Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1nnc(Nc2cc(Br)cn(C)c2=O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3nnc(C)s3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 27.9 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 267a (150 mg, 0.50 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (640 mg, 1.5 mmol), PdCl2(dppf) (37 mg, 0.050 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 267b (80 mg, 28%) as yellow solid. MS-ESI: [M+H]+ 574.2
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O.CCO>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:3]1[C:2]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ncccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cccnc2F)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3-Bromo-2-fluoropyridine (1.5 g, 8.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.16 g, 10.2 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.48 g, 0.68 mmol), sodium carbonate (4.44 g, 41.9 mmol), and 6:1:1 DME-H2O-EtOH (20 mL) were combined in a sealed tube and stirred at 80° C. for 18 h. The cooled reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution; the aqueous layer was back-washed with CH2Cl2 (1×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (10% to 40% EtOAc/Hexanes) gave tert-butyl 4-(2-fluoropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a golden yellow oil. [M+1]=279.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:24][C:25](=[O:26])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=C(CBr)C1CCOCC1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 146.97 mg (0.709 mmol) of 2-bromo-1-(tetrahydropyran-4-yl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:17][C:16]2([CH3:31])[CH3:30])=[CH:10][N:9]=1)(C)(C)C.Cl>O1CCOCC1.CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=3)[C:16]([CH3:31])([CH3:30])[CH2:17]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)OC(C)(C)C)nc3)C(C)(C)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CN2CCN(Cc3ccc(N)nc3)C(C)(C)C2)cc1
Yield: 102.5 %

Procedure:
A mixture of {5-[4-(4-methoxy-benzyl)-2,2-dimethyl-piperazin-1-ylmethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (Step 109.2) (1.88 g, 4.3 mmol), a 4 N solution of HCl in dioxane (25 mL) and MeOH (25 mL) was stirred for 22 h at rt. The reaction mixture was allowed to cool, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated to provide 1.5 g of the title compound as a brown solid: ESI-MS: 341.3 [M+H]+; ]+; tR=1.72 min (System 1).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:15][C:14]=3[C:25]([OH:27])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39]([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:39]([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH:50][C:25]([C:14]1[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[NH:17][C:13]=1[CH2:12][CH2:11][C:1]12[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2)=[O:27])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=C(O)c1nc(-c2ccccc2F)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCNC(=O)c1nc(-c2ccccc2F)[nH]c1CCC12CC3CC(CC(C3)C1)C2)OCc1ccccc1
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of 5-(2-adamantan-1-yl-ethyl)-2-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid (Example 50) (200 mg, 0.50 mmol) and β-alanine benzyl ester p-toluenesulfonate (175 mg, 0.50 mmol) in DCM (5 ml) was added N,N-diisopropylethylamine (0.26 ml, 1.50 mmol), 4-dimethylaminopyridine (cat.) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (230 mg, 0.50 mmol). The solution was kept at room temperature for 16 h, diluted with DCM (10 ml), washed with 5% aqueous potassium hydrogen sulphate and with saturated sodium hydrogen carbonate. The organic phase was dried (MgSO4) and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/ethyl acetate 9:1) to afford the product as colourless foam (153 mg, 58%). 1H NMR (300 MHz, CDCl3) 9.72 (1H, br s), 8.23 (1H, m), 7.68 (1H, t), 7.37-7.15 (8H, m), 5.17 (2H, s), 3.73 (2H, m), 3.07 (2H, m), 2.72 (2H, m), 1.97 (3H, s), 1.73-1.41 (14H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C@@H:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH2:8].[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:17]([O:21][C:22]([NH:24][CH2:25][C:26]([NH:8][C@H:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][C:5]1[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1cccc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1cccc(OC)c1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl 3-methoxyphenylalaninate (526 mg, 2.35 mmol), 2-(tert-butoxycarbonylamino)acetic acid (454 mg, 2.59 mmol, Sigma-Aldrich, St. Louis, Mo.), HATU (1.07 g, 2.82 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (0.819 mL, 4.71 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature for 2 h then diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated aqueous NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 60% EtOAc in hexanes to give ethyl N-(tert-butoxycarbonyl)glycyl-3-methoxyphenylalaninate (822 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[N:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]([CH3:17])=[CH:15][CH:16]=1>ClCCCl>[CH3:17][C:14]1[N:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:12]([CH3:11])=[CH:16][C:15]=1[CH:8]=[O:9]
Reactant: COC(=O)Cn1c(C)ccc1C
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)Cn1c(C)cc(C=O)c1C

Procedure:
17 ml (0.18 mol) of phosphorus oxychloride, 14 ml (0.18 mol) of anhydrous dimethylformamide and 30 g (0.18 mol) of methyl (2,5-dimethyl-pyrrol-1-yl)-acetate are reacted in 140 ml of 1,2-dichloroethane as described above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:23])([CH3:22])[C:9]([CH:11]([C:17](OCC)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:17]([OH:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](=[O:10])[C:8]2([CH3:22])[CH3:23])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(F)cc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 38.3 %

Procedure:
Diethyl 2-(2-(3-fluorophenyl)-2-methylpropanoyl)malonate (13.03 g, 40 mmol) was added to concentrated H2SO4 (65 mL, 769 mmol), and the mixture was stirred at room temperature for 45 minutes. Ice (H2O) was added, and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the crude compound as an orange oil. The crude oil was purified by silica flash chromatography (0-100% DCM/hexane) to give the desired compound as a white solid (4.26 g). MS (m/e)=279.1 (M+H)+.
Reaction SMILES: FC1C(F)=CC=C([N+]([O-])=O)C=1OC[C@H](O[Si](C)(C)C)C.[F:21][C:22]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([N+:38]([O-:40])=[O:39])[C:23]=1[O:24][C@@H:25]([CH3:32])[CH2:26][O:27][Si](C)(C)C.Cl>C(Cl)Cl.CO.CO>[F:21][C:22]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([N+:38]([O-:40])=[O:39])[C:23]=1[O:24][C@@H:25]([CH3:32])[CH2:26][OH:27]
Reactant: C[C@@H](CO[Si](C)(C)C)Oc1c([N+](=O)[O-])ccc(F)c1F
Agent: C[C@H](COc1c([N+](=O)[O-])ccc(F)c1F)O[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](CO)Oc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 0.5 h

Procedure:
The mixture obtained from the above reaction, comprising (R)-1-(2,3-difluoro-6-nitrophenoxy)-2-trimethylsiloxypropane (1) and (S)-2-(2,3-difluoro-6-nitrophenoxy)-1-trimethylsiloxypropane (2), was dissolved in 200 mL of 10:1 CH2Cl2/MeOH at 0° C., and was treated with 5 mL of IM HCl in MeOH with stirring. The cooling bath was removed, and the mixture was aged for 30 minutes. The product mixture, which included (R)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-ol formed by the desilylation of 1 and (S)-2-(2,3-difluoro-6-nitrophenoxy)-propane-1-ol formed by the desilylation of 2, was concentrated to a yellow oil, which was dried under high vacuum to remove the solvent. After concentration, the residue was dissolved in dichloromethane, and triphenylmethyl chloride (trityl chloride, 4 equivalents based on the undesired alcohol regioisomer (S)-2-(2,3-difluoro-6-nitrophenoxy)propane-1-ol) was added, followed by pyridine (1 equivalent based on the triphenylmethyl chloride). The mixture was stirred at ambient temperature, and the progress of the reaction was followed by gas chromatographic analysis. When the product regioisomer ratio, i.e., the ratio of (R)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-ol to the triphenylmeythylated (S)-2-(2,3-difluoro-6-nitrophenoxy)propane-1-ol reached >100:<1, the reaction was concentrated to dryness. The oily residue was then purified by distillation as before, using a wiped film evaporator. The compound that distilled was (R)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-ol, which is the desilylated alcohol derived from 1. The triphenylmeythylated (S)-2-(2,3-difluoro-6-nitrophenoxy)propane-1-ol, i.e., (S)-2-(2,3-difluoro-6-nitrophenoxy)-1-triphenylmethyloxypropane did not distill. The overall yield for the three steps to produce (R)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-ol was 90-95% based upon 2,3-difluoro-6-nitrophenol.
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])#[N:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH:36](OC)[O:37][CH3:38])[C:32]([O:34][CH3:35])=[O:33])[CH:19]=1>O>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2/[C:31](=[CH:36]\[O:37][CH3:38])/[C:32]([O:34][CH3:35])=[O:33])[CH:19]=1)#[N:3]
Reactant: N#Cc1ccccc1O
Reactant: COC(=O)C(c1ccccc1Oc1cc(Cl)ncn1)C(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-dimethoxypropanoate in methylcyclohexane/chloromethoxypyrimidine (185.5 g, 59.71% strength) was vacuum distilled to leave the propanoate melt. A solution of the potassium salt of 2-cyanophenol was then prepared by mixing 2-cyanophenol (49.0 g) and potassium carbonate (30.4 g) in water (50 g). This solution was added to the methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-dimethoxypropanoate melt, which had previously been cooled to 70° C. The reaction solution was then heated to 120° C. and held for 2 hours. Any distillates were allowed to come off under atmospheric conditions. (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate was produced (39.4 area %). The reaction solution was then distilled under vacuum (20 mmHg) at 95° C. for 2 hours and at 120° C. for 1 hour. No further demethanolysis was evident. The reagents were cooled to 95° C. before an additional amount of potassium carbonate (45.6 g) was charged. The solution was again distilled under vacuum (20 mmHg) at 95° C. for 20 minutes and at 120° C. for 20 mins. (E)-Methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate was produced (55.6 area %).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:46]=[CH:47][N:48]=4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:45])[C:35]5[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=5)[CH:28]=4)[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>C(OCC)C.O>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([C:34]([NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[C:22]4[N:23]([CH:46]=[CH:47][N:48]=4)[CH:24]=3)[CH:28]=2)=[O:45])=[CH:40][CH:39]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(NC(=O)c5ccc(C(C)(C)C)cc5)c4)cn4ccnc34)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc(N5CCNCC5)cc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-{6-[3-(4-tert-butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (15) (2.0 mmol), 1M HCl in diethyl ether (20 mL), and dioxane (60 mL) is stirred at room temperature for 16 hr. Water (100 mL) is added and the pH brought to 11 with 1N NaOH. The mixture is extracted with ethyl acetate (3×80 mL), the extracts washed with water (2×70 mL) and brine (1×70 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is slurried with diethyl ether and filtered to give 4-tert-butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide (16) as a cream solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[NH:37][NH2:38]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:38][NH:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)OC(C)(C)C)cnc21
Reaction time: 66 h
Yield: 67.4 %

Procedure:
A suspension of Intermediate 17 (1.48 g), EDC (1.34 g) and HOBT (0.83 g) in DMF (20 ml) was stirred at room temperature for 30 min. t-Butyl carbazate (0.68 g) was then added and stirring continued under nitrogen for a further 66 h. The mixture was concentrated in vacuo and the residue divided into two portions for purification. Each portion was applied to an SPE cartridge (aminopropyl, 10 g) which was eluted with methanol and the combined eluents were concentrated in vacuo. Further purification was carried out by Biotage (silica, 40 g), eluting with cyclohexane:ethyl acetate (1:4). Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 18 (1.39 g). LCMS showed MH+=405; Tm=2.64 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][N:6]([C:32](=[O:33])[CH2:31][C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH:24]=[N:23][N:22]=[N:21]3)=[CH:30][CH:29]=2)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC1=O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40 mg, 0.16 mmol) and [4-(1H-tetrazol-1-yl)phenyl]acetic acid (38 mg, 0.19 mmol) in DCM (3 ml) was added DMAP (25 mg, 0.20 mmol) and EDC (39 mg, 0.20 mmol). The mixture was allowed to stir at RT for 4 hours. LC showed formation of the desired product. The solvent was removed under vacuum, and the residue was redissolved in methanol, and purified by reverse phase HPLC to give the title product. LC-MS (IE, m/z): 442 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:8])[CH2:5][OH:6].[CH2:27](N(CC)CC)C.Cl[P:35]1(=[O:40])[O:39]CC[O:36]1>C1C=CC=CC=1>[P:35]([O:6][CH2:5][CH2:4][N+:7]([CH3:9])([CH3:27])[CH3:8])([OH:40])([OH:39])=[O:36].[CH3:1][O:2][CH2:3][CH:4]([N:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:8])[CH2:5][OH:6]
Reactant: O=P1(Cl)OCCO1
Reactant: CCN(CC)CC
Agent: CCCCCCCCCCCCCCCCCCN(C)C(CO)COC
Solvent: c1ccccc1
Product: C[N+](C)(C)CCOP(=O)(O)O
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Compound of the formula Ia wherein R1 =CH3, R2 =C18H37, R3 =CH3, ##STR12## 2 g (5 mmol) of 3-methoxy-2-(N-methyl-octadecylamino)propanol (IIa) and 3 ml of triethylamine were dissolved in 20 ml of dry benzene, and the mixture was cooled to 5° C. under nitrogen circulation. 1 g (7 mmol) of 2-chloro-2-oxo-1,3,2-dioxaphospholane in 4 ml of benzene was added under stirring, and stirring was continued overnight. The amino salt was filtered off and washed with benzene. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 20 ml of dry methyl cyanide and transferred to a reactor. 20 ml of methyl cyanide, saturated with gaseous trimethylamine, was added, and the mixture was heated at 65° C. for 24 hours. A solid separated on cooling. It was filtered off and chromatographed on silica gel (eluent chloroform:methanol 90:10, then 70:30 by volume, then methanol) to yield 1.1 g (39%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6](C=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[CH:9]=[CH:6][C:5]([OH:10])=[C:4]([CH:11]([O:14][CH3:15])[O:16][CH3:17])[CH:3]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(OC)c1cc(Br)ccc1O
Temperature: -18 °C

Procedure:
A mixture of 5-bromosalicylaldehyde (41.0 g, 0.200 mol), trimethyl orthoformate (205 ml, 1.83 mol) and dry p-toluenesulfonic acid (1.77 g, 0.010 mol) was refluxed for 24 h. After the reaction mixture was cooled to the RT, sodium bicarbonate (50 g) was carefully added, and the mixture was ultrasonicated for 5 min. The liquid was separated; the solid was washed with dry benzene (25 ml) and removed by filtration. Combined solutions were evaporated. The residue was triturated with dry hexane (30 ml) if necessary cooled to −18° C. Precipitate formed was collected by filtration, washed with dry hexane (20 ml). Slightly yellow crystals, 44.2 g (0.179 mol, 89%).
Reaction SMILES: Br[CH:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2[C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])=[CH:13][CH2:14][C:4]=2[CH2:3]1>C(O)C.[Pd]>[CH2:7]1[C:6]2[C:5]3[C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])=[CH:13][CH2:14][C:4]=3[CH2:3][CH2:2][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: CCC(=O)NCCC1=CCC2=C1C1=C(OCCC1)C(Br)C2
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)NCCC1=CCC2=C1C1=C(CC2)OCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a solution of N-[2-(5-bromo-2,3,4,5,6,7-hexahydrocyclopenta[f][1]benzopyran-9-yl)ethyl]propionamide (200 mg, 0.6 mmol.) in ethanol (5 mL) was added 5% Pd-C (200 mg, 50% hydrous). The mixture was stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration. The filtrate was then concentrated under reduced pressure. The concentrate was purified by means of silica gel column chromatography to afford the title compound (yield 130 mg, 85%).