Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:36])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[I:35])[NH2:31]>>[CH3:23][N:24]([CH3:36])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:32]=[CH:33][C:34]=1[I:35]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: CN(C)CCOc1cc(N)ccc1I
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(I)c(OCCN(C)C)c4)cc3)c(C)c2)no1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP0533268A1) and 3-(2-dimethylaminoethoxy)-4-iodoaniline (D50) using a similar procedure to Example 20 (0.4 g, 28%). The free-base was converted to the oxalate salt. mp 219°-221° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C@H:25]2[CH3:37])=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C@H:25]3[CH3:37])=[N:22][CH:23]=2)=[O:8])=[C:4]([F:11])[C:3]=1[O:12][C:13]([F:16])([F:15])[F:14]
Reactant: O=C(O)c1ccc(Br)c(OC(F)(F)F)c1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(NC(=O)c2ccc(Br)c(OC(F)(F)F)c2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 4-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (150 mg, 0.50 mmol, Preparation 52), (R)-tert-butyl 4-(5-aminopyridin-2-yl)-3-methylpiperazine-1-carboxylate (145 mg, 0.50 mmol), and HATU (235 mg, 0.62 mmol) dissolved in DMF (1 mL) was added DIPEA (0.43 mL, 2.48 mmol). The reaction mixture was stirred at RT for 1 h, extracted with EtOAc (80 mL) washed with water (3×20 mL) and brine (20 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (12 g silica gel, 0-40% EtOAc:hexanes over 20 min), to provide the title intermediate (203 mg, 71% yield) as a yellow solid. (m/z): [M+H]+ calcd for C23H25BrF4N4O4 577.10; 579.10. found 579.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31](Cl)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Reactant: COCCn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 32 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 60% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (71 mg, 76%) as a white foam: [α]30589=−90.0° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C21H26N3O5SCl (M+H)+ 468.1355, observed 468.1354; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.79-2.29 (m, 8 H, 4×CH2), 3.19 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.61 (t, J=5.1 Hz, 2H, OCH2), 3.95 (m, 1H, ArCHCO), 4.12 (t, J=5.1 Hz, 2H, NCH2), 6.42 (d, J=2.0 Hz, 1H, Ar), 7.55 (d, J=2.0 Hz, 1H, Ar), 7.62 (d, Jo=8.1 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.1 Hz, 1H, Ar), 10.85 (s, 1H, NH).
Reaction SMILES: C([O:8][C:9]([C:11]1[O:36][C:14]2=[CH:15][CH:16]=[C:17]3[C:21]([N:20]([CH2:22][C@@H:23]([NH:25][C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH3:24])[N:19]=[CH:18]3)=[C:13]2[CH:12]=1)=[O:10])C1C=CC=CC=1.[OH-].[Li+]>C(O)C.O>[CH2:29]([O:28][C:26]([NH:25][C@@H:23]([CH3:24])[CH2:22][N:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]3[O:36][C:11]([C:9]([OH:10])=[O:8])=[CH:12][C:13]3=2)[CH:18]=[N:19]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(=O)OCc4ccccc4)cc3c21)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@@H](Cn1ncc2ccc3oc(C(=O)O)cc3c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a solution of the product of Step A, Example 2 (0.15 g, 0.31 mmol) in ethanol (10 mL) was added lithium hydroxide (0.026 g, 0.62 mmol) in water (1 mL) and stirred at room temperature for 16 h. The reaction mixture was evaporated to a residue and a saturated aqueous solution of ammonium chloride (20 mL) was added followed by the addition of phosphoric acid (1 M) until the solution was neutral. The mixture was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine (30 mL), dried and evaporated. The residue was purified by chromatography (silica, dichloromethane, 5% methanol in dichloromethane, 10% methanol in dichloromethane) to give an oil (0.12 g, 98%): MS (ES) m/z 394 (M+); 1H NMR (CD3OD) δ 7.91 (s, 1H), 7.81 (s, 1H), 7.58 (d, 1H, J=8.8 Hz), 7.25 (d, 1H, J=8.8 Hz), 7.14-7.02 (m, 5H), 4.81 (s, 2H), 4.49-4.42 (m, 2H), 4.17 (m, 1H), 1.18 (d, 3H, J=6.8 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].[I:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([OH:18])=[CH:13][CH:12]=2.[CH3:19][O:20][C:21](=[O:26])[CH:22](Br)[O:23][CH3:24].[I-].[K+]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:26])[CH:22]([O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([I:7])=[CH:17]2)[O:23][CH3:24]
Reactant: COC(=O)C(Br)OC
Reactant: Oc1ccc2ncc(I)cc2c1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(OC)Oc1ccc2ncc(I)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of potassium t-butoxide (1.36 g) in t-butyl alcohol (50 mL) was added a solution of 3-iodo-quinolin-6-ol (3 g) in t-butyl alcohol (5 mL). The reaction mixture was stirred at room temperature for 15 minutes. Bromo-methoxy-acetic acid methyl ester (4.0 g) and a solution of potassium iodide (catalytic quantity) in t-butyl alcohol (5 mL) were then added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured on water and chloroform was added. The mixture was stirred. The two layers were separated, the aqueous layer was extracted with chloroform (twice). The organic layers were combined, washed with brine (twice), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude (4.3 g) was used directly in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]3([CH3:31])[CH3:30])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3([CH3:31])[CH3:30])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3(C)C)cn2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3(C)C)cn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 120.7 %

Procedure:
To the solution of 125c (1.19 g, 1.9 mmol) in dichloromethane (20 mL) was added 3M HCl in diethyl ether (15 mL). The reaction mixture was stirred at room temperature for 4 h. It was then concentrated under reduced pressure to afford 125d (900 mg, 95%). LCMS: [M+H]+ 392.1.
Reaction SMILES: O=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:19]>CO>[NH2:19][C@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C[C@H](N)Cc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ru(OAc)2((R)-dm-binap) (0.248 g, 0.260 mmol), methyl 3-oxo-4-phenylbutanoate (10.00 g, 52.0 mmol), ammonium acetate (4.01 g, 52.0 mmol) and methanol (50 mL) were placed in a 200 mL stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled down to room temperature and further stirred under a hydrogen pressure of 3 MPa at 80° C. for 14 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R)-3-amino-4-phenylbutanoate as a crude material (13.01 g). The enantiomeric excess of methyl (3R)-3-amino-4-phenylbutanoate in the crude product was determined to be 94.7% ee by HPLC analysis using a SUMICHIRAL OA-4100R column after conversion into methyl (3R)-3-(4-nitrobenzoylamino)-4-phenylbutanoate.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[Cl:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[CH3:14])=[O:12])=[CH:9][C:8]=1[C:30]1[CH:31]=[N:32][C:33]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:35]=1[C:36]#[N:37]>CC#N>[Cl:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([N:13]([CH3:14])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([CH3:27])([CH3:26])[C:24]([OH:2])=[O:25])=[O:12])=[CH:9][C:8]=1[C:30]1[CH:31]=[N:32][C:33]([C:38]([F:41])([F:39])[F:40])=[CH:34][C:35]=1[C:36]#[N:37]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCC(C)(C)CO
Reactant: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCC(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To periodic acid (68 mg, 0.30 mmol) in CH3CN (200 μL) at 0° C., Cr(VI)oxide (0.7 mg, 0.0073 mmol) was added and the mixture was stirred for 15 min at 0° C. A solution of 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-N-methyl-benzamide (29 mg, 0.056 mmol) dissolved in CH3CN (200 μL) was added and the mixture was warmed to rt. After 2 hr at rt, the mixture was filtered, rinsed with CH3CN, concentrated, dissolved in MeOH and purified by prep HPLC yielding 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-2,2-dimethyl-propionic acid 52-1. MS: 532.3 (M+H)+, tR=3.65 min (method 3).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1>CCOCC>[Br:9][C:10]1[N:11]=[C:12]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)CCO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CN(C)CCOc1cccc(Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
2-dimethylaminoethanol (2 mL, 20 mmol) was added at rt to a suspension of NaH (oil was not removed) in dry DMF (3 mL). The mixture was stirred at rt for 2 hours and 1 h at 60° C. Then commercial 2,6-dibromopyridine (6.16 g, 26 mmol, 1.3 eq) was added at rt and the whole was stirred at rt overnight. The crude mixture was dissolved in some Et2O and was extracted with 2 portions of citric acid 30%. Combined aqueous phases were washed with 2 portions of Et2O. The aqueous phase was basified with NaOH 5N at 0° C. and was extracted with 3 portions of Et2O. Combined organic phases was dried over MgSO4, filtrated and evaporated. As some DMF remained, HCl in Et2O was added. The solvents were evaporated and the resulting solid was put at the pump for 4 hours. It was dissolved in H2O and basified with NaOH 5 M. The desired product (the base) was extracted with 3 portions of Et2O. Combined organic layers were dried over MgSO4, filtrated and evaporated to give the desired product (XXIII), N-{2-[(6-bromo-2-pyridinyl)oxy]ethyl}-N,N-dimethylamine (4.4309 g, 18.076 mmol, 90.4%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[Li]CCCC>C1COCC1.Cl>[C:7]1([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[B:13]([OH:18])[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccsc1-c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccsc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
To a mixture of 3-bromo-2-phenylthiophene (1.99 g, 8.32 mmol) and B(Oi-Pr)3 (1.81 mL, 12.5 mmol) in THF (20 mL) was added n-BuLi (1.65 M in hexane, 10.1 mL, 16.6 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. The mixture was diluted with 1 M HCl aqueous solution at 0° C., extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=90/10 to 0/100) to yield the title compound (87.4 mg, 5% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 7.19 (1H, d, J=4.9 Hz), 7.27-7.44 (3H, m), 7.46-7.58 (3H, m), 8.06 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][CH:22]([OH:25])[CH2:23][OH:24])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCC(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CO)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A mixture of N-{3-amino-2-[(2,3-dihydroxypropyl)amino]phenyl}-N′-(2,4-dichlorophenyl)thiourea (Reference Example 86; 1.71 g, 4.25 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.44 g, 12.8 mmol) in tetrahydrofuran (43 mL) was stirred at 50° C. for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound (687 mg, 1.87 mmol, 44%) as a colorless amorphous.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Cl[C:17]1[CH:18]=[C:19]([CH3:30])[C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>C(O)C>[CH3:30][C:19]1[C:20]2[N:21]([C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][N:25]=2)[N:22]=[C:17]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH:18]=1
Reactant: N#Cc1ccc(CN2CCNCC2)cc1
Reactant: Cc1cc(Cl)nn2c(C(F)(F)F)nnc12
Solvent: CCO
Product: Cc1cc(N2CCN(Cc3ccc(C#N)cc3)CC2)nn2c(C(F)(F)F)nnc12
Temperature: 70 °C
Yield: 64.8 %

Procedure:
A mixture of 1-(4-cyanobenzyl)-piperazine (0.158 g, 0.79 mmol) and 6-chloro-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine 0.062 g, 0.26 mmol) in ethanol (5 mL) was heated to 70° C. for 20 hours. The reaction mixture was allowed to cool and then concentrated to give an involatile residue that was purified by flash chromatography on silica-gel using an increasing gradient of ethyl acetate in dichloromethane to give 4-((4-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)methyl)benzonitrile (0.0676 g, 64.3%) as a white solid; 1H NMR spectrum (CDCl3) δ 2.47-2.55 (4H, m), 2.61 (3H, d), 3.50-3.60 (6H, m), 6.72-6.76 (1H, m), 7.42 (2H, d), 7.57 (2H, d); m/z 402.69 (M+1)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](Cl)(=[O:12])[CH3:11].O>C(Cl)Cl>[CH2:8]([NH:9][C:10](=[O:12])[CH3:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2-phenylethanamine (5.00 g, 41.32 mmol) and TEA (6.26 g, 61.98 mmol) in anhydrous DCM (50 mL) was added dropwise acetyl chloride (3.57 g, 45.45 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous ammonium chloride, brine and concentrated to give the title product as a yellow oil (6.06 g, 37.19 mmol, 90% yield). MS (ESI) m/z 164.1 [M+H]+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:30](=[CH:31][CH:32]=2)[O:29][C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][C:21]3=[O:33])[CH:15]=[N:14]1.[CH:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[C:44]([C:47](O)=[O:48])[CH:43]=[C:42]3[OH:50])[CH2:36][CH2:35]1.O>CN(C=O)C>[CH:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[C:44]([C:47]([N:26]2[CH2:25][CH2:24][C:23]4([CH2:22][C:21](=[O:33])[C:20]5[C:30](=[CH:31][CH:32]=[C:18]([C:16]6[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=6)[CH:19]=5)[O:29]4)[CH2:28][CH2:27]2)=[O:48])[CH:43]=[C:42]3[OH:50])[CH2:35][CH2:36]1
Reactant: O=C(O)c1cc(O)c2cccc(C3CC3)c2n1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(O)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (0.657 ml, 4.71 mmol) was added to a stirred mixture of HOBT (313 mg, 2.04 mmol), WSCDI (361 mg, 1.89 mmol), 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (629 mg, 1.89 mmol) and 8-cyclopropyl-4-hydroxyquinoline-2-carboxylic acid (360 mg, 1.57 mmol) in DMF (3.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (20 ml) and stirred for 30 min. The resulted precipitate was filtered, washed with water and the solid was dried in vacuo at 70° C. The crude product was purified by silicagel column chromatography (CHCl3/AcOEt) to give intended compound as a pale brown solid.
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.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30](=[O:33])[NH:31][CH3:32]>>[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:26]3[CH:27]=[CH:28][C:29]([C:30]([NH:31][CH3:32])=[O:33])=[C:24]([F:23])[CH:25]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1F
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: CNC(=O)c1ccc(-c2cc3nc(CCc4cc(OC)cc(OC)c4)cnc3[nH]2)cc1F

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 3-fluoro-4-(methylcarbamoyl)phenylboronic acid (from Combi-Blocks). LCMS calculated for C24H24FN4O3 (M+H)+: m/z=435.2. Found 435.2.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([O:32][CH3:33])=[O:31])[CH2:7]1)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[K+]>O1CCCC1>[C:24]1([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C@@H:9]3[C@@H:8]([C:30]([O:32][CH3:33])=[O:31])[CH2:7][C@H:6]([S:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:11][N:10]3[C:12]([O:14][CH3:15])=[O:13])=[O:17])[CH2:19][CH2:20]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Sc2ccccc2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of dimethyl(2S,3S,5R)-5-[(methylsulfonyl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (50.0 mg, 0.000103 mol) and benzenethiol (0.0149 mL, 0.000145 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) was added 1.00 M of potassium tert-butoxide in tetrahydrofuran (0.150 mL). The mixture was stirred at rt overnight. The reaction mixture was carried directly into next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.B(O)(O)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Cc1ccc(B(O)O)cc1
Product: COc1ccc2c(-c3ccc(C)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and p-tolylboronic acid to give (6-methoxy-1-p-tolyl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:30])=[CH:36][CH:35]=3)=[N:7][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(n3)N(Cc3c(F)ccc(F)c3Cl)CCN4)cc2)CC1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 4-(4-Methylpiperazine-1-carbonyl)phenylboronic acid pinacol ester using Suzuki coupling conditions as described in Example 1.