromatographed on silica in a gradient of MeOH (10-20%) in dichloromethane to afford 0.75 g of 25 (combined yield—2.4 g, 77%). 1H NMR (DMSO-d6): δ 10.53 (s, 1H), 7.57 (s, 1H), 7.30 (m, 5H), 6.42 (s, 2H), 4.80 (d, J=4.8 Hz, 1H), 4.36 (d, J=1.5 Hz, 2H), 4.11 (m, 1H), 3.99 (m, 1H), 3.67 (m, 1H), 3.32 (m, 2H), 2.10 (m, 1H), 1.09 (d, J=6.3 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.N1C=CC=CC=1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccnc1C1CCC2(CC1)OCCO2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccnc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyridin-3-ylamine (0.141 g, 0.603 mmol, prepared as described in Example 3: Steps A-B from 3-amino-2-bromopyridine) was dissolved in anhydrous dichloromethane (10 mL) under Ar, treated with methanesulfonyl chloride (0.155 mL, 1.48 mmol), a few drops of anhydrous pyridine, and stirred at ambient temperature for 24 h. The reaction was quenched with saturated aqueous NaHCO3, the aqueous layer extracted thrice with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a very hygroscopic yellow solid. ESI-MS (m/z): Calcd. For C14H20N2O4S: 312. found: 313 (M+H)