Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:18]1([Mg]Cl)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(C2CCCCC2)cc1

Procedure:
The title product was prepared from the product of Example 27 as described in Example 15, Condition 2, with the exception that cyclohexylmagnesium chloride was used instead of cyclopentylmagnesium bromide.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[CH2:23]([O:22][P:20]([C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[C:3]([OH:36])=[O:2])[CH:11]=[CH:10][C:9]=1[P:12]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])=[O:13])([O:25][CH2:26][CH3:27])=[O:21])[CH3:24]
Reactant: CCOP(=O)(OCC)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1P(=O)(OCC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 3-[3,4-Bis-(diethoxy-phosphoryl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester (110 mg, 0.2 mmol) in 5 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (8.5 mg, 0.2 mmol) in 1.0 mL of water. The reaction mixture was stirred at 0° C. for 1 h. THF was removed under reduced pressure to a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (2×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford an oil 107 mg (100%). MS [M−H]− 537.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]([CH3:11])[N:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccnc(Cl)c2)nn1C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a 1000 ml flask was added 8.6 g of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 1.E, 100 ml of DMF, 6.0 ml of DIEA and the reaction was cooled to 0° C. To the reaction was then added 2.8 ml of ethyl bromoacetate and the reaction was stirred at 22° C. for 16 hours at which time the crude was partitioned between 1500 ml EtAc, 2×400 ml of saturated brine, and 2×400 ml of water (Note: no product observed in aqueous layer). The organic solvent was removed by rotary evaporation and the crude purified with a silica gel column (eluting with 30% EtAc in Hexane) to give 6.3 g of ethyl 2-((S)-1-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 17.7.F as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N)c1
Reactant: N#Cc1cnc(Cl)cc1NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc(Nc2cc(NCc3ccccc3)c(C#N)cn2)c1
Temperature: 120 °C

Procedure:
To ˜10 ml of NMP was added 15.1 (150 mg) and DIEA (˜0.1 mL). To this stirring solution was added benzylamine (1.1 eq in ˜5 mL NMP) dropwise. After stirring for 1 hour, H2O was added to the reaction mixture, followed by EtOAc. HPLC analysis indicated substantial amounts of product in each layer. Both layers were concentrated and the resulting oil was dissolved in a H2O/TFA/ACN mixture. This solution was purified via preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 20% to 60% B mixture over 10 minutes to give 205 mg of 4-(benzylamino)-6-chloronicotinonitrile (11). To 100 mg of 4-(benzylamino)-6-chloronicotinonitrile (11) in ˜3 mL NMP was added 1 ml of 60 mg/ml m-toluidine and 45 mg pTSA.H2O. Reaction heated at 120° C. for 72 hours. Due to inadequate conversion to product, the reaction mixture was transferred to a microwave tube and subsequently heated via microwave irradiation at 220° C. for 20 minutes. Water was added to the crude reaction mixture and a preparative rpHPLC was run in order to isolate pure 4-(benzylamino)-6-(m-tolylamino)nicotinonitrile (12). To 12 in ˜3 mL DMSO was added K2CO3 (˜100 mg) and 1.5 mL H2O2 (50% by wt.). The reaction was heated to 70° C. at which point the reaction mixture bubbled rigorously. Heat was removed until bubbling ceased and then the reaction mixture was again heated at 70° C. for an additional hour. The reaction mixture was cooled and a H2O/TFA mixture was added. The resulting solution was purified via preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 15% to 55% B mixture over 10 minutes. UV: 257 nm. M+H found for C20H20N4O: 333.3. NMR (CD3OD): 8.12 (1H, s), 7.37-7.24 (6H, m), 7.14-7.09 (1H, m), 6.99 (1H, br), 6.92-6.87 (1H, m), 5.88 (1H, s), 4.45 (2H, s), 2.38 (3H, s) ppm.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[N:10]=1.[CH3:24][N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].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=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:24]([C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[N:10]=1)#[N:25]
Reactant: O=C(CN1CCc2nc(Br)sc2C1)N1CCN(C2CCC2)CC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1nc2c(s1)CN(CC(=O)N1CCN(C3CCC3)CC1)CC2
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-5-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine (40 mg, 0.1 mmol), Zn(CN)2 (15 mg, 0.2 mmol), Pd2(dba)3 (5 mg, 0.005 mmol) and dppf (6 mg, 0.01 mmol) in DMF (4 mL) is degassed with argon and heated at 110° C. in a sealed tube overnight. The mixture is cooled and solvent is removed in vacuo. The residue is partitioned between water (3 mL) and EtOAc (3 mL). The aqueous layer is extracted with EtOAc (4 ml) and the combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow solid. MS (M+1): 346.0; 1H NMR (δ, CDCl3): 3.92 (s, 2H), 3.55-3.67 (m, 4H), 3.45 (s, 2H), 3.00 (s, 4H), 2.66-2.77 (m, 1H), 2.31 (s, 4H), 1.63-2.08 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C(OCC)C.CCCCCC>[Br:9][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cc(Cl)cc(Br)c1
Temperature: -30 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 1-chloro-3,5-dibromobenzene (Esprit) (20 g, 0.074 mole) in anhydrous ethyl ether (150 mL) in a flame dried flask under N2 and at -78° C. was added 1.6 m butyl lithium in hexane dropwise, keeping the temperature below -78° C., then warmed to -30° C. Anhydrous DMF (6.8 g, 0.092 mole) was added dropwise, keeping the temperature below -20° C. After the addition was complete, the reaction was slowly warmed to 0° C., then stirred overnight at room temperature. The reaction mixture was poured slowly into chilled 10% aqueous HCl (160 mL). After stirring for 15 minutes, the ether was separated, washed with H2O (4×), dried over MgSO4 and removed under vacuum to yield 3-bromo-5-chlorobenzaldehyde (13 g) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C)C=O>[CH2:22]([O:11][C:10](=[O:12])[C@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([O:20][CH2:13][C:14]2[CH:21]=[CH:19][CH:17]=[CH:16][CH:15]=2)[CH:21]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 148.8 %

Procedure:
21.12 g of N-(tert-butoxycarbonyl) DOPA was dissolved in 200 ml of dimethylformamide, and after 50 g of benzyl bromide and 40 g of potassium carbonate were added, the mixture was stirred at a room temperature for 40 hours. After the addition of 400 ml of sodium chloride aqueous solution, the reaction mixture was extracted with 500 ml of ethyl acetate, and the extract was washed twice with saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and concentrated under a reduced pressure. To the resulting residue was added hexane to crystallize the title compound, which was then washed, filtered and dried to obtain 30.0 g of the colorless crystals.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21]C>B(Br)(Br)Br>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21]
Reactant: COc1ccccc1-c1n[nH]c2ccc(-c3nn[nH]n3)cc12
Agent: BrB(Br)Br
Product: Oc1ccccc1-c1n[nH]c2ccc(-c3nn[nH]n3)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 6.3 %

Procedure:
The compound of Example 161 (0.050 g, 0.17 mmol) was suspended in 1 mL of boron tribromide (1.0 M commercial solution in dichloromethane). The reaction mixture was stirred at room temperature in a closed system for 4 days to achieve completion. The product was then collected by filtration and washed with small portions of dichloromethane. Trituration in a few mL of tetrahydrofuran and filtration did not afford satisfactory purity. Final purification by preparative HPLC (30–80% acetonitrile in water, 20 mm) afforded 3 mg of pure product. (6% yield): 1H NMR (DMSO-d6) δ 13.6 (s, 1H), 10.3 (s, 1H), 8.7 (s, 1H), 8.1 (d, 1H), 7.8 (t, 2H), 7.3 (t, 1H), 7.08–7.00 (m, 2H); ES-MS (m/z) 279 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:35])[C:18]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:19]([OH:35])[C:18]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(-c3ccccc3)cc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1cc(-c1ccccc1)c(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-5-phenyl-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.031 g, 0.056 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-5-phenyl-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.023 g, 78%).
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>ClCCl>[F:1][C:2]1([C:6]2[CH:7]=[N+:8]([O-:26])[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)(F)COc1ccncc1C1(F)CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(OCC(F)(F)F)c(C2(F)CCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 3-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine (example 127a, 1.68 g, 6.74 mmol) in dichloromethane (40 ml) was added m-CPBA (3.49 g, 10.1 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was transferred into a separatory funnel and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated down to dryness to yield the crude title compound (1.68 g, 94%) which was used without any purification for the next step; MS (ESI, m/z): 266.5 (M+H+).
Reaction SMILES: [C:1]([O:5]CC)(=O)[C:2]#[CH:3].[NH2:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH3:19]>>[CH3:19][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[CH2:12][CH2:11][C:10]1[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=1[NH:8][C:1](=[O:5])[C:2]#[C:3][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:10]=1
Reactant: C#CC(=O)OCC
Reactant: CN1CCCCC1CCc1ccccc1N
Product: CN1CCCCC1CCc1ccccc1NC(=O)C#Cc1ccccc1

Procedure:
Reaction of ethyl propiolate with 2-(o-aminophenethyl)-1-methylpiperidine according to the procedure of Example 115 affords 2'-[2-(1-methyl-2-piperidyl)ethyl]phenylpropiolanilide, m.p. 104.5° - 106.5° C. (corr.), from ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12](=[O:28])[N:13]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]2=[O:19])S(C)(=O)=O)(=[O:4])=[O:3].[OH-].[Na+]>CC#N>[CH3:1][S:2]([NH:5][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12](=[O:28])[N:13]([CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:14]2=[O:19])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N(S(C)(=O)=O)S(C)(=O)=O)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc(NS(C)(=O)=O)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.6 %

Procedure:
To a solution of tert-butyl 2-(4-(N-(methylsulfonyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (548 mg, 1.267 mmol) in MeCN (5 ml), aqueous 2N NaOH (1457 μl, 2.91 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was diluted with water, acidified and extracted twice with ethyl acetate; the organic phase was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel (EtOAc/hexane 8/2) to obtain tert-butyl 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate as an off-white solid (196 mg, 0.553 mmol, 43.6% yield, MS/ESI+ 376.8 [MNa]+).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2ccnc(C#N)c2)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C#N)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (from Combi-Blocks). LCMS calculated for C22H20N5O2(M+H)+: m/z=386.2. Found 386.2.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C([O-])=O.[NH4+].ClCCl.CO>[Pd].CO>[CH3:15][N:4]1[C:3](=[O:16])[CH:2]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:6]=[N:5]1
Reactant: CN1CCN(c2cnn(C)c(=O)c2Cl)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2cnn(C)c(=O)c2)CC1

Procedure:
To a mixture of 4-chloro-2-methyl-5-(4-methylpiperazin-1-yl)pyridazin-3(2H)-one (4.85 g, 20 mmol) and 10% Pd/C catalyst (1.14 g) in methanol (100 ml) was added ammonium formate (2.90 g, 46 mmol), and the mixture was refluxed under argon with TLC monitoring (dichloromethane:methanol (9:1)). Further portions of ammonium formate were added until the starting material was completely consumed. The catalyst was filtered off and washed with methanol, then the solvent was evaporated under reduced pressure. The residue was taken up in water (30 ml) and extracted with dichloromethane (4×40 ml). The combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by recrystallization from ethyl acetate:light petroleum.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)CC1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (85 mg, 77%), MS (ISP) m/z=443.5 [(M+H)+], mp 181.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and rac-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[NH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:23])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1nc2ccc(OC)cc2nc1Cl
Temperature: 100 °C

Procedure:
6-Methoxy-3-oxo-3,4-dihydro-quinoxaline-2-carboxylic acid ethyl ester (5.2 g, 20.9 mmol) was suspended in 75 mL of POCl3 and resulting mixture heated to 100° C. for 1 h. The reaction mixture was poured onto 500 mL of ice-water and the pH of the solution adjusted to 3 with conc. NH4OH. Mixture was extracted twice with 300 mL of EtOAc. The combined organic layers were dried over Na2SO4 and evaporated to give the 3-chloro-6-methoxy-quinoxaline-2-carboxylic acid ethyl ester (4.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.C(O)(C)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:19][CH:18]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOCC
Product: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(OC(C)C)c1
Reaction time: 2 h
Yield: 30.8 %

Procedure:
To a rapidly stirred solution of (trans)-N-[[2-(3-hydroxyphenyl)cyclopropyl]methyl] butanamide (390 mg, 1.7 mmol), triphenylphosphine (498 mg, 1.9 mmol) and isopropanol (150 mg, 2.5 mmol) in THF (10 mL) at 0° C. was added diethyl azodicarboxylate (331 mg, 1.9 mmol) in one portion. After stirring for 2 h, the suspension was diluted with Et2O (100 mL), washed with H2O, 2N NaOH, and brine, dried (K2CO3) and concentrated to a give a crude wax. The resulting material was purified by chromatography (silica gel, 35% EtOAc/hexane) to afford 144 mg (31%) of the title compound: 1H NMR (300 MHz, CDCl3) δ0.85-0.94 (m, 5H), 1.22-1.24 (m, 1H), 1.29 (d, J=6.7 Hz, 6H), 1.58-1.68 (m, 2H), 1.70-1.77 (m, 1H), 2.14 (t, J=6.0 Hz, 2H), 3.14-3.36 (m, 2H), 4.44-4.54 (m, 1H), 5.81 (br s, 1H), 6.53-6.67 (m, 3H), 7.13 (t, J=7.2 Hz, 1H); IR (NaCl Film) 3294, 2974, 1644, 1610, 1550, 1492 cm-1 ; MS m/e 275; Analysis calc'd for C17H25 NO2 : C, 74.14; H, 9.15; N, 5.09; found: C, 73.77; H, 8.99; N, 4.82.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[NH:13][NH2:14].C(O[CH:18]=[C:19]([C:25]#[N:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>C(O)C>[NH2:26][C:25]1[N:13]([C:3]2[C:4]([F:12])=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]=2[Cl:1])[N:14]=[CH:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: NNc1c(F)cc(C(F)(F)F)cc1Cl
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(F)cc(C(F)(F)F)cc2Cl)c1N
Yield: 80.8 %

Procedure:
200 g (0.88 mol) of 2-chloro-6-fluoro-4-trifluoromethylphenylhydrazine and 151 g (0.88 mol) of ethyl ethoxymethylenecyanoacetate in 400 ml of ethanol are heated to the reflux temperature for 30 hours, the mixture is then concentrated to approximately half of the volume and cooled and the precipitate thus obtained is filtered off, washed with a little cold ethanol and dried. 250 g (81% of theory) of ethyl 5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazol-4-yl carboxylate of melting point 147°-149° C. are obtained.