Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.CON(C)[C:17](=[O:31])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][Si](C)(C)C)=[C:21]([F:30])[CH:20]=1>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:30])[CH:20]=2)=[CH:8][CH:9]=1
Reactant: CON(C)C(=O)Cc1ccc(O[Si](C)(C)C)c(F)c1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)c(F)c1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of 45 ml of n-butyllithium (1.6M in hexane) is added dropwise to a suspension, cooled to -78° C., of 18.2 g of 1,4-dibromobenzene in 140 ml of THF. Then, 10 g of N-methoxy-N-methyl-2-(3-fluoro-4-trimethylsilanyloxy-phenyl)-acetamide (paragraph Bb)) in 35 ml of THF are added dropwise at -78° C. The reaction mixture is stirred at -78° C. for 2 hours, then left to stand at room temperature for 1 hour while stirring. After dilution with ethyl acetate, the mixture is washed with 10% aqueous KHSO4 solution, saturated NaHCO3 solution and 10% aqueous NaCl solution. After extraction with ethyl acetate, the organic phases are dried and concentrated. Then, the silyl group is cleaved with 105 ml of THF, 11 ml of H2 and 5 drops of 1N HCl. Concentration, dissolution in methylene chloride, drying and column chromatography over silica gel with methylene chloride/0.5% methanol as the eluent, give 9.2 g of 1-(4-bromo-phenyl)-2-(3-fluoro-4-hydroxy-phenyl)-ethanone. MS: m/e 308 (M+, 1 Br).
Reaction SMILES: [C:1]1(=O)[NH:6][CH2:5][C:4](=O)[N:3]2[CH2:8][CH2:9][CH2:10][CH2:11][C@H:2]12.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+].Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C1COCC1.CCOCC>[CH2:1]1[N:6]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:5][CH2:4][N:3]2[CH2:8][CH2:9][CH2:10][CH2:11][C@H:2]12
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NCC(=O)N2CCCC[C@H]12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN2CCCC[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
(9aR)-Tetrahydro-2H-pyrido[1,2-a]pyrazine-1,4(3H,6H)-dione (779 mg, 4.63 mmol) was dissolved in 46 mL of THF and cooled to 0° C. LiAlH4 (352 mg, 9.57 mmol) was then added portion wise. The mixture was heated to 85° C. for 2 hours, then cooled to 0° C. The reaction was quenched with sodium sulphate decahydrate (704 mg, 9.27 mmol) and was stirred at 0° C. for 30 min. To this solution was added 1N aq. NaOH (5 mL) and the reaction mixture was stirred at 0° C. for 30 min. Then Et2O (20 mL) was added, followed by benzyl chloroformate (0.783 mL, 5.563 mmol). The reaction mixture was stirred vigorously at 0° C. for 2 h, the phases were separated, and the aqueous phase was extracted with Et2O (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting crude product was purified by RP-HPLC to provide phenylmethyl (9aR)-octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (688 mg, 55%). LCMS: (M+H)+: 275.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.Br[CH2:33][CH2:34][OH:35]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH2:33][CH2:34][OH:35])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: OCCBr
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1nc(Cl)cc2c1c(OCCO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In a manner similar to that previously described (e.g. Scheme 3/Step 1 and the synthesis of Intermediate 20B/Step 6), 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (4B) was reacted with 2-bromoethanol (K2CO3, DMF. 2-bromoethanol. RT, 18 h) to provide 2-((6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)oxy)ethanol (66B). MS: [M+H]+ m/z 470.
Reaction SMILES: CC(C(N)C([NH:7][C@H:8]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])/[CH:20]=[CH:21]\[CH2:22][P:23]([OH:26])([OH:25])=[O:24])=[O:17])[CH2:9][CH2:10][CH2:11][N:12]=[C:13]([NH2:15])[NH2:14])=O)C.[NH2:31][C@H:32]([C:37]([OH:39])=O)[CH2:33][CH:34]([CH3:36])[CH3:35].N[C@H](C(O)=O)[C@H](CC)C>>[CH3:36][CH:34]([CH2:33][CH:32]([NH2:31])[C:37]([NH:7][C@H:8]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])/[CH:20]=[CH:21]\[CH2:22][P:23]([OH:25])([OH:26])=[O:24])=[O:17])[CH2:9][CH2:10][CH2:11][N:12]=[C:13]([NH2:14])[NH2:15])=[O:39])[CH3:35]
Reactant: CC(C)C(N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](/C=C\CP(=O)(O)O)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Product: CC(C)CC(N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](/C=C\CP(=O)(O)O)C(=O)O

Procedure:
After Sephadex G-10 purification isolates of rhizocticine B are microheterogeneous, that is to say 0.5%-5% of the N-terminal amino acid valine is replaced by leucine and by isoleucine. Small amounts of the likewise antifungal tripeptides rhizocticine C (L-Ile-L-Arg-L-APPA) and rhizocticine D (L-Leu-L-Arg-L-APPA) can be isolated from the mixture by means of HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:26]3[CH2:28][CH2:27]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=3)[CH:11]=[C:10]([CH:26]3[CH2:27][CH2:28]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)cc1
Solvent: C1CCOC1
Product: OCCc1ccc(Cc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 81.5 %

Procedure:
A 25-mL round bottom flask was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)methyl)phenyl)acetate (0.149 g, 0.38 mmol) and THF (5 mL) at Borane-dimethylsulfide complex (0.108 mL, 1.13 mmol) was added and the resulting solution was stirred at 55° C. for 2.5 h until the starting material was consumed (monitored by LCMS analysis). The reaction was quenched with methanol then treated with 2N aqueous HCl (5 drops) and concentrated under reduced pressure. The residue was diluted with methanol and then concentrated under reduced pressure. The residue was absorbed onto silica (2 g) and purified by column chromatography on silica using hexanes/ethyl acetate (10:0 to 3:1) as the eluent to afford the title compound (0.113 g, 82%) as a colorless oil. MW=364.87. 1H NMR (DMSO-d6, 500 MHz) δ 8.31-8.27 (m, 2H), 7.59-7.51 (m, 2H), 7.27 (s, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 4.58 (t, J=5.0 Hz, 1H), 4.04 (s, 2H), 3.59-3.52 (m, 2H), 2.68 (t, J=7.0 Hz, 2H), 2.16-2.09 (m, 1H), 1.16-1.05 (m, 4H); APCI MS m/z 365 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3](=[O:4])[CH2:2][NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=2)=[O:37])[CH2:16]1)=[O:27])[CH3:24]
Reactant: CCN(CC)C(=O)C1CCCN(C(=O)CN(C(=O)CN)c2ccccc2)C1
Reactant: Cc1cccc(N=C=O)c1
Product: CCN(CC)C(=O)C1CCCN(C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)C1
Yield: 37.7 %

Procedure:
Following a procedure analogous to that described in Example 106, but using 1.8 g of (RS)-2-amino-N-[2-(3-(N,N-diethylcarbamoyl)piperidino)-2-oxoethyl]-N-phenylacetamide and 0.64 g of 3-methylphenyl isocyanate as the starting material, 0.92 g of (RS)-N-[2-(3-(N,N-diethylcarbamoyl)piperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenyl acetamide melting at 156° C is obtained after recrystallization from an ethyl acetate/diisopropyl ether mixture (50/50 by volume).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:35])[N:4]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:28](O)=[O:29])[C:5]([CH3:24])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][NH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C[N:37]1CC[O:40][CH2:39][CH2:38]1.ClC(OCC(C)C)=O>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:35])[N:4]([C:25]2[CH:26]=[C:27]([C:28]([NH:37][CH2:38][CH2:39][OH:40])=[O:29])[CH:31]=[CH:32][C:33]=2[CH3:34])[C:5]([CH3:24])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][NH:18][C:19](=[O:20])[O:21][CH2:22][CH3:23]
Reactant: CN1CCOCC1
Reactant: CCOC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1Br
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)NCCO)ccc2C)c(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−10° C.) solution of 3-[3-bromo-4-[(2-{[(ethoxycarbonyl)amino]methyl}-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (0.25 g, 0.46 mmol) and 4-methylmorpholine (0.06 mL, 0.55 mmol) in DMF was added isobutyl chloroformate (0.07 mL, 0.55 mmol). The colorless solution gradually turned dark brown. After 30 min, ethaolamine (0.04 mL, 0.69 mmol) was added and the solution warmed to RT. After 1 h, solvent was removed and the crude product was purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (20 mL) and extracted in DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to a white solid, dried in vacuo (0.09 g, 33%). 1H NMR (CD3OD/400 MHz) δ 7.88 (m, 1H), 7.61 (s, 1H), 7.53 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H), 4.43 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.68 (t, 2H, J=5.6 Hz), 3.48 (t, 2H, J=5.6 Hz), 2.09 (s, 3H), 2.00 (s, 3H), 1.22 (t, 3H, J=7.2 Hz). ESHRMS m/z 590.1266 and 592.1254 (M+H calculated for C27H30BrFN3O6 requires 590.1297 and 592.1281).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11].[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)[C@@H]1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 3-(2,6-difluorophenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (90 mg, 232 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol, Eq: 112) and the resulting solution stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the residue azeotroped with n-heptanes to give (S)—N-(2,6-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide trifluoroacetate which was used without purification (93 mg), m/z=289 (M+H).
Reaction SMILES: Cl.[C:2]([NH2:11])(=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH2:5].O=[CH:13][C:14]([Cl:17])([Cl:16])[Cl:15]>>[Cl:15][C:14]([Cl:17])([Cl:16])[CH:13]1[NH:11][C:2](=[O:10])[C:3]2[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:5]1
Reactant: NC(=O)c1ccccc1N
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl
Product: O=C1NC(C(Cl)(Cl)Cl)Nc2ccccc21

Procedure:
Anthranilamide hydrochloride (63.5 g.) was heated under reflux with anhydrous chloral (650 ml.) for three hours. The resulting solution was evaporated to dryness, and the residue was triturated with toluene (700 ml.) to give a yellow product containing one mole of chloral. This was removed by boiling the product with methanol (2 l.) for 15 minutes, cooling the solution and filtering. The filtrate was concentrated to half its volume, and allowed to cool, to produce 1,2-dihydro-2-trichloromethylquinazolin-4-one, m.p. 201°-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:29])[CH:14]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([S:40]([CH3:39])(=[O:42])=[O:41])[CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:29])[CH:14]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 27 (0.9 g, 2.2 mmol) in DCM (20 mL) was cooled to 0° C. and treated with DIPEA (0.75 mL, 4.3 mmol) and DMAP (31 mg, 0.25 mmol). Methanesulfonyl chloride (0.3 mL, 3.9 mmol) was then added. After 1.5 h, the solution was diluted with DCM, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford sulfonamide 28 as an off-white foam (1.1 g) which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ5.23 (d, J=9.0 Hz, 1H), 4.74 (d, J=5.1 Hz, 1H), 4.31-4.28 (m, 2H), 4.03 (app t, J=9.3 Hz, 1H), 3.83-3.76 (m, 1H), 3.76 (s, 3H), 3.59-3.47 (m, 2H), 3.42-3.4 (m, 1H), 2.91 (s, 3H), 2.51 (dd, J=5.7, 13.8 Hz, 1H), 2.09-2.05 (m, 1H), 1.75-1.53 (m, 6H), 1.43 (s, 9H), 1.26-1.04 (m, 6H) ppm; 13C NMR (CDCl3, 75 MHz): δ172.7, 171.6, 155.9, 79.8, 66.1, 63.1, 56.9, 52.8, 50.7, 47.2, 46.2, 41.2, 35.6, 33.3, 29.8, 28.5, 28.4, 26.2, 26.1, 26.0 ppm.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[OH:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:37](=[O:38])[CH2:36][C:35]([OH:34])([CH3:41])[CH3:40])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CC(C)(O)CC(=O)O
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)CC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 120 h
Yield: 77.3 %

Procedure:
A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (68 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 5 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=9:1). Crystallization from ethyl acetate-diisopropyl ether gave the title compound (122 mg) as colorless crystals.
Reaction SMILES: [C:1]([CH2:9][C:10](OCC)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.Cl.O1CCOCC1>C1(C)C=CC=CC=1.O>[C:2]1([C:1]2[CH:9]=[C:10]([OH:11])[C:20]3[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[N:23]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1cccc(N)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a solution of ethyl benzoylacetate (10.00 g, 52.0 mmol., 1 eq) and m-anisidine (7.05 g, 57.2 mmol., 1.1 eq) in toluene (85 mL) was added 4M HCl in dioxane (0.520 mL, 2.08 mmol., 0.04 eq) dropwise. The reaction mixture was refluxed for 15 hours while water was collected in a Dean-Stark apparatus. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was suspended in diphenyl ether (28 mL) and the mixture was heated for 2 h at 240° C. The reaction mixture was then left to cool to ambient temperature and dichloromethane (55 mL) was added, leading to the precipitation of a yellow solid. Stirring was continued at ambient temperature for a further 30 min and the solid collected by filtration, rinsing the cake with a small amount of dichloromethane. The solid was transferred to a 100 mL round bottom flask and stirred with dichloromethane (50 mL) for another 45 min at ambient temperature. After filtration and drying under high vacuum, 2.85 g (22%) of the title compound was isolated as a pale yellow solid. 1H NMR (250 MHz, DMSO-d6) δ ppm 11.54 (s, 1 H), 7.99 (d, J=8.91 Hz, 1 H), 7.73-7.90 (m, 2 H), 7.48-7.64 (m, 3 H), 7.20 (d, J=2.32 Hz, 1 H), 6.94 (dd, J=2.34, 8.97 Hz, 1 H), 6.26 (s, 1 H), 3.86 (s, 3 H). LC-MS: purity 98% (UV), tR 1.52 min, m/z [M+1]+ 252.10.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:8]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12.C(O)(=O)C.[O-:18][C:19]#[N:20].[K+].[OH-].[NH4+]>O>[N:1]1[CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[C:10]([NH:13][C:19]([NH2:20])=[O:18])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12
Reactant: Nc1ccc2sc3nccn3c2c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc2c(c1)N1CCN=C1S2
Reaction time: 8 h

Procedure:
To a stirred mixture of 3 parts of imidazo[2,1-b]benzothiazol-6-amine, 16 parts of acetic acid and 32 parts of water is added dropwise a solution of 1.54 parts of potassium cyanate in 32 parts of water (slightly exothermic reaction). Upon completion, stirring is continued overnight at room temperature. The reaction mixture is alkalized with ammonium hydroxide. Upon stirring, the product is precipitated. It is filtered off and dried, yielding 3 parts of N-(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)urea; mp. +300° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH2:7][CH2:8][C:9]2[C:10]([CH3:32])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.I[CH3:34]>>[CH:1]1([N:4]([CH3:34])[C:5]([CH2:7][CH2:8][C:9]2[C:10]([CH3:32])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CI
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)NC1CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)N(C)C1CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-Cyclopropylcarbamoyl-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and iodomethane.
Reaction SMILES: [F-].[K+].[F:3][C:4]([Si](C)(C)C)([F:6])[F:5].[Br:11][C:12]1[CH:13]=[N:14][C:15](I)=[N:16][CH:17]=1.N>CN1C(=O)CCC1.CN(C)C=O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([C:4]([F:6])([F:5])[F:3])=[N:16][CH:17]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Brc1cnc(I)nc1
Agent: N
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ncc(Br)cn1

Procedure:
A mixture of potassium fluoride (1.77 g) and cuprous iodide (5.79 g) was stirred and heated together using a heat gun under vacuum (˜1 mm) for 20 min. After cooling, dimethyl formamide (20 ml) and N-methyl pyrrolidinone (20 ml) were added followed by (trifluoromethyl)trimethylsilane (4.1 ml) and 5-bromo-2-iodopyrimidine (6.5 g). The mixture was stirred at rt for 5 h and then the brown solution was poured into 6N ammonia solution. The product was extracted into ethyl acetate and the extracts were washed with sodium bicarbonate solution and brine and then dried (Na2SO4) and evaporated. Chromatography on silica gel (elution with 20-50% dichloromethane in pentane) gave the title compound (D30) as a white solid (2.4 g). 1H NMR (CDCl3): 8.97 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[N:25]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:32][CH2:31][CH2:30][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: NCCN1CCCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCN4CCCC4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-benzoic acid 14 (100 mg, 0.39 mmol) in DCM (2 mL) was heated with thionyl chloride (0.11 mL, 0.77 mmol) at 80° C. for 1 hour, the mixture was cooled to room temperature and concentrated to dry, 2-pyrrolidin-1-ylethanamine (CAS 7154-73-6) (0.05 mL, 0.58 mmol) was then added, and was stirred overnight. The reaction mixture was purified with prep HPLC to give pure 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide 24. LC/MS (ESI+): m/z 363 (M+H).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH2:22]>C1COCC1>[O:9]=[C:1]([CH2:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH:2]([C:1]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:10][CH2:11][CH3:12]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NCCCCNCCCN
Solvent: C1CCOC1
Product: CCOC(=O)CC(NCCCCNCCCNC(CC(=O)OCC)C(=O)OCC)C(=O)OCC
Temperature: 60 °C
Reaction time: 72 h

Procedure:
11.9 g (69 mmol) of diethyl maleate were added to a solution of 5 g (34.5 mmol) of spermidine in 5 ml of THF. The reaction mixture was stirred for 3 days at 60° C. After removing the solvent in vacuo, the product was obtained quantitatively as a yellow liquid.