Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][C:40]=1[C:46]([F:49])([F:48])[F:47]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[O:45][C:42]1[CH:43]=[CH:44][C:39]([F:38])=[C:40]([C:46]([F:49])([F:47])[F:48])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccccc1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Oc1ccc(F)c(C(F)(F)F)c1)n2Cc1ccccc1
Temperature: 90 °C
Yield: 90.4 %

Procedure:
Step 1 7-Benzyl-8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.985 mmol, intermediate 83), potassium carbonate (0.272 g, 1.97 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.19 g, 1.03 mmol) were combined in DMF (5 mL). The reaction was heated at 90° C. After 6 h the reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a white solid. This solid was purified using a 25 g silica column eluted with 20% ethyl acetate/hexanes to give 7-benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.54 g, 90% yield) as a white solid. LCMS retention time=5.342 min and 97% purity, LCMS MH+=607.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:13]([OH:15])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:63][C@@H:64]([CH2:78][C:79]1[CH:84]=[C:83]([F:85])[CH:82]=[C:81]([F:86])[CH:80]=1)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=1.[ClH:87]>C(Cl)Cl.CO.C(OCC)C>[ClH:87].[ClH:87].[F:85][C:83]1[CH:84]=[C:79]([CH:80]=[C:81]([F:86])[CH:82]=1)[CH2:78][C@H:64]([NH:63][C:13](=[O:15])[C:12]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:10]([CH2:9][N:5]2[CH2:6][CH2:7][CH2:8][C@@H:4]2[CH2:3][O:2][CH3:1])[CH:11]=1)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: COC[C@H]1CCCN1Cc1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(CN3CCC[C@@H]3COC)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}-5-methylbenzoic acid (113 mg, 0.43 mmol) in methylene chloride (3 mL) is added HBTU (165 mg, 0.66 mmol), HOBt (89 mg, 0.66 mmol), and N,N -diisopropylethylamine (0.220 mL, 1.30 mmol), followed by (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (175 mg, 0.43 mmol), and the reaction mixture is stirred for 12 h at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% methanol/chloroform) affords a clear oil, which was dissolved in methanol (2 mL). To this solution is added hydrochloric acid (5 mL, 4 N dioxane, 20 mmol), and the reaction mixture is stirred for 1 h at room temperature. The reaction mixture is then diluted with ethyl ether (10 mL). The precipitate that is formed is collected by filtration to provide the title compound. ESI MS m/z 580.4 [M+H]+.
Reaction SMILES: C(N)CC1C=CC=CC=1.C(Cl)(=O)CC.[CH2:15]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)[CH3:16].C1C2C(=CC=CC=2)C=CN=1.[Cl:37][CH:38]([Cl:42])[C:39](Cl)=[O:40]>C1(C)C=CC=CC=1>[Cl:37][CH:38]([Cl:42])[C:39]([N:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]1[CH2:15][CH3:16])=[O:40]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCC1NCCc2ccccc21
Agent: CCC(=O)Cl
Agent: NCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccc2cnccc2c1
Product: CCC1c2ccccc2CCN1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1 (Method A), phenethylamine and propionyl chloride were converted to 1-ethyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 2.5 g of this isoquinoline compound in 50 ml toluene. With this mixture stirred, 1.5 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was refluxed until a clear solution appeared. The mixture was stripped of solvent and subjected to Kugelrohr distillation (150° C. @ 0.25 mm Hg) to provide 2.7 g of product having the elemental analysis reported in Table I.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13]C)=[O:12])[CH2:4]1.[OH-].[Na+]>CO>[CH3:1][N:2]([CH3:18])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=[O:12])[CH2:4]1
Reactant: COC(=O)c1cccc(N2CC[C@H](N(C)C)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)[C@H]1CCN(c2cccc(C(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 3-(3-(dimethylamino)pyrrolidin-1-yl)benzoate (0.555 g, 2.24 mmol) in MeOH (2.5 mL) was added 1N NaOH (2.5 mL). The reaction was sealed and heated to 70 deg. C. for 1 h. The reaction was cooled to ambient temperature and was concentrated to % the volume in vacuo. Water was added, followed by 1N HCl until pH 5-6 is obtained. The resulting thick oily mixture was extracted seven times with dichloromethane. The aqueous layer was concentrated in vacuo to a solid, which was rinsed with 1:1 MeOH/MC and filtered. The filtrate was concentrated in vacuo to give (S)-3-(3′-(dimethylamino)pyrrolidin-1-yl)benzoic acid as a yellow solid. MS m/z=235 [M+1]+. Calc'd for C13H18N2O2: 234.29.
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1Cl)=[S:6])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CS(C)=O>[C:1]([C:5]1[S:6][C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:13][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=S)Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1

Procedure:
A solution of 171 g of N-t-butylthiocarbonyl-2,5-dichloro-4-nitroaniline, described in Example 1, and 605 ml of N-methylpiperazine in 1700 ml of dimethylsulphoxide is heated at 140° for 8 hours, cooled and poured into water. The solid is filtered, washed with water and cold isopropanol to yield 2-tert-butyl-5-[4-methylpiperazin-1-yl]-6-nitrobenzothiazole, melting at 132°-135°.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[O:11][CH3:12].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([I:23])=[CH:16][N:15]=1.[OH-].[K+]>C(#N)C>[I:23][C:17]1[CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([OH:2])=[C:4]([O:11][CH3:12])[CH:5]=2)=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: COc1cc(CN)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-hydroxy-3-methoxybenzylamine hydrochloride (1.32 g, 6.82 mmol) and 2-chloro-5-iodo-3-nitropyridine (2.00 g, 6.82 mmol) in acetonitrile (20 mL) was added N,N-disopropylethylamine (5.96 ml, 34.10 mmol) The suspension was stirred and heated to 100° C. After 1 h, the mixture was allowed to cool to room temperature, and 2N aqueous potassium hydroxide solution (0.68 mL) was added. The mixture was concentrated to provide 4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2-methoxyphenol as an impure solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[SH:12].[CH2:13]([N:20]1[C:28]2[C:27](Cl)=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1.O>[CH2:13]([N:20]1[C:28]2[C:27]([S:12][C:5]3[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=3[CH3:3])=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(S)c(C)c1
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(Sc2nc(N)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a stirred suspension of NaH (48 mg, 2 mmol) in dry NMP (2 mL) was added 2,4,6-trimethyl-benzene-1-thiol (191 mg, 1.2 mmol) The mixture was and stirred at room temperature for 30 min under argon. The reaction mixture was then added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (103 mg, 0.4 mmol) in dry NMP (2.5 mL) and heated at 60° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, and brine; dried over Na2SO4; filtered; and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1-1:3) to give the product as a light yellow solid (131 mg, 88%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N(OC(C)(C)C)=O.[ClH:19]>C(#N)C.[Cu](Cl)Cl>[Cl:19][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cl
Reactant: Nc1nc2ccc(F)cc2s1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Fc1ccc2nc(Cl)sc2c1
Temperature: 65 °C
Yield: 83 %

Procedure:
To a round bottomed flask was added 2-amino-6-fluorobenzothiazole (1.0017 g, 5.96 mmol, Sigma-Aldrich Chemical Company, Inc.), copper (II) chloride (1.201 g, 8.93 mmol, Sigma-Aldrich Chemical Company, Inc.), and tert-butyl nitrite (1.063 ml, 8.93 mmol, Acros Organics) in ACN and was heated to 65° C. for 2 hours. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (0.9249 g, 4.93 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm s 7.45 (td, J=9.10, 2.74 Hz, 1 H) 7.97-8.07 (m, 2 H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].ClC1C=CC(C2CC(=O)C(=CN(C)C)C(=O)C2)=CC=1>>[CH3:16][N:17]([CH:19]=[C:9]1[C:10](=[O:12])[CH2:11][CH:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8]1=[O:13])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Agent: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Product: CN(C)C=C1C(=O)CC(c2cccs2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 5-thien-2-yl-cyclohexane-1,3-dione (388 mg, 2.0 mmol) and N,N-dimethylformamide dimethylacetal (2 ml), following the procedure described for 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction mixture was stirred at ambient temperature for 30 min.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:10])[C:7](=[O:9])[CH3:8])[C:3](=O)[CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:4][C:3]1[O:9][C:7]([CH3:8])=[C:6]([CH3:10])[C:2]=1[CH3:1]
Reactant: CC(=O)C(C)C(C)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1oc(C)c(C)c1C
Yield: 19.4 %

Procedure:
A solution of 3,4-dimethylhexane-2,5-dione (3.00 g, 21.1 mmol) and p-toluenesulfonic acid (401 mg, 2.11 mmol) in benzene (30 mL) was heated to reflux in a Dean-Stark trap overnight. The reaction mixture was distilled at atmospheric pressure to remove the excess benzene. The remaining mixture was transferred to a smaller flask and distilled at atmospheric pressure. The fraction that came over between 80-100° C. was collected to give 509 mg (19%) of compound 219A as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20](C)C=O.[Cu]C#N.Cl>[Fe](Cl)(Cl)Cl.O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]#[N:20])=[CH:3][CH:4]=2)=[N:9][CH:10]=1)[CH2:15][CH2:16][CH:17]=[CH2:18]
Reactant: C=CCCCc1ccc(-c2ccc(Br)cc2)nc1
Reactant: CN(C)C=O
Agent: Cl[Fe](Cl)Cl
Agent: N#C[Cu]
Agent: Cl
Solvent: O
Product: C=CCCCc1ccc(-c2ccc(C#N)cc2)nc1
Temperature: 180 °C

Procedure:
A suspension of 5.59 g of 2-(p-bromophenyl)-5-(4-pentenyl)pyridine, 4 ml of dimethylformamide and 1.98 g of copper(I) cyanide was heated to 180° C. for 3 hours while stirring. The brown reaction mixture was then cooled to room temperature, subsequently poured into a mixture of 3.67 g of iron(III) chloride, 36.7 ml of water and 0.245 ml of concentrated hydrochloric acid and stirred at 55° C. for a further 1 hour. Thereafter, the mixture was cooled and partitioned between methylene chloride and water. The organic phase was washed with water, dried over sodium sulphate and filtered. The filtrate was evaporated and the residue was purified by chromatography on 250 g of silica gel with 2.5 l of methylene chloride under slight pressure. The p-[5-(4-pentenyl)-2-pyridyl]benzonitrile obtained had a m.p. (C--N) of -12° C. and could not be crystallized by cooling to below -70° C.
Reaction SMILES: N1(C2N=[C:9]([CH2:16][CH2:17][CH2:18][NH2:19])[C:10]3SC[CH2:13][C:11]=3N=2)CCNCC1.[CH2:20]([NH:23][C:24]1[C:25]2[S:47][CH2:46][CH2:45][C:26]=2[N:27]=[C:28]([N:30]2[CH2:35][CH2:34][N:33](C3C=C(C=CC=3)C(O)=O)[CH2:32][CH2:31]2)[N:29]=1)[CH2:21][CH3:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:20]([NH:23][C:24]1[C:25]2[S:47][CH2:46][CH2:45][C:26]=2[N:27]=[C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:10]3[CH:9]=[CH:16][C:17]([C:18]#[N:19])=[CH:13][CH:11]=3)[CH2:32][CH2:31]2)[N:29]=1)[CH2:21][CH3:22]
Reactant: CCCNc1nc(N2CCN(c3cccc(C(=O)O)c3)CC2)nc2c1SCC2
Reactant: NCCCc1nc(N2CCNCC2)nc2c1SCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CCCNc1nc(N2CCN(c3ccc(C#N)cc3)CC2)nc2c1SCC2
Temperature: 80 °C
Reaction time: 24 h

Procedure:
0.150 g (0.5 mmol) of (2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (VII), 0.082 g (0.45 mmol) of 4-bromobenzonitrile (VIII), 0.011 g (0.05 mmol) of palladium acetate, 0.041 g (0.07 mmol) of Xantphos, and 0.204 g (0.6 mmol) of cesium carbonate are placed in 1 mL of toluene, then stirred for 24 hours at 80° C. Then the reaction mixture is combined with water and extracted with ethyl acetate. The organic phase is washed with water, dried, and evaporated to dryness. The residue is purified by chromatography through an RP column using HPLC (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B).
Reaction SMILES: C(O)(=O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.CNCCOCCOCCOCCC(OC(C)(C)C)=O>ClCCl.CN(C)C1C=CN=CC=1>[C:5]([OH:7])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Solvent: ClCCl
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of isophthalic acid (1.7 g, 10.24 mmol, 2.98 equiv) in dichloromethane (10 mL), EDC.HCl (660 mg, 3.44 mmol, 1.00 equiv), 4-dimethylaminopyridine (420 mg, 3.44 mmol, 1.00 equiv), and tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate 8b (1 g, 3.44 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was washed with 2×20 mL of water and 1×20 mL of NH4Cl (aq). The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (1 g) was purified by reverse phase chromatography with a water/methanol gradient to yield 500 mg (33%) of 3-(14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl)carbamoyl)benzoic acid. as yellow oil. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.087(s, 2H), 7.664-7.560(m, 2H), 3.785-3.499(m, 14H), 3.144-3.705(m, 3H), 2.489-2.448(m, 2H), 1.469-1.456(s, 9H). MS (ES, m/z): 440 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22].[C-:24]#[N:25].[K+]>CS(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:24]#[N:25])=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22]
Reactant: CCCc1c(OCc2ccc(CBr)cc2)ccc(C(C)=O)c1O
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1c(OCc2ccc(CC#N)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[2-Hydroxy-3-propyl-4-(4-bromomethylphenylmethoxy)phenyl]ethanone (7.2 g; 0.02 m) and potassium cyanide (2.5 g; 0.04 m) where dissolved in dry dimethylsulphoxide (60 ml) and stirred at room temperature for 2 hours. The solution was poured onto water with stirring and filtered to give a cream solid, which was dried at 60° C. under reduced pressure; Recrystallised from ethanol to give a pale cream crystalline solid m.p. 75°-76° C.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[C:6]([OH:16])=[CH:5][CH:4]=1.[CH3:17]I>CN(C=O)C>[CH3:17][O:16][C:6]1[C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]=2[CH:3]=[CH:4][CH:5]=1
Reactant: Oc1cccc2c1oc1ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1oc1ccccc12

Procedure:
To a solution of 50% NaH (15.6 g, 0.32 mol) in DMF (100 ml), a solution of dibenzofuran-4-ol (40 g, 0.217 mol) in DMF (200 ml) was added drop wise at 0-5° C. under stirring and under a nitrogen atmosphere. The reaction mass was allowed to stir for 15 min at a temperature of 0-5° C. under N2. A solution of methyl iodide (20.3 ml, 0.32 mol) in DMF (50 ml) was added drop wise at 0-5° C. and the reaction mass was allowed to stir for 1 hr at room temperature. When TLC confirmed absence of starting material, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and evaporated under vacuum to give product 4-Methoxydibenzofuran. Yield 43 g (98%)
Reaction SMILES: Cl.Cl.[CH:3]1([C@@H:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[NH2:7])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Br[C:28]1[C:29]2[CH2:37][N:36]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)[CH2:35][CH2:34][C:30]=2[N:31]=[CH:32][N:33]=1>C(#N)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([N:36]2[CH2:35][CH2:34][C:30]3[N:31]=[CH:32][N:33]=[C:28]([NH:7][C@@H:6]([CH:3]4[CH2:5][CH2:4]4)[C:8]4[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=4)[C:29]=3[CH2:37]2)=[N:39][CH:40]=1
Reactant: N[C@H](c1ccc(C(F)(F)F)nc1)C1CC1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc([C@@H](Nc2ncnc3c2CN(c2ccc(Cl)cn2)CC3)C2CC2)cn1
Temperature: 180 °C
Yield: 12.1 %

Procedure:
To a stirred solution of (S)-cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methanamine dihydrochloride (0.048 g, 0.17 mmol) and N,N-diisopropylethylamine (96 uL, 0.55 mmol) in acetonitrile (1.8 mL) was added 4-bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.045 g, 0.14 mmol). The reaction was heated in microwave for 7 hours at 180° C. The mixture was concentrated and the residue was purified by silica gel column followed by semi-prep HPLC to obtain 7.8 mg of white solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])=[C:10]([F:20])[CH:9]=1.[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24](Cl)[N:23]=1.O>O1CCOCC1.C(OCC)(=O)C>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24]([O:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][C:10]=2[F:20])[C:15]([F:18])([F:17])[F:16])[N:23]=1
Reactant: OC(c1ccc(Br)cc1F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccc(Br)cc3F)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 82.6 %

Procedure:
Cs2CO3 (8.45 g, 26 mmol) was added to the solution of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanol (1.4 g, 5.2 mmol) in 10 ml of anhydrous 1,4-dioxane, the mixture was stirred for 5 minutes, then (S)-3-[4-(2-amino-6-chloro-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (2.0 g, 5 mmol) was added, and the resulting mixture was heated at 110° C. overnight. After cooling, 5 ml of water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 2.6 g of (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl} phenyl)2tertbutoxycarbonylamino-propionic acid (yield: 82%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O=S(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:15][CH:14]=2)=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 1A (570 mg, 2.86 mmol) in SOCl2 (10 mL) was refluxed for 1 hour. The solution was allowed to cool to room temperature and SOCl2 was removed under reduced pressure. The residue was taken up in tetrahydrofuran (10 mL) and treated with DIEA (2.5 mL, 14.4 mmol, 5 eq) and 4tert-butylaniline (0.41 mL, 2.57 mmol). After stirring overnight at room temperature, the tetrahydrofuran was removed under reduced pressure and replaced with ethyl acetate (20 mL). The ethyl acetate was washed with H2O and brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel (eluant gradient from 7:3 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.71–8.74 (m, 1H), 8.23–8.26 (m, 2H), 8.07–8.10 (m, 3H), 7.94 (td, j=7.4 Hz, 2.1 Hz, 1H), 7.70–7.73 (m, 2H), 7.37–7.44 (m, 3H), 1.29 (s, 9H); MS (ESI+) m/z 331 (M+H)+.