Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:32][CH:33]=2)[C:28]([Sn](CCCC)(CCCC)CCCC)=[N:27]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:39])[F:38])[CH:30]=4)[N:26]([CH3:25])[N:27]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC(F)(F)F)cc12
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)(F)F)cc34)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
In a 25 mL round-bottomed flask, 2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (107 mg, 258 μmol) and 1-methyl-3-(tributylstannyl)-5-(trifluoromethoxy)-1H-indazole (209 mg, 413 μmol) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (14.9 mg, 12.9 μmol) and CuI (9.83 mg, 51.6 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (40 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give N-isopropyl-2-(1-methyl-5-(trifluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (113 mg, 206 μmol, 80%) as a light yellow solid. MS (M+H)+=549; 1H NMR (CDCl3) δ: 9.23 (s, 1H), 8.35 (s, 2H), 8.01 (d, J=7.9 Hz, 1H), 7.44-7.53 (m, 1H), 7.34-7.43 (m, 1H), 5.70 (s, 2H), 4.38-4.56 (m, 1H), 4.19 (s, 3H), 3.52-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 0.84-1.00 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[OH:13].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1.O>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1
Reactant: Oc1ccnc2c(C(F)(F)F)cccc12
Reactant: O=c1cc(CO)occ1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Reaction time: 0.17 h
Yield: 35 %

Procedure:
8-Trifluoromethyl-quinolin-4-ol (0.84 g, 2.88 mmol) was dissolved in DMF (5 mL). Cs2CO3 (0.98 g, 3.02 mmol) was added at room temperature and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.86 g, 3.02 mmol) in DMF (5 mL) was added via syringe. This mixture was stirred at 50° C. for 18 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 14 was obtained (0.53 g, 35% yield) as a pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:33](=O)[CH:34]([CH3:36])[CH3:35].C(O)(=O)C>ClCCl>[CH3:33][CH:34]([CH3:36])[CH2:35][NH:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: N#Cc1ccc(-n2cnc3c(N)cccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CNc1cccc2c1ncn2-c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a stirred solution of 4-(4-amino-1H-benzimidazol-1-yl)benzonitrile (246 mg, 1.05 mmol) in dichloromethane (10 mL) at rt was added sodium triacetoxy borohydride (311 mg, 1.47 mmol, 1.4 eq), isobutyraldehyde (91 mg, 1.26 mmol, 1.2 eq) and acetic acid (63 m g, 1.05 mmol, 1 eq) and the mixture was stirred for 2 h. The mixture was poured on water and extracted with DCM. After evaporation of the organic phase, purification of the residue by flash chromatography yielded 190 mg 4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzonitrile (62.3%).
Reaction SMILES: C([N:5](C1C=CC=CC=1)[C:6](=[O:27])[CH2:7][N:8]1[C:14](=[O:15])[CH2:13][C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[N:47]=1>C1COCC1>[C:58]([O:57][C:55]([N:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]([CH2:45][CH:13]2[C:14](=[O:15])[N:8]([C:7]([C:58]([CH3:61])([CH3:60])[CH3:59])([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:6](=[O:27])[NH2:5])[C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[N:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:12]2=[O:16])=[N:47]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(c3ccccc3)c3ccccc3N(C(C(N)=O)(c3ccccc3)C(C)(C)C)C2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a stirred slurry of 514 mg (1.17 mmol) N-tert-Butyl-2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-phenyl-acetamide, prepared as in Part B, in 15 mL THF cooled to 0° C. is added 1.28 mL (1.28 mmol, 1.1 equiv) of 1M Sodium bis(trimethylsilyl)amide in THF at ambient temperature and stirred 0.5 h. To this solution is added 381 mg (1.22 mmol, 1.05 equiv) 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole and the resultant reaction mixture stirred 1 h at 0° C. followed by 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into EtOAc (50 mL), washed with H2O (30 mL) and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on 20 g silica gel eluted with EtOAc/Hexanes (1:3, 350 mL). Appropriate fractions were combined and concentrated in vacuo to give 263 mg (0.392 mmol) of the title compound as a white foam: 1H NMR (CDCl3, 300 MHz) δ8.04 (d, 1H, J=8.4), 7.89 (d, 1H, J=7.9), 7.51-7.20 (m, 14H), 7.10 (m, 1H), 6.94 (m, 1H), 4.28 (m, 1H), 4.20-4.06 (m, 2H), 3.84 (m, 1H), 3.56 (m,1H), 1.66 (s, 9H), 1.39 (s, 9H); TLC Rf =0.16 (EtOAc/Hexanes, 1:3).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]2[C:10]=1[C:9]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])=[N:8][NH:7][C:6]2=[O:21].[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C=O)C>[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:15]([C:14]2[CH:13]=[C:12]([CH:20]=[CH:19][CH:18]=2)[CH2:11][C:9]2[C:10]3[C:5](=[C:4]([CH3:22])[NH:3][C:2]=3[CH3:1])[C:6](=[O:21])[NH:7][N:8]=2)=[O:16])[CH2:27][CH2:26]1
Reactant: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(C(=O)O)c3)c12
Reactant: COC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.179 g, 0.47 mmol) was added to 3-((5,7-dimethyl-1-oxo-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-4-yl)methyl)benzoic acid (51) (0.100 g, 0.34 mmol), 4-methoxypiperidine (0.043 g, 0.37 mmol) and triethylamine (0.117 mL, 0.84 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 5 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.054 g, 40.9% yield). 1H NMR (400.132 MHz, DMSO) δ 1.18-1.93 (4H, m), 2.24 (3H, s), 2.51 (3H, s), 3.02-3.19 (2H, m), 3.25 (3H, s), 3.40 (2H, m), 3.76-3.97 (1H, m), 4.09 (2H, s), 7.14 (1H, s), 7.20 (1H, d), 7.27 (1H, d), 7.36 (1H, t), 11.08 (1H, s), 11.92 (1H, s); m/z (LC-MS, ESI+), RT=1.38 min (M+H=395.09).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][N+:9]([O-:11])=[O:10].[OH-].[Na+].Cl>O.CO>[N+:9]([CH:8]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=Cc1cccs1
Temperature: -5 °C

Procedure:
To 7.85 g (0.07 mol) of 2-thiophenecarboxaldehyde were added 148 ml of MeOH and 12.82 g (0.210 mol) of CH3NO2 ; and 74 ml of 50% aqueous solution of NaOH was added dropwise to the mixture with stirring at -5° C. After being stirred at 10° C. for 1 hr., the reaction solution was poured into a mixture of 296 ml of 36% HCl and 493 ml of water at 0° C. The crystals separating out were collected by filtration and washed with water, whereby 6.65 g (Yield : 61.2%) of the objective compound, 2-(2-nitroethenyl)thiophene (d-1) was obtained as greenish brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH3:19])=[C:9]2[CH2:20][CH2:21][C:22](O)=[O:23])=[O:7])=[CH:4][CH:3]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].[N+](=C1CCCCC2C1CCCC=2)=[N-].CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH3:19])=[C:9]2[CH2:20][CH2:21][C:22]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:23])=[O:7])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc2c(c1)c(C)c(CCC(=O)O)n2C(=O)c1ccc(Cl)cc1
Agent: [N-]=[N+]=C1CCCCC2=CCCCC21
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C)c(CCC(=O)NS(C)(=O)=O)n2C(=O)c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a cooled mixture (0-5° C.) of 3-(1-(4-chlorobenzoyl)-5-methoxy-3-methyl-1H-indol-2-yl)propanoic acid (40 mg, 0.11 mmol) in CH2Cl2 (1 mL), 1′1′-carbonyldiimidazole (CDI) (17.4 mg, 0.11 mmol) was added. After the mixture was stirred for 2 h at 0-5° C., methansulfonamide (10 mg, 0.11 mmol) and diazobicyclo-[5.4.0]undec-7-ene (DBU) (16.1 μL, 0.11 mmol) were added. The mixture was left stirring overnight. Glacial AcOH (13.2 μL) was added, the reaction mixture was diluted with CH2Cl2 (1 mL), and the organic layer was washed with 10% NaH2PO4 (pH 4) (1×1 mL) and water (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue that was purified by flash chromatography (SiO2, ethyl acetate/hexane, 0.5% AcOH gradient) to afford the title compound as a bright yellow solid (32 mg, 66%). C21H21ClN2O5S, Mr=448.92; 1H NMR (400 MHz, DMSO-d6) d: 2.21 (s, 3H), 2.55 (t, J=7.2 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 3.16 (s, 3H), 3.75 (s, 3H), 6.43 (d, J=9.2 Hz, 1H), 6.64 (dd, J=9.0 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 7.64-7.69 (m, 4H); LCMS (ESI) tR: 2.74 min (>95%, UV254, ELSD), m/z: 249.1 [M+1]+.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12](Cl)=[O:13].S(Cl)(Cl)=O.Cl>ClCCl>[C:1]([NH:6][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:9]([O:8][CH3:7])[CH:10]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)N
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCC(C)(C)NC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
30 ml of tert-amylamine are added at 10° C. to a solution of 27 g of 3-methoxy-4-nitrobenzoyl chloride (obtained from 25 g of the corresponding acid and thionyl chloride at reflux for 4 hours, followed by evaporation under vacuum) in 250 ml of dichloromethane. The reaction mixture is stirred for 30 minutes at 20° C., 100 ml of a 1N hydrochloric acid solution are then added, the organic phase is separated by settling, washed and dried over MgSO4, the solvent is then evaporated and the residue is chromatographed on silica gel, elution being carried out with dichloromethane, to obtain 31 g of the expected product; M.p.=65° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:44])[F:43])[CH:36]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cccc(-c2cccc(Br)n2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(C(F)(F)F)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(3-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[OH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([O:12][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2nc(C)c(C)nc2C)cc1
Temperature: 85 °C
Yield: 63.3 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.86 g, 0.0040 mol), ethyl p-hydroxybenzoate (0.948 g, 0.0057 mol), anhydrous potassium carbonate (1.38 g, 0.0103 mol), and DMF (60 mL) into a 100 mL three-necked bottle in turn, heating to 85° C. with oil bath, stirring to react for 12 hours, TLC [V(cyclohexane):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.5, Rf of product=0.4), and the reaction solution appears yellow, filtering to obtain yellow filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(cyclohexane):V(ethyl acetate)=3:1, collecting product, rotating distilling to obtain light yellow solid, recrystallizing with anhydrous alcohol to obtain 0.76 g 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)benzoic acid ethyl ester, a yield is 63.3%, m.p. 75.0-75.7° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.[Br:12]N1C(=O)CCC1=O.C(OCCCC)(=O)C>C(#N)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:11][C:1]1[CH:2]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCOC(C)=O
Solvent: CC#N
Product: O=C(O)Cc1cccc(CBr)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
m-Tolylacetic acid (4.0 g, 26.64 mmol) and AIBN (α,α′-azobisisobutyronitrile) (0.044 g, 0.266 mmol) were dissolved in acetonitrile (11.9 g) and the solution was raised to 80° C. To this solution was dropped a solution of N-bromosuccinimide (4.98 g, 27.97 mmol) and AIBN (α,α′-azobisisobutyronitrile) (0.044 g, 0.266 mmol) in acetonitrile (32 g) for 1.5 hours. After stirring for 30 minutes the mixture was cooled to 50° C. and thereto was added butyl acetate (38.7 g). The mixture was concentrated to remove only acetonitrile. The resulting succinimide (crystal) was removed and the residue was washed three times with water. After concentrating to a desired concentration, thereto was added at 45° C. n-heptane (45.6 g) to produce a crystal. After cooling to 5° C., the crystal was filtered to give the sub-subject compound (3.76 g) as a white crystal. Yield: 62%
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]3[C:21]=2[C:16](=[C:17]2[CH:33]=[CH:32][CH:31]=[CH:30][C:18]2=[CH:19]3)[C:15]1=[O:34])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]([CH3:11])[CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]3[C:21]=2[C:16](=[C:17]2[CH:33]=[CH:32][CH:31]=[CH:30][C:18]2=[CH:19]3)[C:15]1=[O:34]
Reactant: COc1ccc2c3c(c4ccccc4cc13)C(=O)N(CCN(C)CCNC(=O)OC(C)(C)C)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c3c(c4ccccc4cc13)C(=O)N(CCN(C)CCN)C2=O

Procedure:
Method (ii)—Removing Boc protection by Preparing Trifluoroacetic salt: The trifluoroacetic salt of 2-{2-[(2-aminoethyl)methylamino]ethyl}-6-methoxy-1,2-dihydro-3H-dibenzo[de,h]isoquinoline-1,3-dione was prepared by stirring (2-{[2-(6-Methoxy-1,3-dioxo-1H,3H-dibenzo[de,h]isoquinolin-2-yl)-ethyl]-methyl-amino}-ethyl)-carbamic acid tert-butyl ester with 50% trifluoroacetic acid in DCM for 40 minutes. The reaction was quantitative.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:27])([F:26])[F:25])=[N:17]3)[CH2:8][C@@H:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.[CH3:36][NH2:37].[C-]#N.[Na+]>CCO>[CH2:28]([C@H:7]1[CH2:8][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:27])([F:25])[F:26])=[N:17]3)[CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH:37][CH3:36])=[O:3])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN
Reactant: CCOC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Reaction time: 48 h
Yield: 63 %

Procedure:
A solution of [(S)-2-Benzyl-4-(8-methoxy-2-trifluoromethyl-quinolin-5-yl)-piperazin-1-yl]-acetic acid ethyl ester in a ˜33% methylamine solution in EtOH (5 mL) was treated with catalytic amount of sodium cyanide and allowed to stir for 48 h. The reaction mixture was then evaporated, washed with water and air dried to afford the title compound as a yellow solid (68 mg, 63%). LC/MS (Method B) 2.82 min, [M+1]+ 472.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1>O.C(O)C>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1

Procedure:
A mixture of 10 g (36.4 mmol) of 4-chloro-2-(4-chlorophenyl)quinoline, and 20 ml of ethyl isonipecotate was stirred and heated at 160°-170° for 2 hr. It was then cooled and diluted with 200 ml of water and 5 ml of ethanol. The solid which formed was collected, and recrystallized from ethanol to give 5.5 g of product ester, mp 124°-126°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]([CH3:27])([CH3:26])[CH2:23][O:24][CH3:25])=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:24][CH2:23][C:22]([C:18]1[NH:19][C:20](=[O:21])[N:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)[N:17]=1)([CH3:27])[CH3:26]
Reactant: COCC(C)(C)c1nn(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCC(C)(C)c1nn(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 85 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
1-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(1-methoxy-2-methylpropan-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.10 g, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.07 g, 0.33 mmol), and K2CO3 (0.09 g, 0.66 mmol) were suspended in a solution of dioxane (2.0 mL) and water (0.4 mL). The suspension was sonicated and sparged with Ar for 10 min followed by the addition of Pd(PPh3)4 (0.03 g, 0.026 mmol). The reaction mixture was stirred at 85° C. for 12 h, allowed to cool to RT, diluted with water (2.0 mL), and extracted with EtOAc (5×3 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford an orange oil. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(1-methoxy-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.085 g, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.93 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H), 3.39 (s, 2H), 3.25 (s, 3H), 2.33 (s, 3H), 1.24 (s, 6H); MS (ESI) m/z: 436.2 (M+H+).
Reaction SMILES: [ClH:1].[NH2:2][C:3](=[O:33])[C@@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.N[C@H](C1C=CC=CC=1)C(N)=O>>[ClH:1].[NH2:2][C:3](=[O:33])[C@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Agent: NC(=O)[C@H](N)c1ccccc1
Product: NC(=O)[C@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 29.5 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with (R)-2-amino-2-phenylacetamide hydrochloride (Bachem, 28 mg, 0.15 mmol) in a manner similar to that which is described in Step C of Example 1 to give (R)—N1-(2-amino-2-oxo-1-phenylethyl)-N3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide, hydrochloride salt (14 mg, 30% yield). 1H NMR (DMSO-d6) δ 10.65 (s, 1H), 8.76 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=7.0 Hz), 7.75-7.88 (m, 4H), 7.20-7.43 (m, 8H), 6.66 (m, 1H), 6.09 (s, 1H), 5.35 (d, 1H, J=8.0 Hz), 3.45 (d, 1H, J=15.0 Hz), 3.37 (d, 1H, J=15.0 Hz); MS(ESI+) m/z 438.23 (M+H)+.