Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=C(O)C=2)C(F)=C[N:29]=1.N1C=CC=CC=1CN>>[F:18][C:17]1[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)=[N:13][C:14]([NH:19][CH2:20][C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][N:29]=2)=[N:15][CH:16]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: NCc1ccccn1
Product: Oc1cccc(Nc2nc(NCc3ccccn3)ncc2F)c1
Yield: 62 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and 2-pyridylmethylamine (68 mg, 0.63 mmol) gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (CDCl3): δ 4.73 (d, J=6.3 Hz, 2H), 5.85 (t, J=6.0 Hz, 1H, NH), 6.48 (d, J=6.9 Hz, 1H), 6.61 (dd, J=2.7 and 8.1 Hz, 1H), 6.67 (s, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.21 (dd, J=5.1 and 7.5 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.69 (td, J=1.8 and 7.8 Hz, 1H), 7.85 (d, J=3.6 Hz, 1H), 8.38 (br, 1H), 8.56 (dd, J=1.2 and 3.9 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −170.49; LCMS: ret. time: 10.10 min.; purity: 100%; MS (m/e): 312.08 (MH+).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=2)=[O:40])=[CH:35][CH:34]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)([C:41]3[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1cncc1C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(F)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (75.8 mg, 0.177 mmol, Intermediate 16) in dry THF (3 mL) in a dry ice-acetone bath. After 1 minute, a solution of (4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (37.8 mg, 0.185 mmol, Intermediate 29: step b) in dry THF (0.6 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-50% EtOAc-Hexanes) to provide the title compound as a clear foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=2.1 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.57-7.50 (m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 2H), 7.25 (s, 1H), 7.04-6.96 (m, 2H), 6.45-6.40 (m, 1H), 6.30 (s, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.34 (s, 3H); MS m/e 554.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C=O.[C:30](=O)([O-])[O-:31].O>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH2:30][OH:31])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reactant: O=C([O-])[O-]
Agent: C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCO
Yield: 93.3 %

Procedure:
In a solution of 7.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19 in 70 mL of 1,4-dioxane, 1.82 g of 37% formalin, 7.00 g of potasiium carbonate and 15 mL of water were added at room temperature with stirring, and stirred at the same temperature for 3 hours. After the completion of the reaction, the reaction mixture was diluted by adding 200 mL of ethyl acetate, washed with water (50 mL×1), and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, filtered through silica gel, and the solvent was distilled off under reduced pressure to obtain 7.00 g of the crude product as white crystal.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11]2)=[CH:6][C:5]=1[O:19][CH3:20].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11]2)=[CH:6][C:5]=1[O:19][CH3:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCc2cc(OC)c(O)cc2O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2cc(OC)c(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 8.9 mmol of a 60% strength suspension of sodium hydride in paraffin oil are added a little at a time to 1.86 g of ethyl 7-hydroxy-6-methoxy-2-chromancarboxylate in 23 ml of dimethylformamide. The mixture is stirred at room temperature for 60 minutes, and 8.1 mmol of benzyl bromide are then added. The reaction mixture is stirred at room temperature for 5 hours. For aqueous work-up (three times washing with water, once with saturated sodium chloride solution), the mixture is diluted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. Two recrystallizations from cyclohexane give pure ethyl 7-(benzyloxy)-6-methoxy-2-chromancarboxylate; further product fractions are obtained from the mother liquors of the recrystallizations by preparative HPLC purification (column; chromsil, mobile phase: acetonitrile/water).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH:11]([CH2:23][CH:24](C)C)[CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:27](N(C)CCC(O)C(C)C)C1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH:11]([CH:23]([CH3:24])[CH3:27])[CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:15])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Reactant: CC(C)C(O)CCN(C)Cc1ccccc1
Product: CC(C)C(CCN(C)Cc1ccccc1)Oc1cccc2sccc12

Procedure:
Using a method similar to that for [3-(Benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine, 1-(benzyl-methyl-amino)-4-methyl-pentan-3-ol affords the title compound: mass spectrum (ion spray) m/z=354.3(M+1); 1H NMR (CDCl3) δ 7.49 (d, 1H), 7.43 (d, 1H), 7.31-7.19 (m, 7H), 6.85 (d, 1H), 4.48-4.44 (m, 1H), 3.51-3.43 (m, 2H), 2.61-2.48 (m, 2), 2.19 (s, 3H), 2.11-1.85 (m, 3H), 1.03 (d, 3H), 0.99 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[C:8]1[CH:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.Cl.[C:43]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[C:8]1[N:9]=[CH:10][N:11]=[C:12]([NH:51][CH2:50][CH2:49][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:52])[CH:13]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ncn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(NCCC(=O)OC(C)(C)C)ncn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-(6-chloropyrimidin-4-yl)-amine (300 mg) is dissolved in toluene (5 ml), and thereto are added 3-aminopropionic acid tert-butyl ester hydrochloride (888 mg) and N-ethyldiisopropylamine (1.7 ml), and the mixture is stirred at 120° C. overnight. To the reaction solution are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane:ethyl acetate=9:1→3:1) to give tert-butyl 3-(6-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-4-ylamino)-propionate (70 mg). MS (m/z): 722 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(Cl)(Cl)[Cl:14].CO>C(O)C.O=[Pt]=O>[ClH:14].[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: ClC(Cl)Cl
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC1CCCCN1
Product: Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(pyridin-2-yl)acetate (24.51 g, 148.4 mmol) was dissolved in ethanol (130 ml), and PtO2 (3.37 g, 14.84 mmol, 0.1 eq.) and chloroform (20 ml) were added. The suspension was stirred under an H2 atmosphere (8 bar) at 40° C. overnight. According to TLC control (silica gel, MC/methanol 95:5), the reaction was not complete, so that further chloroform (15 ml) was added and the mixture was stirred under an H2 atmosphere (8 bar) at 40° C. for a further 2 d (TLC control). After cooling, the catalyst was first removed by filtering over filtering earth and the filtrate was concentrated to dryness in vacuo. The ethyl 2-(piperidin-2-yl)acetate hydrochloride was employed in the next stage without further purification.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1.Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:29][CH2:30][CH2:31][N:32]4[C:40](=[O:41])[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]4=[O:42])[CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(CCCN5C(=O)c6ccccc6C5=O)CC4)c4cc(Cl)ccc43)c21
Temperature: 150 °C
Yield: 63.2 %

Procedure:
A mixture of (R)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]dihydrochloride (15 mg, 0.035 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (13 mg, 0.049 mmol), DIEA (0.018 mL, 0.11 mmol) and DMF (0.5 mL) was heated at about 150° C. in microwave for about 30 min. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 20:1) to give (R)-2-(3-(5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-yl)propyl)isoindoline-1,3-dione (12 mg, 63%). LCMS (APCI+) m/z 542, 544 [M+H]+; Rt=3.79 min.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH2:18]=O>CO>[ClH:1].[CH2:18]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH2:7][C@@H:5]([C:4]([O:3][CH3:2])=[O:17])[NH:6]1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C=O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
5.09 g of L-tryptophan methyl ester hydrochloride are dissolved in 60 ml of methanol. 1.89 g of 35% formalin are added thereto, and the mixture is stirred at room temperature overnight. After distilling off the solvent, the resulting residue is recrystallized from methanol. 4.42 g of methyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride are obtained as colorless needles. Yield: 82.9%
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-].B(F)(F)F.CC[O:29]CC>>[O:29]=[C:12]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOCC
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Product: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1=O

Procedure:
The synthesis of compounds 21A-21F is outlined in Scheme 21. Condensation of 1-Boc-4-piperidone 1.2 with ethyl diazoacetate (21.1) in the presence of boron trifluoride diethyl etherate provided 1-tert-butyl 4-ethyl 3-oxoazepane-1,4-dicarboxylate in equilibrium with its enol form (21.2). Ester hydrolysis followed by decarboxylation of 21.2 under acidic conditions provided the azepan-3-one (21.3), which was protected as its Boc derivative 21.4 by treatment with tert-butyloxycarbonyl anhydride (4.7). The 2′-hydroxyacetophenone 1.1a was condensed with 21.4 in refluxing methanol in the presence of pyrrolidine to provide the racemic ketone 21.5. Conversion of 21.5 to the enol triflate derivative 21.6 was achieved using the triflating reagent N-phenylbis(trifluoromethanesulphonimide) 1.4. Suzuki type coupling of the enol triflate derivative 21.6 with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid (1.6) in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride, and an aqueous solution of sodium carbonate afforded the racemic derivative 21.7, which was hydrolyzed under acidic conditions to give the compound 21A (racemic mixture). The two enantiomers derived from 21.7, i.e. compounds 21.7a and 21.7b, were separated by chiral HPLC. The pure enantiomers 21.7a and 21.7b were converted to compounds 21B and 21C, respectively under acidic conditions. Palladium catalyzed hydrogenation of compounds 21B and 21C afforded compounds 21D (diastereoisomeric mixture) and 21E (diastereoisomeric mixture), respectively. Treatment of compound 21A with benzyl chloroformate (21.8) in dichloromethane in the presence of triethylamine provided the Cbz-protected derivative 21.9, which was converted to the sulfonyl chloride 21.10 using sulfur trioxide N,N-dimethylformamide complex (4.3) as sulfating agent. Condensation of 21.10 with ethylamine (3.4c) in dichloromethane in the presence of triethylamine, afforded the ethyl sulfonamide derivative 21.11 which was converted to compound 21F by treatment with iodotrimethylsilane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[C:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH2:9][N:19]1[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCN(C[C@@H](C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.1 %

Procedure:
(R)-(1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.85 g, 10.7 mmole) and acetyl piperazine (1.53 g, 12 mmole) were combined in dichloroethane (125 mL). NaBH(OAc)3 (4.53 g. 21 mmole) was added. The resultant reaction solution was stirred at room temperature for 20 h. An equal volume of saturated NaHCO3 was added. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic extracts were washed with saturated NaCl, dried over Na2SO4 and concentrated under vacuum. Purification by silica chromatography (5% methanol in CH2Cl2 provided (R)-[2-(4-acetylpiperazin-1-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (Intermediate XXIXa, 2.6 g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13][N:14]([CH2:16][CH3:17])[CH3:15])[CH2:7][CH2:6][CH2:5]2>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]([CH2:16][CH3:17])[CH3:15])[CH2:7][CH2:6][CH2:5]2
Reactant: CCN(C)CC(=O)N1CCCc2cc(Br)ccc21
Solvent: CO
Solvent: C1CCOC1
Product: CCN(C)CCN1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.9 %

Procedure:
A solution of 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-(ethyl(methyl)amino)ethanone (1.05 g, 3.37 mmol) in THF (10 mL) was cooled to 0° C. then treated with BH3 in THF (1M) (33.7 mL, 33.7 mmol). The clear solution was allowed to warm to room temperature and stirred at this temperature for 3 days. The mixture was cooled to 0° C. and treated with methanol (5 mL) dropwise with caution. After stirring for 15 minutes, the mixture was concentrated to dryness then dissolved in methanol (25 mL) and concentrated again. The residue was dissolved in 25 mL methanol and heated at reflux for 5 hours then stirred at room temperature overnight. The reaction was concentrated to dryness to give a light yellow residue. This residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/95% CH2Cl2 to give a colourless residue (0.89 g, 89%). 1H-NMR (CDCl3) δ 7.09 (dd, J=1.8, 6.6 Hz, 1H), 7.02-7.01 (m, 1H), 6.44 (d, J=6.6 Hz, 1H), 3.36 (t, J=5.7 Hz, 2H), 3.29 (t, J=4.2 Hz, 2H), 2.70 (t, J=4.8 Hz, 2H), 2.53-2.43 (m, 4H), 2.28 (s, 3H), 1.94-1.88 (m, 2H), 1.06 (t, J=5.4 Hz, 3H). MS (ESI): 397.1 and 399.1 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(OC([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1B(O)O)=O)(C)(C)C.O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[NH3:1].[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[N:9][C:10]=2[C:38]2[NH:37][C:45]3[C:40]([CH:39]=2)=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: N
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Yield: 5 %

Procedure:
A mixture of benzyl {[trans-4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.00 g, 0.00180 mol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (0.517 g, 0.00198 mol), 1,2-dimethoxyethane (7.7 mL), water (1.4 mL, 0.081 mol) and Cesium Carbonate (1.17 g, 0.00360 mol) degassed three times, treated with tetrakis (triphenylphosphine)palladium(0) (200 mg, 0.0002 mol) and degassed once more. The resulting mixture was heated at 100° C. overnight before being diluted with EtOAc (40 mL), washed with water (2×30 ml) and brine (20 ml) then dried over Na2SO4 and concentrated in vacuo. The crude product thus isolated was chromatographed over silica gel eluting with hexane→EtOAc:hexane:5% 2M NH3 in MeOH 1:1:0.05 to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 1.13-1.22 (m, 2H), 1.75-1.86 (m, 2H), 1.94-1.97 (m, 2H), 2.11-2.13 (m, 2H), 2.86 (m, 1H), 3.12-3.16 (m, 2H), 4.82 (m, 1H), 5.12 (s, 2H), 5.69 (br, 2H), 6.78 (s, 1H), 7.13-7.15 (m, 2H), 7.19-7.25 (m, 2H), 732-7.38 (m, 5H), 7.42 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 9.09 (br, 1H). MS (ES+): m/z 495 [MH+].
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10](OC)=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[F:24][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[C@@:13]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:12]=2[CH:11]=[C:10]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[CH:9]=1
Reactant: OB(O)c1cccnc1F
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(-c3cccnc3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in method A7 above, but using intermediate 20B, 2-fluoropyridin-3-ylboronic acid and 3-pyridineboronic acid. MS m/z=457.0 [M+H]+. Calculated for C26H18F2N4O2: 456.14
Reaction SMILES: [CH:1](C1CC(=O)OC1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([CH:24]1[CH2:29][C:28](=[O:30])[NH:27][C:25]1=[O:26])=CCCCCCC.[NH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][NH2:43]>O.C(O)(C)C>[CH:1]([N:27]1[C:28](=[O:30])[CH2:29][CH2:24][C:25]1=[O:26])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32][NH2:31]
Reactant: CCCCCCC=CC1CC(=O)OC1=O
Reactant: CCCCCCC=CC1CC(=O)NC1=O
Agent: NCCNCCNCCNCCN
Solvent: CC(C)O
Solvent: O
Product: CCCCCCC=CN1C(=O)CCC1=O
Temperature: 142 °C

Procedure:
N-octenyl succinimide of tetraethylene pentamine was prepared by placing one mole of the amine in a reaction flask fitted with an additional funnel containing one mole of n-octenyl succinic anhydride, a water collector, a stirring and heating means and a reflux condenser. While stirring the amine, the anhydride in the funnel was slowly added to the flask. Upon completion of the addition, the resulting reaction mixture was heated to about 142 degrees C. where water of reaction started to distill over. At about 180 degrees C., the resulting reaction product, viz., n-octenyl succinimide of tetraethylene pentamine, was a clear bright orange liquid. About one mole of water was collected in the collector signifying that the imide-forming reaction was complete. The flask and its contents were then cooled to about 80 degrees C. and sufficient isopropanol and distilled water were added to yield a solution which was: (i) 40 volume percent isopropanol, (ii) about 60 volume percent water and (iii) about 30 weight percent imide. Into this solution, based upon the total weight of the solution, about 1 weight percent mono-9-octadeceneoate of poly(oxy-1,2-ethanediyl) sorbitol (about 20 ethanediyl groups) surfactant was added to facilitate effective dispersion of the imide agent when added to cooling water. The flask and its contents were maintained at about 80 degrees C. with stirring until a clear solution resulted. The cooled solution was ready for use in accordance with the invention.