Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[N:26]1([CH2:31][CH2:32][N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)CC)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][CH:21]=[C:20]([C:36]4[CH:35]=[N:34][N:33]([CH2:32][CH2:31][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:37]=4)[N:19]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(-c2cncc(Cl)n2)c2cccnc2n1
Reactant: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3cnn(CCN4CCCC4)c3)n2)c2cccnc2n1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A slurry of 115 mg (0.31 mmol) 2-(5-chloro-2-fluoro-phenyl)-4-(6-chloro-pyrazin-2-yl)-[1,8]naphthyridine, 99.3 mg (0.34 mmol) 1-(2-pyrrolidin-1-yl-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 165 mg (0.62 mmol) tri-potassium-phosphate-trihydrate in 1 ml 1,2-dimethoxyethane was heated to 80° C. under nitrogen. Then 4.3 mg (0.006 mmol) bis-(triphenylphosphine)-palladium(II)-chloride and a drop of triethylamine were added. The reaction mixture was stirred for 18 hours at 80° C. The reaction mixture was cooled to room temperature and water was added. The resulting precipitate was filtered off, washed with water and chromatographed on a silica gel column with dichloromethane/methanol as eluent to yield 2-(5-chloro-2-fluoro-phenyl)-4-{6-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-pyrazin-2-yl}-[1,8]naphthyridine as grey crystals; HPLC-MS: 1.52 min, [M+H] 500.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:59]1[CH2:64][CH2:63][CH:62]([C:65]2[C:66](=[O:75])[NH:67][C:68]3[C:73]([CH:74]=2)=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:61][CH2:60]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:59]4[CH2:60][CH2:61][CH:62]([C:65]5[C:66](=[O:75])[NH:67][C:68]6[C:73]([CH:74]=5)=[CH:72][CH:71]=[CH:70][CH:69]=6)[CH2:63][CH2:64]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (44 mg, 0.088 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (70 μl, 0.402 mmol) was added to the mixture followed by TBTU (31.5 mg, 0.098 mmol). 3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (25.7 mg, 0.097 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Reaction was quenched with 50% acetonitrile-water. Mixture was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as light tan solid in 51% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.91 (s, 1H) 11.78 (s, 1H) 7.71 (s, 1H) 7.62 (d, J=7.93 Hz, 1H) 7.48 (s, 1H) 7.44 (t, J=7.63 Hz, 1H) 7.28 (d, J=8.24 Hz, 1H)7.15 (t, J=7.48 Hz, 1H) 5.58 (d, J=17.70 Hz, 1H) 5.40 (d, J=17.40 Hz, 1H) 4.55 (d, J=11.90 Hz, 1H) 4.29-4.46 (m, 1H) 4.07-4.23 (m, 2H) 3.91-4.05 (m, 1H) 3.11-3.24 (m, 2H) 2.95-3.09 (m, 2H) 2.82-2.95 (m, 1H) 2.64 (t, J=13.12 Hz, 1H) 2.43 (dd, J=16.48, 4.27 Hz, 1H) 1.89-1.96 (m, 1H) 1.78-1.88 (m, 1H) 1.47-1.64 (m, 1H) 1.30-1.46 (m, 1H). High resolution MS m/e (M+H)+=708.0445.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]([CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:7]([NH:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])=[O:8])C.[OH-].[Na+]>C(O)C>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][N:6]([C:7]([NH:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])=[O:8])[CH2:5][C:4]([OH:29])=[O:3])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Nn1cc(C)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn(NC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O
Reaction time: 6 h

Procedure:
The product from Example 6, 9, is dissolved in ethanol (500 mL) and 2M sodium hydroxide (50 mL) is added. The reaction is stirred for 6 hours, then neutralized with 50 mL of 2M HC1 solution, and evaporated to remove the ethanol. The residue is dissolved in dichloromethane (250 mL) and is extracted with water (2×50 mL), dried, filtered, and evaporated to a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].Cl.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44]Cl.[Cl-].[NH4+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])[C:18]3[C:23]([C:24]=2[CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1
Reactant: CN(C)CCCl
Reactant: O=C(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCN(c2ccccc2Cl)CC1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCn1c(C(=O)N2CCN(c3ccccc3Cl)CC2)c(C(c2ccccc2)c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a solution of Compound 88 (1.0 g, 1.98 mmol) obtained in Example 88 in 10 ml of N,N-dimethylformamide was portionwise added sodium hydride (60% in oil, 166 mg, 4.15 mmol) with stirring at room temperature, and 2-dimethylaminoethylchloride hydrochloride (298 mg, 2.07 mmol) was added thereto, followed by heating to 80° C. and then stirring for one hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution for neutralization, water was added thereto, and the resulting crystals were collected by filtration to give 1.1 g of a crude product. The obtained crude product was recrystallized from ethanol (65 ml) to give 0.67 g (yield: 59%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([NH2:17])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24](O)=[O:25].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.CCOC(C)=O>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([NH:17][C:24]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][N:18]=4)=[O:25])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc2ccc(-c3ccccc3)nc12
Reactant: O=C(O)c1cnccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2ccc(-c3ccccc3)nc12)c1cnccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.3 %

Procedure:
2-Phenylquinolin-8-amine (60 mg, 0.27 mmol) was taken up in 2 mL of DMF along with pyrazine-2-carboxylic acid (34 mg, 0.27 mmol), HATU (207 mg, 0.54 mmol) and DIEA (95 μL, 0.54 mmol). The reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (using aqueous CH3CN that has been buffered with 0.1% TFA) to afford 10 mg of the product. MS (ESI) calcd for C20H14N4O (m/z): 326.12. found: 327 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[CH3:13][N:14]([CH3:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1>>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([N:14]([CH3:24])[CH3:13])[CH:20]=[CH:19][C:18]=1[C:6]([C:5]1[CH:11]=[CH:12][C:2]([NH2:1])=[CH:3][C:4]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Nc1ccc2c(c1)C(=O)OC2=O
Product: CN(C)c1ccc(C(=O)c2ccc(N)cc2C(=O)O)c(N(C)C)c1

Procedure:
Condensation of 4-aminophthalic anhydride and N,N,N',N'-tetramethyl-m-phenylenediamine by the method of part A of Example 3 affords 2-(2,4-bis(dimethylamino)benzoyl)-5-aminobenzoic acid.
Reaction SMILES: Br[C:2]([F:22])([F:21])[C:3]([NH:5][CH2:6][C:7]1([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:4].CC(C)([O-])C.[K+]>C1COCC1>[F:21][C:2]1([F:22])[C:3](=[O:4])[NH:5][CH2:6][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNC(=O)C(F)(F)Br)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C(F)(F)O2
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-((2-bromo-2,2-difluoroacetamido)methyl)-4-hydroxypiperidine-1-carboxylate (example 37, step a) (3.2 g) in THF (40 mL) was added dropwise over 15 minutes to a stirred solution of potassium tert-butoxide (1M in t-butanol, 16.53 mL) and THF (60 mL) at 70° C. under nitrogen. At the end of the addition the mixture was heated for a further 10 minutes and then cooled to room temperature. The mixture was partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% isohexane in ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.55 g.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C@H:12]([NH:14]C(=O)COC)[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].N(CCO)(CCO)CCO.[OH-].[Na+]>O>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)N[C@H](C)c1cccc(OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCN(CCO)CCO
Solvent: O
Product: C[C@@H](N)c1cccc(OC(C)(C)C)c1
Yield: 92 %

Procedure:
(R)—N-1-(3-tert-Butoxyphenyl)ethylmethoxyacetamide from example 2.3 (63.5 g with a purity of 93%; corresponds to 0.22 mol of pure substance) was mixed with triethanolamine (6 ml) with stirring and then admixed with 50% NaOH (23.2 g, 0.29 mol). The mixture was then stirred at a bath temperature of 140° C. for another 16 hours, after which all of the amide had reacted according to GC analysis. The mixture was diluted with water (100 ml), cooled and extracted with tert-butyl methyl ether (3×100 ml). The combined extracts were washed with saturated sodium chloride solution (50 ml) and dried over Na2SO4. After the solvent had been removed on a rotary evaporator, 41 g (92%) of (R)-1-(3-tert-butoxyphenyl)ethylamine were obtained in the form of a colorless oil. The chemical purity was 99.4%, the optical purity 98.9% ee.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1)=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:58]=[N+:59]=[N-:60])(C)C>C1COCC1.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[N:60]=[N:59][N:58]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-{[4-cyano-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 21, 65 g) in THF (300 mL) was added triphenylphosphine (161 g, 0.615 mol) and diisopropylazodicarboxylate (124 g, 0.615 mol) at 0° C. The reaction mixture was stirred for 30 minutes. Trimethylsilylazide (71.1 g, 0.615 mol) was added dropwise at room temperature and then heated to reflux for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with ice-water. The organic layer was separated and washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using an eluent of 20% ethyl acetate in petroleum ether to yield 1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (45 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)=O.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[S:21])=[CH:18][C:17]=1[O:25][CH2:26][CH2:27][CH3:28]>CO>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[S:21][CH:2]=[C:3]([C:5]3[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=3)[N:22]=2)=[CH:18][C:17]=1[O:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)c1ccc(C(=O)CBr)o1
Reactant: CCCOc1cc(C(N)=S)ccc1OC
Solvent: CO
Product: CCCOc1cc(-c2nc(-c3ccc(C(=O)OC)o3)cs2)ccc1OC
Yield: 79.2 %

Procedure:
To a solution of 877 mg of 5-(2-bromoacetyl)-2-methoxycarbonylfuran in 40 ml of methanol was added 800 mg of 4-methoxy-3-propoxythiobenzamide, and the mixture was refluxed for 1 hour. The reaction mixture was concentrated approximately ¼, then added diethyl ether. After cooling the solution, a precipitate was collected by filtration and dried to obtain 1.05 g of 2-(4-methoxy-3-propoxyphenyl)-4-(5-methoxycarbonyl-2-furyl)thiazole as a brown powder. mp. 141.0-142.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])=[CH:6][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CCN(CC)CC>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([F:8])=[CH:6][CH:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 97 %

Procedure:
A solution of 3-amino-6-fluorobenzotrifluoride (2.0 g, 11.17 mmol, Aldrich) in acetic anhydride (10 mL) and Et3N (1 mL) was stirred at room temperature for 24 h, and then most of the acetic anhydride was removed. The white needle crystals were collected by filtration and washed with water (2×2 mL), affording 2.4 g (97%) of 3-acetamido-6-fluorobenzotrifluoride. 1H NMR (CDCl3): δ2.184 (s, 3H); 7.136 (t, 1H, J=9.9 Hz); 7.733 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([N:30]([CH2:48][CH2:49][CH2:50][CH3:51])[CH:31]2[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:33]([CH3:47])([CH3:46])[CH2:32]2)[N:3]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:40]1([O:39][N:34]2[C:33]([CH3:47])([CH3:46])[CH2:32][CH:31]([N:30]([CH2:48][CH2:49][CH2:50][CH3:51])[C:4]3[N:5]=[C:6]([N:8]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:9]4[CH2:10][C:11]([CH3:24])([CH3:25])[N:12]([O:17][CH:18]5[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]5)[C:13]([CH3:15])([CH3:16])[CH2:14]4)[N:7]=[C:2]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[N:3]=3)[CH2:36][C:35]2([CH3:37])[CH3:38])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCN(c1nc(N2CCOCC2)nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 55 %

Procedure:
A mixture of 10.0 g (13.7 mmol) of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)-n-butylamino]-1,3,5-triazine (see Example 75), 1.43 g (16.4 mmol) of morpholine, 0.8 g of sodium hydroxide, and 30 g of toluene is heated at reflux for four hours. Water is collected in a Dean-Stark trap. The liquid phase is decanted and residual solids are washed with toluene. The combined organic solutions are dried over magnesium sulfate and concentrated to give a viscous oil. Purification by HPLC (Waters Prep. 500 A, 29:1 heptane:ethyl acetate) affords 5.9 g (55% yield) of the title compound, a white powder, m.p. 159°-63° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Cl:32]N1C(=O)CCC1=O>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Cl:32])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(Cl)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (116 mg, 0.310 mmol) was dissolved in anhydrous THF (5 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., cooled to −78° C. and N-chlorosuccinimide (1.5 equiv) in THF (3 mL) was added dropwise. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude aryl chloride, which was purified by flash chromatography (0-2% EtOAc/hexanes) to afford the title compound as a clear oil (73 mg, 57%): 1H NMR (CDCl3, 600 MHz) 7.29-7.26 (m, 2H), 7.18-7.17 (m, 3H), 6.82 (s, 1H), 4.71 (t, 1H, J=7.2 Hz), 2.60 (t, 2H, J=7.8 Hz), 1.88-1.80 (m, 2H), 1.62-1.60 (m, 2H), 1.43-1.35 (m, 6H), 0.89 (s, 9H), 0.09 (s, 3H), −0.01 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.6, 143.6, 136.9, 129.3, 129.1, 126.5, 122.9, 69.5, 37.0, 36.8, 32.3, 29.9, 29.9, 26.6, 19.1, −4.2, −4.3.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (110 mg) is dissolved in ethanol (2 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (233 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (69 mg). The resulting carboxylic acid is dissolved in ethanol (0.2 mL) and thereto is added 2N-aqueous sodium hydroxide solution (50 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (70 mg). MS (m/z): 679 [M−Na]−
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][C:3]=1[CH2:15]O.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:15][C:3]1[N:4]=[C:5]2[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][N:6]2[C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)nc2c3c(ccn12)CCCC3
Solvent: ClCCl
Product: Cc1c(CCl)nc2c3c(ccn12)CCCC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product of (3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinolin-2-yl)methanol (200 mg) was dissolved in 5 mL of DCM. To the mixture was added thionyl chloride (0.5 mL) at 0° C. The mixture was stirred overnight at room temperature. After removal of the solvent, the residue was dried under vacuum to give 2-(chloromethyl)-3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinoline (200 mg). ESI MS: m/z 235 [M+H]+.
Reaction SMILES: Cl.C(OCC)(=O)C.[C:8]12([NH:18][C:19](=[O:32])[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23][CH3:24])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[C:8]12([NH:18][C:19](=[O:32])[CH2:20][NH:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2
Reactant: CCCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCNCC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
Next, a 4 N solution of hydrogen chloride in ethyl acetate (55 ml, 0.22 mol) was added to 2-[N′(t-butoxycarbonyl)-N-propylamino]acetic acid N-(1-adamantyl)amide (7.68 g, 21.9 mmol), and the mixture was stirred at room temperature for one hour. The resulting crystals were filtered off with ethyl acetate and washed with ethyl acetate to give 5.97 g (95%) of the titled compound as colorless crystals.
Reaction SMILES: [NH3:1].CO.[S:4]1[CH:8]=[CH:7][C:6]2[C:9]([NH:13][C:14]3[N:15]=[C:16]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]4[NH:32]C(OC(C)(C)C)=O)[N:17]=[N:18][C:19]=3[C:20](OCC)=[O:21])=[CH:10][CH:11]=[CH:12][C:5]1=2>>[NH2:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:16]1[N:17]=[N:18][C:19]([C:20]([NH2:1])=[O:21])=[C:14]([NH:13][C:9]2[C:6]3[CH:7]=[CH:8][S:4][C:5]=3[CH:12]=[CH:11][CH:10]=2)[N:15]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2sccc12
Solvent: CO
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 7 M ammonia-methanol solution (2 ml) was added to ethyl 5-(benzo[b]thiophen-4-ylamino)-3-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 2 (71.8 mg), and then the reaction solution was allowed to react in a microwave reactor at 130° C. for 1 hour. The solvent was evaporated under vacuum, then trifluoroacetic acid (0.5 ml) was added to the resultant residue, and the reaction solution was stirred at room temperature for 5 minutes. The solvent was evaporated under vacuum, and then the resultant residue was purified by column chromatography on basic silica gel (developing solvent:hexane/ethyl acetate) to obtain the titled compound as a white solid.