Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([O:45]C)=[O:44])=[CH:39][C:38]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[Cl:36])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+]>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([OH:45])=[O:44])=[CH:39][C:38]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[Cl:36])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
Methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (25 mg, 0.034 mmol), aqueous potassium hydroxide (300 μL, 3M, 0.90 mmol) and ethanol (2 mL) were stirred at 20° C. overnight. Volatiles were removed under reduced pressure. The resulting residue was treated with brine followed by extraction with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford an oil. This oil was purified by preparative TLC on SiO2 (eluted with 50% EtOAc in hexanes) to afford a clear glass. The glass was further purified by reverse phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting by a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture affording 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=715.12; found=716.12 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 7.99 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.85 (d, J=5 Hz, 1H), 7.72-7.68 (m, 1.5H), 7.67-7.60 (m, 2.5H), 7.47-7.36 (m, 2H), 7.32 (d, J=8.0 Hz, 0.5H), 7.28 (d, J=8.0 Hz, 0.5H), 7.15 (s, 1H), 7.08 (dd, J=8.5, 7.0 Hz, 1H), 5.58 (d, J=8.0 Hz, 0.5H), 5.29 (d, J=6.5 Hz, 0.5H), 4.97 (d, J=15.5 Hz, 0.5H), 4.94 (d, J=14 Hz, 0.5H), 4.16 (d, J=16 Hz, 0.5H), 3.96 (d, J=15.5 Hz, 0.5H), 3.87 (s, 3H), 3.83-3.74 (m, 1H), 2.38, 2.33 (s, 3H), 0.55 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=7 Hz, 1.5H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]([OH:28])[CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C:21]3=[O:26])=[C:16]([F:27])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[C:29](=C1N=CC=N1)=[O:30].CN(C1C=CC=CN=1)C.C(#N)C>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:28][C:29](=[O:30])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][C:21]4=[O:26])=[C:16]([F:27])[CH:15]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCC(O)CNc1ccc(N2CCOCC2=O)c(F)c1)c1ccc(Cl)s1
Reactant: O=C=C1N=CC=N1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(NCC1CN(c2ccc(N3CCOCC3=O)c(F)c2)C(=O)O1)c1ccc(Cl)s1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
260 mg (0.608 mmol) of 5-chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]-amino}-2-hydroxypropyl)-2-thiophenecarboxamide (from Example 61), 197 mg (1.22 mmol) of carbonylimidazole and 7 mg of dimethylaminopyridine in 20 ml of dioxane are boiled under reflux for 5 hours. 20 ml of acetonitrile are then added, and the mixture is stirred in a closed vessel in a microwave oven at 180° C. for 30 minutes. The solution is concentrated using a rotary evaporator and chromatographed on an RP-HPLC column. This gives 53 mg (19% of theory) of the target compound.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:11]O>Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: COC(=O)CCC(=O)CN
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a 500 ml glass reactor containing 200 ml methanol, was added 1 gram 5-amino-levulinic acid hydrochloride and 1 drop conc. HCl. The reaction mixture was then stirred overnight at 60° C. The progress of the esterification was followed by 1H-NMR. Excess methanol was removed by distillation, and the product further dried, under vacuum at 30-40° C., giving methyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[C:11](O)=[O:12])=[CH:7][CH:6]=1)=[O:4].[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[OH:12][CH2:11][CH:10]([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=1)[CH2:9][C:8]1[CH:26]=[CH:27][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCC(Cc2ccc(C(=O)OC)cc2)C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(CO)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
At −10° C., 112.8 ml (112.8 mmol) of a 1 M borane/THF complex solution are added dropwise to a solution of 20.9 g (56.4 mmol) of 2-[4-(methoxycarbonyl)benzyl]-4-[4-(methoxycarbonyl)-phenyl]butanoic acid in 600 ml of THF. The reaction mixture is then warmed to 0° C. and stirred at this temperature for 4 h. After the reaction has gone to completion, saturated ammonium chloride solution is added, the reaction mixture is diluted with water and ethyl acetate, the phases are separated and the aqueous phase is re-extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and, after filtration, freed from the solvent under reduced pressure. This gives 20.11 g (purity 94%, 100% of theory) of a colorless solid.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:80])[CH2:47][C:48]1[CH:53]=[C:52]([O:54]S(C(F)(F)F)(=O)=O)[CH:51]=[C:50](O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:49]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>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>[CH3:44][O:45][C:46](=[O:80])[CH2:47][C:48]1[CH:49]=[C:50]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])[CH:51]=[C:52]([OH:54])[CH:53]=1
Reactant: COC(=O)Cc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Temperature: 85 °C
Reaction time: 15 h
Yield: 85.9 %

Procedure:
Degassed N,N-dimethylformamide (0.24 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 17.4 mg, 0.0287 mmol), [3-(t-butyl-diphenyl-silanyloxy)-5-trifluoromethanesulfonyloxy-phenyl]acetic acid methyl ester (Example 164-(2); 17.1 mg, 0.0309 mmol), tetrakis(triphenylphosphine)palladium (0) (5.4 mg, 0.0047 mmol) and potassium phosphate (11.5 mg, 0.0542 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 80 to 90° C. for 15 hours. 50% saturated aqueous ammonium chloride was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (15.9 mg, 86%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]#[C:29][C:30](O)=[O:31]>ClCCl.CO>[N:1]1([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][C:30](=[O:31])[C:29]#[C:28][C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=4[Cl:17])=[CH:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc2oc(CN3CCCC3)nc2c1
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc2oc(CN3CCCC3)nc2c1

Procedure:
Prepared analogously to Example 2.3.f. from 0.2 g (0.92 mmol) of 2-pyrrolidin-1-ylmethylbenzoxazol-5-ylamine and 0.2 g (0.8 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 290 mg (81% of theory); C22H17ClF3N3O2 (M=447.84); melting point: 218° C.-223° C.; calc.: molecular ion peak (M+H)+: 448/450 (Cl); found: molecular ion peak (M+H)+: 448/450 (Cl); Rf value: 0.33 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O>C1COCC1>[NH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][N:13]([CH2:22][C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH3:15])=[C:4]([CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)C(C)c1ccccn1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)C(C)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of 5-cyano-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzoic acid methyl ester (0.88 g, 2.2 mmol) in dry THF (11 mL) under Ar at 0° C. was slowly added 1.0 M LiAlH4 in THF (22 mL, 22.0 mmol). The reaction was stirred at room temperature for 2 hours, then cooled to 0° C. Saturated aqueous KNa Tartrate (Rochelle's salt, 30 mL) was slowly added, and the phases were separated. The aqueous phase was extracted with THF (1×35 mL), and the organic extract was dried (MgSO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography twice on silica gel (33:1:1 and 50:1:1 CH2Cl2-MeOH—NH4OH respectively) provided 75.1 mg (9%) of COMPOUND 394 as a white solid. 1H NMR (CDCl3) δ 1.56 (d, 6H, J=6.9 Hz), 2.04 (s, 3H), 3.66-3.98 (m, 6H), 4.05-4.12 (m, 1H), 4.26 (s, 2H), 7.04-7.08 (m, 1H), 7.14-7.23 (m, 3H), 7.27-7.28 (m, 1H), 7.34-7.39 (m, 2H), 7.63-7.69 (m, 1H), 8.39 (d, 1H, J=4.5 Hz), 8.58 (d, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 11.85, 18.43, 46.48, 52.54, 53.97, 58.89, 63.56, 122.53, 122.60, 124.15, 126.40, 130.15, 131.98, 132.93, 135.93, 136.65, 138.51, 142.48, 143.57, 146.57, 148.92, 156.73, 161.25. ES-MS m/z 377 (M+H). Anal. Calcd. for C23H28N4O.0.1H2O.0.3CH2Cl2: C, 69.31; H, 7.19; N, 13.88. Found: C, 69.56; H, 7.27; N, 13.70.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH2:25]([N:1]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (5 g, 19.30 mmol), potassium carbonate (10.70 g, 77.20 mmol) and benzyl bromide (7.90 g, 46.30 mmol) were dissolved in 120 mL of the mixture solvent of ethanol and water (V/V=5:1). The reaction solution was heated to 60° C. and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, added with 100 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-(dibenzylamino)-2-hydroxy-propyl]piperazine-1-carboxylate 35a (3.65 g, yield: 43.0%) as a light yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[N:14]=[C:13]([Cl:20])[C:12]=1[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=1[F:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:11]2[N:16]3[CH:17]=[CH:18][N:19]=[C:15]3[N:14]=[C:13]([Cl:20])[C:12]=2[C:21]2[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=2[F:29])[N:5]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2c(-c3c(F)cc(F)cc3F)c(Cl)nc3nccn23)n1
Yield: 47.7 %

Procedure:
Into a mixture of 0.040 g of sodium hydride (60% in oil) and 2 ml of tetrahydrofuran, a solution of 0.096 g of 3,5-dimethylpyrazole in 3 ml of tetrahydrofuran was added dropwise. The mixture was added to a solution of 0.32 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine in 5 ml of tetrahydrofuran under ice-cooling. To the reaction mixture, chloroform and aqueous citric acid solution were added. The separated organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 0.18 g of 5-(3,5-dimethylpyrazol-1-yl)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: C[Zn]C.[CH3:4]CCCCCC.Br[C:12]1[CH:13]=[C:14]([C:35]([F:38])([F:37])[F:36])[C:15]2[N:16]([N:19]=[C:20]([CH2:22][CH2:23][C:24]3[N:25]([CH3:34])[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:28]=3)[N:21]=2)[C:17]=1[CH3:18]>O1CCOCC1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ni](Cl)Cl>[CH3:18][C:17]1[N:16]2[N:19]=[C:20]([CH2:22][CH2:23][C:24]3[N:25]([CH3:34])[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:28]=3)[N:21]=[C:15]2[C:14]([C:35]([F:38])([F:36])[F:37])=[CH:13][C:12]=1[CH3:4]
Reactant: Cc1c(Br)cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)nn3C)nn12
Reactant: CCCCCCC
Agent: Cl[Ni]Cl
Agent: C[Zn]C
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)nn3C)nn2c1C
Temperature: 100 °C
Yield: 62.1 %

Procedure:
1 M dimethylzinc in heptane (70 μL, 70 μmol, Eq: 1.00) was added to 6-bromo-5-methyl-2-[2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-8-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 65.5 μmol, Eq: 1.00) and 1,3-bis(diphenylphosphino)propane-nickel(II) chloride (13 mg, 24.0 μmol, Eq: 0.366) in dioxane (1 ml). The mixture was heated to 100° C. for 1 h in a microwave oven. Purification by preparative HPLC gave the desired product (16 mg, 61.7%) as a white solid. MS: m/z=394.4 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]1([C:20](O)=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]=[C:20]([C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=1)[NH:8]2
Reactant: O=C(O)c1cccc2ccccc12
Reactant: Nc1ncnc(Cl)c1N
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]c(-c3cccc4ccccc34)nc12
Temperature: 110 °C
Yield: 80.4 %

Procedure:
A mixture of 6-chloro-4,5-diaminopyrimidine (519 mg, 0.00359 mol) and 1-naphthalenecarboxylic acid (618 mg, 0.00359 mol) in phosphoryl chloride (2.0 mL, 0.021 mol) was heated at 110° C. under an atmosphere of nitrogen for 5.5 hours. The reaction was cooled and the residue was washed several times with ether. The residue was dissolved in CH2Cl2 and aqueous NaHCO3. The layers were separated and the aqueous was extracted with EtOAc (1×) and CH2Cl2 (1×). The combined organics were washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and collected in vacuo to obtain 810 mg (80%) of an orange solid. LC/MS: Rt=1.68 min, ES+ 261 (FA standard).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[C:5]=1[O:15][CH2:16][CH2:17][CH3:18].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:12])([F:13])[F:14])[C:5]=1[O:15][CH2:16][CH2:17][CH3:18])[C:19](=[O:22])[CH:20]=[CH2:21]
Reactant: CCCOc1c(CNC)cccc1OC(F)(F)F
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1cccc(OC(F)(F)F)c1OCCC
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a solution of methyl-(2-propoxy-3-trifluoromethoxybenzyl)amine (0.890 g, 3.35 mmol) in CH2Cl2 (30 mL) was added acryloyl chloride (0.30 mL, 3.6 mmol) drop-wise. After stirring for five minutes, triethylamine (0.51 mL, 3.6 mmol) was added. The solution was allowed to stir under N2 for 3 h. The solution was diluted with CH2Cl2 (30 mL), washed with H2O (3×50 mL) and brine (2×50 mL), dried (Na2SO4) filtered and concentrated to yield the title compound (0.95 g, 90%) as a yellow oil and as a mixture of amide rotamers: 1H NMR (500 MHz, CDCl3) δ 7.21-7.00 (m, 3H), 6.67-6.48 (m, 1H), 6.41-6.36 (m, 1H), 5.76-5.66 (m, 1H), 4.75-4.65 (m, 2H), 3.99-3.93 (m, 2H), 3.03 (s, 3H), 1.83-1.78 (m, 2H), 1.07-1.03 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13](=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-hydroxy-3,4-dihydro-2(1H)-quinolinone (90.8 g, 0.56 mol, 1 equiv) in CH3CN (2 L) was added potassium carbonate (230.67 g, 1.67 mol, 3 equiv). The mixture was stirred for 1 h at 25° C., then Mel (75 g, 0.53 mol, 0.95 equiv) was added and the mixture was maintained at 60° C. for 12 hours. The mixture was filtered and the filtrate was taken to a residue under reduce pressure. The crude 6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone was directly use to the next step. (128 g, crude) 1H NMR (400 MHz, DMSO) δ, 2.34-2.38 (m, 2 H), 2.79 (t, 2 H, J=7.2 Hz), 3.65 (s, 3 H), 6.67 (m, 1H), 6.72-6.75 (m, 2 H), 9.86 (br, 1 H). This procedure was reproduced multiple times to prepare >300 g quantities of 6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]=[C:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)C1=NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Agent: [Pd]
Solvent: CO
Product: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12

Procedure:
A solution of 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole (140 mg, 0.25 mmol), 10% Palladium on charcoal (37 mg, 0.025 mmol) and methanol (5 mL) was stirred at rt under 1 atmosphere of hydrogen for 3 h. The mixture was filtered through Celite® and the Celite® was washed thoroughly with methanol. Combined solvent was removed under reduced pressure to afford 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole. It was used directly without further purification. A small portion of product was purified by chromatography for characterization. LC-MS m/z 561 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.73-7.70 (m, 5H), 7.47-7.40 (m, 6H), 6.36 (s, 1H), 5.20 (d, J=2.0 Hz, 2H), 4.24-4.19 (m, 1H), 4.11-4.00 (m, 2H), 3.52-3.47 (m, 1H), 3.20-3.13 (m, 1H), 3.03 (s, 3H), 2.47-2.39 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.09 (s, 9H), 0.96 (d, J=6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 143.06, 135.68, 134.04, 133.31, 131.52, 130.26, 129.79, 129.51, 127.77, 121.39, 111.22, 97.14, 63.76, 59.28, 45.00, 42.94, 42.47, 31.55, 26.94, 19.72, 19.31, 16.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.C(C1C=CC(OC2N=CC(N[C:33]([C@H:35]([NH:38][C:39](=O)[O:40]C(C)(C)C)[CH2:36][CH3:37])=[O:34])=CC=2)=CC=1C(C)C)#N.Cl>ClCCl.CN(C1C=CN=CC=1)C.CCOCC>[CH2:36]([C@H:35]1[NH:38][C:39](=[O:40])[N:14]([C:13]2[CH:15]=[CH:16][C:10]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:11][CH:12]=2)[C:33]1=[O:34])[CH3:37]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1
Reactant: COc1cccc(Oc2ccc(N)cc2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc(OC)c3)cc2)C1=O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To Boc-anhydride (138 mg, 0.631 mmol) in dichloromethane (1 mL) was added DMAP (55.1 mg, 0.451 mmol) followed by a solution of 4-{[3-(methyloxy)phenyl]oxy}aniline (97 mg, 0.451 mmol) in dichloromethane (1 mL). The mixture was stirred for 10 min. The brown solution thus obtained was added to Solution 1 via syringe with shaking at 35° C. and shaking was continued at this temperature for 2 hours. The solution was then kept at room temperature for ca. 64 hours. Conc. aq. HCl (ca. 0.8 mL) was added and the heterogenous mixture was heated at 100° C. for 2 hours with shaking, allowing the DCM to distill off through a glass capillary. After cooling to room temperature, the residue was diluted with water (ca. 3 mL) and extracted with dichloromethane (2 times ca. 2 mL). The dichloromethane extracts were concentrated under vacuum. The residue was purified by silica gel chromatography (Biotage system, 10 g column) eluting with a gradient cHex/EtOAc from 95/5 to 0/100 to give a brown viscous oil that was dissolved in Et2O (ca. 0.7 mL) and cHex (ca. 0.1 mL) and kept over night. The overstanding faint brown solution was decanted from a small quantity of a brown oil that had separated out. As the solvent was allowed to evaporate from this solution crystallisation initiated. The material thus obtained was allowed to dry and then triturated with Et2O (2 times ca. 0.5 mL) to afford, after drying, the title compound as a solid (28 mg).