Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.FC(F)(F)S(O[C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[C:36]([C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1[F:46])[N:35]=[CH:34]2)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:45][C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([F:46])[C:39]=1[C:36]1[N:35]=[CH:34][C:33]2[C:38](=[C:29]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[N:8]3[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]3)[CH:30]=[CH:31][CH:32]=2)[N:37]=1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Reactant: O=S(=O)(Oc1cccc2cnc(-c3c(F)cccc3F)nc12)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2Nc2cccc3cnc(-c4c(F)cccc4F)nc23)C1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of the tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 eq) in 1,4-dioxane (0.067M) was added 2-(2,6-difluorophenyl)quinazolin-8-yl trifluoromethanesulfonate (1.0 eq), palladium acetate (0.2 eq), BINAP (1.5 eq), and cesium carbonate (3.0 eq). The reaction mixture was stirred at 120° C. for 10 min in microwave. The residue was dissolved in ethyl acetate (120 mL), and washed with water, brine, then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by column (ethyl acetate:hexanes=1:1 with 10% methanol) to yield tert-butyl (3S,5R)-1-(3-(2-(2,6-difluorophenyl)-quinazolin-8-ylamino)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (79%). LC/MS (m/z): 547.1 (MH+), Rt=0.87
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:46])[C@@H:20]([NH:30][C:31]([C:33]2[CH:38]=[C:37](Cl)[N:36]=[C:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:34]=2)=[O:32])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14]1)=[O:12])[CH3:9].O>C1COCC1>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:46])[C@@H:20]([NH:30][C:31]([C:33]2[CH:38]=[C:37]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[N:36]=[C:35]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:34]=2)=[O:32])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-n3ccnc3)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Imidazole (3 mg) was added to a suspension of NaH (1.7 mg) in anhydrous THF (0.2 ml) at RT. After 30 min stirring at RT, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (25 mg) dissolved in THF (0.2 ml) was added. The mixture was allowed to stir at RT overnight. Water was added and the resulting mixture was extracted with DCM. The org. phases were dried (Na2SO4) and evaporated off.
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[C:47]1([CH:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:47]1([CH:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:29]2[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[N:30]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCC3c3ccccc3)n2)c1

Procedure:
B33 was prepared following the procedure reported for B4 using A1 and rac-2-phenylpyrrolidine, and it was obtained as a white powder; yield: 90 mg (24%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.77-2.05 (m, 3H), 2.26-2.48 (m, 1H), 3.61-3.80 (m, 1H), 3.80-3.98 (m, 1H), 4.07 and 4.22 (2 s, 2H), 5.28 and 5.30 (2 s, 1H), 6.75-6.92 (m, 3H), 6.94-7.07 (m, 1H), 7.09-7.42 (m, 6H), 7.70 and 7.90 (2 s, 1H), 8.06 and 8.27 (2 s, 1H), 9.55 and 9.72 (2bs, 1H). MS (ES) C20H22N6O2S requires: 410. found: 411 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([CH:7]([OH:10])[CH:8]=[CH2:9])[CH2:4][O:3]1.C(=O)([O-])O.[Na+].C(O[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1Br)(=O)C>CN(C=O)C.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[O:10][CH:7]([C@H:5]1[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[O:6]1)[CH:8]=[CH:9]2
Reactant: CC(=O)Oc1ccc(F)cc1Br
Reactant: C=CC(O)[C@H]1COC(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](C2C=Cc3cc(F)ccc3O2)O1
Temperature: 120 °C
Reaction time: 19 h

Procedure:
1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-prop-2-en-1-ol (0.3 g, 1.90 mmol), sodium hydrogen carbonate (0.22 g, 2.58 mmol), 2-bromo-4-fluorophenyl acetate (0.3 g, 1.29 mmol), palladium acetate (14 mg, 0.06 mmol) and CYTOP 216, 2,4,6 trioxy 1,3,5,7 tetramethyl 8 phosphaadamantane (19 mg, 0.06 mmol) were suspended in DMF (5 ml) under nitrogen. The reaction mixture was stirred at 120° C. for 19 h, cooled to 25° C. and then diluted with ethyl acetate (20 ml) and demi water (20 ml). The phases were separated and the organic layer dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to dryness. The crude reaction mixture was then purified by flash chromatography on silica (heptane:ethyl acetate 9:1) and 6-fluoro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene was isolated as a pale yellow oil (60 mg, 19% yield).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:16]/[CH2:17][O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:11][CH:10]=1.[CH2:38]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[C:39]#[CH:40]>O1CCCC1.[Cu]I.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>[CH3:31][C:21]1[CH:20]=[C:19]([O:18][CH2:17]/[CH:16]=[C:15](/[C:12]2[CH:13]=[CH:14][C:9]([C:40]#[C:39][CH2:38][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:10][CH:11]=2)\[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][C:22]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C
Temperature: 50 °C

Procedure:
Dry triethylamine (8 mL), copper(I) iodide (29 mg, 0.152 mmol) and tetrakis(triphenylphosphine)palladium (68 mg, 0.059 mmol) were added to a degassed solution of the above ester (448 mg, 0.931 mmol) and N-propargylmorpholine (291 mg, 2.32 mmol) in dry tetrahydrofuran (18 mL). In atmosphere of argon, the resulting mixture was heated at 50° C. for 10 h, cooled down and subsequently evaporated in vacuo. The residue was dissolved in dichloromethane (20 mL); the solution was washed with water (3×10 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 4:1-1:1) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-phenylallyloxy]phenoxy]acetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)C(C)C)(C)C.[I-].[Na+].[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>C(O)C>[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: COCCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 90 °C

Procedure:
To a solution of 2-chloro-5-(2-chloroethylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.2 g) and N,N-diisopropylethylamine (0.27 ml) in ethanol (5 ml) was added sodium iodide (0.08 g) and 2-methoxyethylamine (0.11 g). The reaction vessel was sealed and the reaction mixture heated at 90° C. for 15 h before concentration under reduced pressure. The residue was partitioned between ethyl acetate and sodium hydrogencarbonate solution, and the aqueous phase extracted with additional ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by NPHPLC (eluting with 0-25% ethanol in dichloromethane) to afford 5-(N-(2-methoxyethyl)-2-aminoethyl)amino-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a semi-solid. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentrated under reduced pressure to leave the title compound as a white solid (0.085 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
92.3 mg of brown powdered 3-{4-[3-(4-trifluoromethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-trifluoromethoxyphenyl isocyanate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CCCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture of 1-benzyl-3-hydroxypiperidine (2.0 g, 10 mmoles), p-fluoro-nitrobenzene (1.06 ml, 12 mmoles) and sodium hydride (0.285 g, 12 mmoles) in DMF was stirred at room temperature for 3 hours, diluted with H2O and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified by flash chromatography using as eluent 50% EtOAc/hexane to afford the title compound (3.0 g, 9.43 mmoles).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([NH:11][C:12](=O)OC(C)(C)C)[C:4]([N:6]1[CH2:9][CH:8]([OH:10])[CH2:7]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.CCOC(C)=O>C(Cl)Cl.O.C1COCC1>[F:20][C:2]([F:1])([F:19])[CH:3]([NH:11][CH3:12])[CH2:4][N:6]1[CH2:7][CH:8]([OH:10])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CC(O)C1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(CN1CC(O)C1)C(F)(F)F
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
Tert-butyl 1,1,1-trifluoro-3-(3-hydroxyazetidin-1-yl)-3-oxopropan-2-ylcarbamate (Compound B3.1) (3.97 gg, 13.3 mmol) was added under argon in portions to 1M solution of LAH in THF (53 mL, 53 mmol) over 15 min. The mixture was heated under argon to reflux for 7 h. After additional standing for 15 h at rt EtOAc (10 mL) was added dropwise under ice cooling, followed by addition of water/THF (1:1, 12 mL). The mixture was diluted with DCM (120 mL). Celite was added and the suspension was stirred for 10 min. The mixture was filtered, the solids washed with DCM (2×50 mL). The combined filtrates were dried (Na2SO4) and concentrated under reduced pressure to give the title compound (2.39 g, 91%). The obtained crude product was used in the next step without characterization.
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1.CC(C)([O-])C.[K+].[F:35][C:36]1[CH:37]=[C:38]([CH:44]2CCC(=O)[CH2:46][CH2:45]2)[CH:39]=[C:40]([F:43])[C:41]=1[F:42]>O>[F:35][C:36]1[CH:37]=[C:38]([CH:44]2[CH2:26][CH2:25][CH:24]([CH:28]=[O:27])[CH2:46][CH2:45]2)[CH:39]=[C:40]([F:43])[C:41]=1[F:42]
Reactant: O=C1CCC(c2cc(F)c(F)c(F)c2)CC1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Product: O=CC1CCC(c2cc(F)c(F)c(F)c2)CC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To dried methoxymethyltriphenylphosphonium chloride (abbreviated as MTP, hereinafter) 25 g (72.9 mmol), THF 300 ml was added, and potassium-t-butoxide 8.2 g (73.1 mmol) was added. The mixture was stirred for about one hour. To the reactant, a THF solution (150 ml) of the above 4-(3,4,5-trifluorophenyl)cyclohexanone 14.8 g (64.9 mmol) was added dropwise, and the mixture was stirred for 2 hours. Water 300 ml was added to the reactant, the product was extracted with toluene. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene). The resulting purified material was stirred in mixture solvent of 3N-hydrochloric acid 200 ml and THF 200 ml for 5 hours, and the product was extracted with toluene. The extract was washed with a saturated sodium bicarbonate aqueous solution and then with water, and dried over anhydrous magnesium sulfate. Toluene was distilled off to obtain 4-(3,4,5-trifluorophenyl) cyclohexanecarboaldehyde 10.5 g (43.3 mmol). The yield was 66.7% from 4-(3,4,5-trifluorophenyl) cyclohexanone.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>N1C=CC=CC=1.Cl>[CH:1]1([C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)C1CCCC1
Yield: 48.1 %

Procedure:
Cyclopentanoyl chloride (946 mg, 7.14 mmol) was added dropwise to a stirred suspension of 2-amino-5-nitropyrimidine (1.0 g, 7.14 mmol) in pyridine (10 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere. The reaction mixture was cooled then stirred in 2N hydrochloric acid (100 ml) and the resulting solid collected by suction filtration. Purification by flash chromatography on silica gel, eluting with 2% methanol in dichloromethane, yielded 2-(N-cyclopentanoyl)amino-5-nitropyrimidine (812 mg, 48% yield) as an beige solid:
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[C:15]1(=O)[CH2:20]CC[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:20][CH2:15][CH2:16][CH2:17][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: O=C1CCCCC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CCCC2
Yield: 94.5 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (2.4 g, 0.012 mole), cyclohexanone (1.18 g, 0.012 mole) and ammonia solution (2.0M, 120 mL) in methanol was refluxed overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (2.02 g, 94% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[NH2:12][C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.[H-].[Na+].CS(C)=O>O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:12])[CH:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: Cc1c[nH]c2ccc(O)cc12
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c[nH]c2ccc(Oc3ccnc(N)c3)cc12
Temperature: 160 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
A mixture of 5-hydroxy-3-methylindole (4.7 g), 2-amino-4-chloropyridine (4.1 g), sodium hydride (1.3 g), and dimethyl sulfoxide (40 ml) was stirred at 160° C. for 15 hours. Water was added thereto; extraction was performed with ethyl acetate; and purification was performed by silica gel column chromatography (ethyl acetate, sequentially, ethyl acetate:methanol=20:1). The solvent was distilled off to yield the title compound as a brown solid (1.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)=[O:27]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:36][CH:35]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc2c(SC(=O)c3ccc(C(=O)OC)cc3)cccn2c1=O
Yield: 87 %

Procedure:
To a mixture of 30 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1, 2.49 g of powdery potassium carbonate and 500 ml of acetone is added 23.8 g of 4-methoxycarbonylbenzoyl chloride with stirring, and the resultant mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated to dryness in vacuo and the residue is distributed in water-chlofororm. The chloroform layer is washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue is recrystallized from ethyl acetate to give 43 g of the titled compound Ie-66.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]([NH:20][CH2:21][C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>ClCCl>[C:16]([O:15][C:13]([NH:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:23])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)c1cc(N)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CNC(=O)OC(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 46.9 %

Procedure:
To a solution of methyl 5-amino-2-hydroxybenzoate (1.5 g, 9.0 mmol) in dichloromethane (50 mL) was added BOC-glycine (1.57 g, 9.0 mmol), EDCI (1.89 g, 9.9 mmol) and dimethylaminopyridine (0.11 g, 0.9 mmol). The reaction was stirred (RT, 2.5 h), and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to afford methyl 5-(2-(tert-butoxycarbonylamino)-acetamido)-2-hydroxybenzoate (1.37 g). Mass calculated for C15H20N2O6=324.33; found: [M+Na]+=347.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]#[N:10])[CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:8][C:6]1[N:5]=[C:4]([C:9]#[N:10])[CH:3]=[C:2]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:7]=1
Reactant: Oc1cncnc1
Reactant: Cc1cc(Cl)cc(C#N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cncnc2)cc(C#N)n1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
4-chloro-6-methylpicolinonitrile (4.0 g, 26 mmol, 1.0 eq), 5-hydroxypyrimidine (5.56 g, 57.9 mmol, 2.20 eq), K2CO3 (7.24 mg, 52.4 mmol, 2.0 eq) and DMF (66 mL) were added to a reaction vessel and heated at 80° C. for 16 hours. The reaction was filtered and concentrated on silica gel (25 g). The silica gel was loaded on top of a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude solid was purified by flash chromatography on silica gel to afford 4.31 g (77%) of the title compound as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.85 (s, 2H), 7.74 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 2.48 (s, 3H); ES-MS [M+1]+: 213.2.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:35])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:37]1[N:42]=[CH:41][N:40]=[C:39]2[N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:55])([F:54])[F:53])[N:44]=[CH:45][C:38]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:35][C:37]1[N:42]=[CH:41][N:40]=[C:39]2[N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:55])([F:54])[F:53])[N:44]=[CH:45][C:38]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccccn1)(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F)C(=O)Nc1ccccn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
Sodium hydride (117 mg, 2.93 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(pyridin-2-yl)propanamide (618 mg, 1.33 mmol) (Intermediate AQ2) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (514 mg, 1.46 mmol) (Intermediate B4) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane to afford the product (919 mg, 95%). 1H NMR: (400 MHz, CDCl3) δ 0.99 (9H, t), 3.70-3.72 (2H, m), 3.82 (2H, t), 4.16-4.25 (2H, m), 6.05-6.07 (1H, m), 7.04-7.07 (1H, m), 7.31-7.75 (14H, m), 7.89-7.92 (1H, m), 8.24-8.28 (2H, m), 8.36 (1H, s), 8.55 (1H, s), 8.73 (1H, s); m/z (ES+) (M+H)+=279.1; HPLC Rt=3.71 min.