Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[CH2:11][CH:12]([CH2:14][N:15]=[N+]=[N-])[O:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[CH2:11][CH:12]([CH2:14][NH2:15])[O:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=NCC1Cc2ccc(-c3ccccc3)cc2O1
Agent: [Pd]
Product: NCC1Cc2ccc(-c3ccccc3)cc2O1
Yield: 90 %

Procedure:
Treatment of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.280 g, 0.736 mmol) with sodium azide (0.191 g, 2.94 mmol) generally according to the procedure described for Intermediate 98 gave (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.026 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.190 g (90%) of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a tan solid, hydrobromide salt. mp 218-221° C. Anal. calcd. for C15H15NOHBr: C, 58.84; H, 5.27; N, 4.57. Found: C, 54.80; H, 4.88; N, 4.18.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)nc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccccc2)nc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (62 mg, 0.088 mmol, 0.05 equiv.) was dissolved in 5 ml THF. (500 mg, 1.76 mmol) 5-Bromo-2-iodopyridine and phenylacetylene (216 mg, 2.11 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (0.74 ml, 5.28 mmol, 3 equiv.) and copper(I)iodide (10 mg, 0.053 mmol, 0.03 equiv.) were added and the mixture was stirred for 16 hours at 60° C. The reaction mixture was evaporated to dryness and loaded directly to a silica gel column. The crude product was purified by flash chromatography on a silica gel column eluting with a heptane:ethyl acetate gradient 100:0 to 90:10. The desired 5-bromo-2-phenylethynyl-pyridine (354 mg, 78% yield) was obtained as a light yellow solid, MS: m/e=258.0/259.9 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH:16][C:17]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[N:23][NH:24]4)=[O:18])[CH2:7][C:8]([CH2:14][CH3:15])([CH2:12][CH3:13])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].S(OC)(O[CH3:35])(=O)=O>CN(C)C=O>[CH2:12]([C:8]1([CH2:14][CH3:15])[CH2:7][CH:6]([NH:16][C:17]([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[N:23][N:24]3[CH3:35])=[O:18])[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[O:9]1)[CH3:13]
Reactant: CCC1(CC)CC(NC(=O)Nc2cccc3[nH]ncc23)c2ccc(F)cc2O1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(CC)CC(NC(=O)Nc2cccc3c2cnn3C)c2ccc(F)cc2O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 77D (212 mg, 0.554 mmol) in N,N-dimethylformamide (2.2 mL) was treated with 60% NaH (28 mg, 0.7 mmol), and the mixture was stirred at rt for 45 min. Dimethyl sulfate (0.06 mL, 0.634 mmol) was then added, and the reaction was allowed to stir for 1 h. Concentration in vacuo, followed by silica gel chromatography (98:2 dichloromethane-methanol, eluent) afforded the title compound as a tan foamy solid, 109 mg (50%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.72 (s, 1H), 8.03 (s, 1H), 7.70 (d, J=7.1 Hz, 1H), 7.25-7.36 (m, 2H), 7.17 (m, 1H), 6.70-6.77 (m, 2H), 6.63 (dd, J=10.5, 2.7 Hz, 1H), 4.94 (m, 1H), 4.00 (s, 3H), 2.19 (m, 1H), 1.58-1.77 (m, 5H), 0.84-0.94 (m, 6H). MS (ESI) m/z 397 (M+H).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl>[CH:1]1([N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[S:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Fc1cccc(NC2CCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(F)cc1)N(c1cccc(F)c1)C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of cyclobutyl-(3-fluoro-phenyl)-amine (447 mg, 2.7 mmol) in DCM (8 mL) was added pyridine (438 μL, 5.4 mmol) followed by 4-fluorobenzenesulfonyl chloride (633 mg, 3.3 mmol) in DCM (3 mL) and then the reaction was stirred at room temperature for 2 hrs. The reaction was left to stand at room temperature for 64 hours. 1 M aqueous HCl was added then extracted with DCM, filtered through a phase separator and then purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give N-cyclobutyl-4-fluoro-N-(3-fluoro-phenyl)-benzenesulfonamide (756 mg, 2.3 mmol, 85%). LCMS (m/z, Method A) ES+ 324 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].CCN(C(C)C)C(C)C.C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>ClCCl>[CH3:9][C:3]1[C:2]2[NH:1][C:24](=[O:25])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(O)c1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.0 g (0.39 mol) 2-amino-m-cresol and 0.21 L (1.23 mol) DIPEA in 400 mL dichloromethane were cooled to 0° C. A mixture of 76.0 g (0.45 mol) CDI in 1.2 L dichloromethane was added dropwise and stirred overnight at RT. The reaction mixture was washed with a 1M KHSO4 solution and water. The organic phase was separated off and evaporated down i.vac. The residue was combined with boiling ethyl acetate and while the mixture cooled PE was added dropwise. The precipitate formed was suction filtered, washed with PE and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[C:8]2[CH2:14][N:13]([S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)(=[O:17])=[O:16])[C:12]([CH3:27])([CH3:26])[C:9]=2[NH:10][N:11]=1)=[O:5].C(N(CC)C(C)C)(C)C.C1C2C(COC([NH:65][C@@H:66]([CH3:70])[C:67](Cl)=[O:68])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl>[NH2:65][C@@H:66]([CH3:70])[C:67]([NH:1][C:2]1[CH:31]=[C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)[CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[C:8]2[CH2:14][N:13]([S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)(=[O:17])=[O:16])[C:12]([CH3:27])([CH3:26])[C:9]=2[NH:10][N:11]=1)=[O:5])=[O:68]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)C4(C)C)c(N)c2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N)C(=O)Nc1cc(N2CCN(C)CC2)ccc1C(=O)Nc1n[nH]c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (0.188 g, 0.34 mmol), N,N-diisopropylethylamine (0.59 mL, 3.4 mmol) and dichloromethane (10 mL), (S)-2-[(9H-fluoren-9-ylmethoxycarbonyl)amino]-propionyl chloride (0.448 g, 1.36 mmol, 4 eq.) was added and the reaction mixture stirred at room temperature overnight. After evaporation to dryness, the residue was treated with dichloromethane (10 mL), triethylamine (5 mL) and MeOH (5 mL) and the mixture stirred at room temperature for 72 hours. The solvent was then removed under vacuum and the residue purified by preparative HPLC/MS affording the title compound as white solid (0.105 g).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:8]([N:15]1[CH:24]([CH3:25])[CH2:23][C:22]2[C:17](=[N:18][C:19](Cl)=[C:20]([NH:26][CH2:27][CH:28]([F:30])[F:29])[N:21]=2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[F:33][C:34]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:35]=1[O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([N:15]1[CH:24]([CH3:25])[CH2:23][C:22]2[C:17](=[N:18][C:19]([N:40]3[CH2:39][CH2:38][CH:37]([O:36][C:35]4[CH:43]=[CH:44][C:45]([F:47])=[CH:46][C:34]=4[F:33])[CH2:42][CH2:41]3)=[C:20]([NH:26][CH2:27][CH:28]([F:30])[F:29])[N:21]=2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCNCC2)c(F)c1
Reactant: CC1Cc2nc(NCC(F)F)c(Cl)nc2CN1Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1Cc1ccccc1

Procedure:
A solution of 6-benzyl-3-chloro-N-(2,2-difluoroethyl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (120 mg, 0.257 mmol), 4-(2,4-difluorophenoxyl)piperidine hydrochloride (77 mg, 0.308 mmol), Pd2(dba)3 (23.5 mg, 0.026 mmol), BINAP (32.0 mg, 0.051 mmol), and sodium tert-butoxide (74.1 mg, 0.771 mmol), in toluene (1.28 mL) was stirred at 100° C. overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give 6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine as a TFA salt (135 mg, 82%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[CH:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:18]1[C:19]([NH:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1.C(N(CC)CC)C.[Cl-].[NH4+]>C1COCC1.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.[Cu]I>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][NH:26][C:19]1[C:18]([C:16]#[C:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)=[CH:23][N:22]=[C:21]([C:24]#[N:25])[N:20]=1
Reactant: C#CCc1ccc(N2CCN(C)CC2)cc1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(CC#Cc3cnc(C#N)nc3NCC(C)(C)C)cc2)CC1
Temperature: 60 °C
Yield: 25 %

Procedure:
To a solution of 1-methyl-4-(4-prop-2-ynyl-phenyl)-piperazine (0.75 mmol) and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (0.5 mmol) in THF (7 ml), triethylamine (1.5 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.025 mmol) and copper (I) iodide (0.05 mmol) are added. The reaction mixture is heated at 60° C. ca. for 3 h. Saturated aqueous solution of ammonium chloride is added to the reaction mixture and then aqueous layer is extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product which is purified by reverse phase HPLC. Yield: 25%. Rf=0.5 (MeOH:CH2Cl2=5:95)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30](O)=[O:31])=[CH:5][CH:4]=1)#[N:2].[CH3:33][CH2:34][N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>CN(C=O)C>[CH2:34]([NH:35][C:30]([C:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:14]2[C:15](=[O:18])[NH:16][N:17]=[C:13]2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:11]=1[CH3:29])=[O:31])[CH3:33]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2n[nH]c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49.2 %

Procedure:
To a solution of Example 9 (100 mg, 0.23 mmol) in DMF (3 ml), were added DIPEA (102 μl, 0.6 mmol) and HATU (133 mg, 0.35 mmol) and the reaction mixture was stirred at RT for 45 mins. Ethylamine (2 M in THF, 175 μL, 0.35 mmol) was then added, and stirring at RT was continued for 16 hours. Further ethylamine (2 M in THF, 175 μL, 0.35 mmol) was added, the temperature was raised to 60° C., and stirring was continued for 1.5 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 80-100% EtOAc in cyclohexane to yield the title compound as a white solid (53 mg).
Reaction SMILES: COC([C:5]1[CH2:10][C:9]([C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)([C:11]#[N:12])[CH2:8][CH2:7][C:6]=1[OH:20])=O.[Cl-].[Na+].O>CS(C)=O>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([C:9]2([C:11]#[N:12])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1=C(O)CCC(C#N)(c2ccc(Cl)nc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Cl)nc2)CCC(=O)CC1
Temperature: 160 °C
Yield: 51.7 %

Procedure:
To a solution of 5-(6-chloro-pyridin-3-yl)-5-cyano-2-hydroxy-cyclohex-1-enecarboxylic acid methyl ester (4.2 g, 14 mmol) in DMSO (15 mL) was added sodium chloride (090 g, 16 mmol) and water (0.77 mL). The reaction mixture was heated at 160° C. for 6 hours. The reaction mixture was then cooled to room temperature and poured into water (50 mL). The aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel to afford 1-(6-chloro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (1.7 g, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (s, 1 H), 7.83 (dd, J=8.4, 2.2 Hz, 1 H), 7.44 (d, J=8.5 Hz, 1 H), 2.89-2.98 (m, 2 H), 2.60-2.66 (m, 2 H), 2.48-2.54 (m, 2 H), 2.25-2.33 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:30])[C:10]1[N:14]([CH2:15][CH2:16][C:17]([O:19]C)=O)[C:13]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1.[OH-].[Na+].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:13]=3[N:14]2[CH2:15][CH2:16][C:17](=[O:19])[O:30]1
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCC(=O)OC)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)OC3c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propanoate (92.9 mg, 0.200 mmol) in tetrahydrofuran (1 mL) was added aqueous sodium hydroxide (8 M, 0.05 mL) at room temperature. After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (2 mL) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (76.7 mg, 0.400 mmol) was added at room temperature. After 6 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to afford the desired product as colorless amorphous (44.6 mg, 0.107 mmol, 53%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27]COC)=[CH:23][CH:22]=3)[N:18]=[C:17]3[N:31](C4CCCCO4)[N:32]=[C:33]([CH3:34])[C:16]=23)[CH2:8][C:7]1([CH3:42])[CH3:41])=[O:5])[CH3:2].Cl>O1CCOCC1>[CH2:1]([NH:3][C:4]([N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:18]=[C:17]3[NH:31][N:32]=[C:33]([CH3:34])[C:16]=23)[CH2:8][C:7]1([CH3:41])[CH3:42])=[O:5])[CH3:2]
Reactant: CCNC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(OCOC)cc3)nc3c2c(C)nn3C2CCCCO2)CC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3)nc3[nH]nc(C)c23)CC1(C)C

Procedure:
325 mg of 4-[6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazine-1-carboxylic acid ethylamide in 2 ml of dioxane were reacted with 2 ml hydrochloric acid (4M in dioxane). After 4 h at rt the volatiles were removed in vacuo. After purification by preparative HPLC 142 mg (56%) of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc(N)nc4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (50 mL) was added 5-(3-aminophenoxy)pyridine-2-amine dihydrochloride (3.5 g, 12.7 mmol) produced in Example A1(ii), and the mixture was stirred at room temperature for 18 hr. 5% Aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate and hexane to give the title compound (3.84 g, 75%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12
Reaction time: 2 h
Yield: 77.4 %

Procedure:
2-[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)amide (50 mg, 0.085 mmol) was combined with dichloromethane (1 mL) and trifluoroacetic acid (0.19 ml, 2.56 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (1 mL). Ethylenediamine (0.17 ml, 2.56 mmol) was added. After stirring for 20 min, the reaction was concentrated in vacuo. The residue was triturated with water (2 mL). The precipitate was filtered, washed with water and dried to obtain 30 mg (73%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a yellow solid. MS: (M+H)+=456; 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.51 (d, J=8.5 Hz, 1H), 8.44 (s, 1H), 8.45 (s., 1H), 8.20 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.26 (d, J=8.3 Hz, 1H), 4.62 (br. s., 2H), 4.38 (br. s., 1H), 3.50 (dd, J=16.1, 4.0 Hz, 2H), 3.28 (s, 3H), 2.81 (br. s., 2H), 2.21 (s, 6H), 1.31 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1.[OH-].[Na+].Cl.[CH3:22][C:23]1[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([N:33]2[CH2:34][CH2:35][N:30]([C:24]3[C:23]([CH3:22])=[CH:28][C:27]([CH3:29])=[CH:26][N:25]=3)[CH2:31][CH2:32]2)=[O:8])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Temperature: 65 °C
Yield: 81.6 %

Procedure:
To methyl 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoate (2 g) described in Preparation Example 116 were added 1N aqueous sodium hydroxide solution (9 mL) and methanol (18 mL), and the mixture was stirred at 60-70° C. 1N hydrochloric acid (9 mL) was added, a solution of 1-(3,5-dimethylpyridin-2-yl)piperazine (1.14 g) described in Preparation Example 47 in methanol (2 mL) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.65 g) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After evaporation of the solvent, the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (2.4 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)[NH2:33]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]3[O:29][N:33]=[C:32]([C:34]4[CH:39]=[N:38][CH:37]=[CH:36][N:35]=4)[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cnccn1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cnccn3)no2)C1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 50 mg (0.36 mmol, 1.5 eq.) of N′-hydroxypyrazine-2-carboximidamide were reacted according to the General Method 2. Yield: 34 mg (27% of theory)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([NH:17][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2)[CH2:14][CH2:15][CH3:16]
Reactant: BrCc1ccc2nccnc2c1
Reactant: CCCCN
Product: CCCCNCc1ccc2nccnc2c1

Procedure:
Example 10 shows that some organic solvent-soluble nucleophiles (alkylamines, for example) can readily react with 6-bromomethyl-quinoxaline because the compound is completely soluble in the organic phase. Example 10 shows that 6-bromomethyl-quinoxaline completely reacted with n-butylamine in few minutes at room temperature to give 6-n-butylaminomethyl-quinoxaline. In this example, n-butylamine acted as both the nucleophile and the solvent.