Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([SH:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20]CS([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([S:15][CH2:20][CH2:19][CH2:18][O:17][CH3:16])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCCS(=O)(=O)[O-]
Reactant: Sc1ccc(Br)c(Cc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCSc1ccc(Br)c(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A mixture of 500 mg of 2-benzyl-3-bromo-6-mercaptopyridine, 360 mg of 3-methoxypropylmethane sulfonate, 370 mg of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was stirred at room temperature for one hour in a nitrogen atmosphere. The reaction solution was partitioned between ethyl acetate-water, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 1-2% ethyl acetate/hexane, to give 425 mg of the target compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[C:27]2[CH:26]=[CH:25][C:24]([CH3:28])=[C:23]([NH2:29])[C:22]=2[CH:21]=[CH:20][N:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([C:7]2[C:2]([NH:29][C:23]3[C:22]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:17])[C:27]=4[CH:26]=[CH:25][C:24]=3[CH3:28])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH:12]=1
Reactant: Fc1ncccc1-c1ncnc2[nH]ccc12
Reactant: Cc1ccc2c(Cl)nccc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(Cl)nccc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Temperature: 22 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
A mixture of 4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (2.17 g, 10.1 mmol) and 1-chloro-6-methylisoquinolin-5-amine (1.95 g, 10.1 mmol) in THF (4 mL) was sonicated for 3 min until throughly mixed. Lithium bis(trimethylsilyl)amide (7.63 g, 45.6 mmol) (1 N in THF from Aldrich) was added in a stream and the resulting dark brown solution was stirred at 22° C. for 4 h. The reaction was quenched with NaHCO3 (aq., sat.) while cooled in an ice bath. The reaction mixture was then partitioned between EtOAc and NaHCO3 (aq., sat). The aqueous layer was washed with EtOAc twice. The organic layers were combined and concentrated in vacuo. The light brown solid residue was triturated with EtOAc (˜50 mL) to give a yellow solid. This solid was collected by filtration and washed with EtOAc twice and then dried in a vacuum oven (45° C.) over the weekend to give N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine as a yellow solid (2.85 g, 73% yield). MS (ESI, pos. ion) m/z: 387 [M+H]+
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].[Si:47]([O:54][C:55]1[NH:59][N:58]=[C:57]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH:56]=1)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>C1COCC1>[C:42]([O:41][C:40]([NH:39][CH2:38][CH2:37][N:58]1[C:57]([C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:56][C:55]([O:54][Si:47]([C:50]([CH3:51])([CH3:53])[CH3:52])([CH3:49])[CH3:48])=[N:59]1)=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)[nH]n1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)nn1CCNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
Di-tert-butyl azodicarboxylate (1.07 g, 4.66 mmol) was added to a stirred solution of triphenylphosphine (1.22 g, 4.66 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (0.8 mL, 5.18 mmol) and ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-3-carboxylate (0.7 g, 2.59 mmol) in THF (22 mL). The mixture was stirred at 80° C. for 16 hours and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo to yield ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-5-carboxylate (1.01 g, 94% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11].[CH3:26][Al](C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:8]([OH:13])=[C:9]([CH:10]([OH:11])[CH3:26])[CH:12]=1
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Reactant: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C(C)C)c(O)c(C(C)O)c2)c1Br
Temperature: 4 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
5-(2,6-Dibromo-3-methyl-4-nitrophenoxy)-2-hydroxy-3-isopropylbenzaldehyde of Part 8D (210 mg, 0.44 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 4° C. Me3Al in toluene (0.355 mL, 0.67 mmol, 2N) was added to the mixture and the reaction was stirred for 16 hours at room temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Filtration through a pad of silica gave 195 mg (93%) of 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-(1-hydroxyethyl)-6-isopropylphenol as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:23])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.[CH:24](=O)[CH3:25].C([BH3-])#N.[Na+].Cl>CO>[Cl:23][C:7]1[C:6]2[C:2]([NH:1][CH2:24][CH3:25])=[N:3][NH:4][C:5]=2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[N:8]=1
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2c(Cl)n1)c1ccccc1
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.5 %

Procedure:
To a stirred solution of (R)-1-(3-amino-4-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (0.06 g, 0.18 mmol) in methanol (2.0 mL) was added aqueous acetaldehyde (0.025 mL, 35 wt. % in water, 0.20 mmol) followed by sodium cyanoborohydride (0.03 g, 0.54 mmol) and stirred at room temperature for 12 h. After confirming the completion of reaction by TLC, the reaction mixture was acidified with 1.5 N HCl and concentrated under reduced pressure. The crude product was dissolved in ethyl acetate, washed with 10% NaOH followed by water and brine solution. The organic layer was concentrated under reduced pressure and crude product was purified by preparative HPLC to afford (R)-1-(4-chloro-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (0.021 g, 32.0%). 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.92 (s, 1H), 9.05 (s, 1H), 7.44 (s, 1H), 7.37-7.32 (m, 4H), 7.26-7.22 (m, 2H), 5.44 (t, J=5.6 Hz, 1H), 4.84 (m, 1H), 3.28-3.23 (m, 2H), 1.39 (d, J=8.00 Hz, 3H), 1.20 (t, J=6.8 Hz, 3H). MS ES calc'd. for C17H19ClN6O2 [M+H]+ 359. Found: 359.
Reaction SMILES: Cl[Si](C)(C)C.C([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)(=O)C1C=CC=CC=1>>[N:23]1[C:15]([NH2:14])=[C:16]2[C:20]([N:19]=[CH:18][NH:17]2)=[N:21][CH:22]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)c1ccccc1
Agent: C[Si](C)(C)Cl
Product: Nc1ncnc2nc[nH]c12

Procedure:
N6-Benzoyl-9-(2′-fluoro-b-D-ribofuranosyl) adenine was prepared from 9-β-D-arabinofuranosyladenine in a five-step synthesis using a modification of a procedure reported by Ikehara at al. [Nucleosides and Nucleotides, 2, 373-385 (1983)]. The N6-benzoyl derivative was obtained in good yield utilizing the method of transient protection with chlorotrimethylsilane. Jones [J. Am. Chem. Soc., 104, 1316 (1982)]. Selective protection of the 3′ and 5′-hydroxyl groups of N6-Benzoyl-9-β-D-arabinofuranosyladenine with tetrahydropyranyl (THP) was accomplished by modification of the literature procedure according to Butke et al. [Nucleic Acid Chemistry, Part 3, p.149, L. B. Townsend and R. S. Tipson, Eds., J. Wiley and Sons, New York, 1986], to yield N6-Benzoyl-9-[3′,5′-di-O-tetrahydropyran-2-yl) -β-D-arabino-furanosyl]adenine in good yield. Treatment of N6-Benzoyl-9-[3′,5′-di-O-tetrahydropyran-2-yl) -β-D-arabino-furanosyl]adenine with trifluoromethanesulfonic anhydride in dichloromethane gave the 2′-triflate derivative N6-Benzoyl-9-[2′-O-trifluoromethylsulfonyl-3′,5′-di-O-tetrahydropyran-2-yl) -β-D-arabinofuranosyl]adenine which was not isolated due to its lability. Displacement of the 2′-triflate group was effected by reaction with tetrabutylammonium fluoride in tetrahydrofuran to obtain a moderate yield of the 2′-fluoro derivative N6-Benzoyl-9-[2′-fluoro-3′,5′-di-O-tetrahydropyran-2-yl) -β-D-arabinofuranosyl]adenine. Deprotection of the THP groups of N6-Benzoyl-9-[2′-fluoro-3′,5′-di-O-tetrahydro-pyran-2-yl) -β-D-arabinofuranosyl]adenine was accomplished by treatment with Dowex-50W in methanol to yield N6-benzoyl-9-(2′-deoxy-2′-fluoro-β-D-ribofuranosyl) adeninein moderate yield. The 1H-NMR spectrum was in agreement with the literature values. [Ikehara and Miki, Chem. Pharm. Bull., 26, 2449 (1978)]. Standard methodologies were employed to obtain the 5′-dimethoxytrityl-3′-phosphoramidite intermediates N6-Benzoyl-9-[2′-fluoro-5′-O-(4,4′-dimethoxytrityl) -β-D-ribo-furanosyl]adenine and N6-Benzoyl-[2′-deoxy-2′-fluoro -5′-O-(4,4′-dimethoxytrityl)]adenosine-3′-O-(N,N-diisopropyl-β-cyanoethylphosphoramidite. [Ogilvie, Can J. Chem., 67, 831-839 (1989)].
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[C:24]2[C:32]3[CH:31]=[N:30][CH:29]=[N:28][C:27]=3[N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[C:19]([F:44])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:44][C:19]1[N:18]=[C:17]([NH:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH:22]=[CH:21][C:20]=1[CH2:23][C:24]1[C:32]2[CH:31]=[N:30][CH:29]=[N:28][C:27]=2[NH:26][CH:25]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncncc34)c(F)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)c(F)n2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To {6-fluoro-5-[hydroxy-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (67, 27 g, 42.5 mmol) in 700 mL of acetonitrile, triethylsilane (67.8 mL, 425 mmol) and trifluoroacetic acid (32.7 mL, 425 mmol) were added. The reaction was stirred at 50° C. overnight, solvents removed under vacuum, and the residue taken up in ethyl acetate and poured into aqueous potassium carbonate. The organic layer was separated, concentrated under vacuum and purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (P-0105, 4.5 g, 12.38 mmol, 29.2% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C1CCCCC1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:5][CH2:4][CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: ClCCCBr
Reactant: CN1CCCNCC1
Solvent: C1CCCCC1
Product: CN1CCCN(CCCCl)CC1
Reaction time: 8 h
Yield: 42 %

Procedure:
A round-bottom, 250 milliliter, three-necked flask was equipped with a mechanical stirrer, a Claisen adapter, equipped with a thermocouple and a dry-ice condenser with a gas inlet, and a pressure-equalizing dropping funnel. This apparatus was baked in an oven overnight at 125° C., assembled hot, and purged with argon until cool. The reaction flask was charged with 1-bromo-3-chloropropane 15.75 grams, (0.10 moles, 1 equivalent) and cyclohexane 8.68 grams, (0.10 moles, 1 equivalent). The reaction mixture was stirred with a magnetic stir bar. 1-Methylhomopiperizine 22.64 grams, (0.20 moles, 2 equivalents) was added dropwise via the addition funnel over a period of thirty-three minutes. A hexane/dry ice cooling bath was applied as needed to maintain a reaction temperature no greater than 35° C. After addition was complete, samples of the reaction mixture were removed periodically, washed with saturated sodium bicarbonate solution, and assayed for unreacted 1-bromo-3-chloropropane by gas chromatography (GLC). The reaction was allowed to stir until 1-bromo-3-chloro-propane was consumed. Next, 75 milliliters of saturated sodium bicarbonate solution and 25 milliliters of distilled water were added to the reaction flask. The reaction mixture was then transferred to a separatory funnel (homogeneous mixture). The mixture was extracted 2×75 milliliters with ethyl ether. The resulting organic layer was then dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator, to afford a slightly hazy solution with a yield=42%; (GC assay=98.3%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]([C:13]1[N:14]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[S:16][C:17]=1[C:18]([OH:20])=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH:5]2[CH2:4][CH2:3][NH:2][C:18](=[O:20])[C:17]3[S:16][C:15]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][C:13]2=3)=[CH:11][CH:10]=1
Reactant: NCCC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NCCC(c2ccc(Cl)cc2)c2nc(N3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[3-amino-1-(4-chlorophenyl)propyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid hydrochloride (0.264 g, 0.631 mmol) in DCM (12.7 mL) was added 1-hydroxybenzotriazole (0.103 g, 0.763 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.239 g, 1.24 mmol) and N,N-diisopropylethylamine (0.320 mL, 1.84 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM, then the layers were separated and the organic layer was washed with water then brine and dried over anhydrous sodium sulfate then concentrated. The residue was purified using column chromatography on silica gel (12 gr Analogix column, gradient DCM to 10% MeOH in DCM over 15 minutes) to give the product. The racemic product was then separated into enantiomers on a Chiralpak IA 20×250 mm column using 70/10/20 hexane/IPA/EtOH mixture, with retention time 10.4 min for peak 1 (53 mg, 23%) and 14.5 min for peak 2 (53 mg, 23%). Absolute configuration for the enantiomers is unknown. LCMS: (AA) ES+ 364, 366. 1H NMR (400 MHz, d6-DMSO) δ: 7.95 (t, J=4.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 4.34 (dd, J=7.1, 5.3 Hz, 1H), 3.64-3.57 (m, 4H), 3.31-3.24 (m, 4H), 3.14-3.01 (m, 2H), 2.28-2.13 (m, 1H), 2.04-1.84 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[H-].[Na+].Br[CH:14]([C:16]1[N:21]2[N:22]=[CH:23][N:24]=[C:20]2[N:19]=[CH:18][CH:17]=1)[CH3:15]>COCCOC>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:14]([C:16]2[N:21]3[N:22]=[CH:23][N:24]=[C:20]3[N:19]=[CH:18][CH:17]=2)[CH3:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)c1ccc(OC(C)c2ccnc3ncnn23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxyacetophenone (1.36 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 above) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred at room temperature for 24 hours. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. Evaporation of the solvent afforded a crude product which was recrystallised from ethyl acetate, to give 7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.87 g, (m.p. 136°-138° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=O)=[CH:5][CH:4]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:31])[CH3:30])[CH:24]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:30][N:29]([CH3:31])[C:25]1[CH:24]=[C:23]([N:22]([CH3:32])[CH3:21])[CH:28]=[CH:27][C:26]=1[C:7]1([C:6]2[CH:18]=[CH:19][C:3]([N:2]([CH3:20])[CH3:1])=[CH:4][CH:5]=2)[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)cc1
Temperature: 95 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)benzoic acid (26.8 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (16.4 g.) and acetic anhydride (80 g.) was heated (to 95° C.) during one hour, cooled and poured into dilute hydrochloric acid. The resulting mixture was basified. Recrystallization of the resulting solid from a mixture of toluene and hexane afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)phthalide (I: X = Y4 = (CH3)2N, Y2 = Z4 = Z5 = Z6 = Z7 = H) (m.p. 190°-194° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].C[O:11][C:12](OC)(N(C)C)[CH3:13]>CN(C=O)C>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9])[C:12]([CH3:13])=[O:11]
Reactant: Cc1ccncc1C#N
Reactant: COC(C)(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccncc1C#N
Yield: 68.7 %

Procedure:
A solution of 4-methyl-3-cyanopyridine (4 g, 33.9 mmol) and N,N-dimethylacetamide dimethylacetal (5.4 g, 40.6 mmol) in dry DMF (20 ml) was stirred at 130° for 7 h. The volatiles were removed in vacuo to afford a dark oil which solidified on standing. This material was chromatographed (SiO2; 50% EtOAc/Hexane—100% EtOAc) affording the title compound as an off-yellow solid (3.73 g, 69%). δH (CDCl3) 8.87 (1H, s), 8.74 (1H, d, J 5.2 Hz), 7.28 (1H, d, J 5,2 Hz), 4.00 (2H, s) and 2.36 (3H, s); m/z (ES+, 70V) 161 (MH+).
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][N:6]=1>C(Cl)(Cl)Cl>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:12][C:2]#[N:1])=[CH:9][CH:10]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: N#CBr
Solvent: ClC(Cl)Cl
Product: N#CNCc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cyanogen bromide (220 mg, 2.09 mmol) was dissolved in 10 mL of anhydrous chloroform, and the solution was cooled to 0° C. To this was dropwise added a solution of 500 mg (3.49 mmol) of 2-chloro-5-aminomethylpyridine dissolved in 10 mL of anhydrous chloroform, and the resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was filtered, then water was added and liquid-liquid extraction was carried out, following which the chloroform phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=1:1), giving 122 mg (yield, 35%) of the target compound.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.CN(C)[CH:32]=[O:33].Cl>O1CCCC1.CCCCCC>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][C:23]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
A solution of y mol of 2,2,6,6-tetramethylpiperidine in 400 ml of anhydrous tetrahydrofuran is cooled under a stream of argon to to and there is added dropwise thereto at this temperature within 30 minutes 100·y/0.16 ml of a 1.6M solution of n-butyllithium in hexane. Subsequently, 20.2 ml (0.13 mol) of 1,3-bis(trifluoromethyl)benzene are added dropwise thereto at to within 15 minutes, the wine-red solution obtained is stirred for a further×minutes at to and then at this temperature 20 ml (0.26 mol) of N,N-dimethylformamide are allowed to flow in rapidly from a dropping funnel. The internal temperature t rises by about 15° as a consequence of the exothermic reaction. The dark red solution obtained is then slowly added dropwise and while stirring and cooling to 500 ml of cold 3M hydrochloric acid (strongly exothermic). The emulsion obtained is diluted with 300 ml of hexane, the aqueous phase is separated, the organic phase is extracted with 500 ml of cold 3M hydrochloric acid, washed neutral twice with 250 ml of saturated sodium chloride solution each time, dried over sodium sulphate and the organic solvent is largely distilled off at 40° bath temperature/20 kPa. The residue is distilled over a column having a length of 20 cm, whereby firstly residual solvent is removed at 50° bath temperature/20 kPa and then the bath temperature is increased to 80° and the vacuum is increased to 1.4 kPa. During the increase in the internal temperature a forerun of about 1 g is removed and then the 2,4-bis(trifluoromethyl)benzaldehyde obtained distils over at 56°./1.4 kPa as a colourless liquid.
Reaction SMILES: [N:1]([C:4]([CH3:54])([CH3:53])[CH2:5][C@@H:6]1[NH:11][CH2:10][C@H:9]([O:12][CH:13]([C:24]2[CH:25]=[CH:26][C:27]3[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=3[CH:38]=2)S(C2C=CC(C)=CC=2)(=O)=O)[C@@H:8]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][O:46][CH2:47][C@H:48]([O:50][CH2:51][CH3:52])[CH3:49])=[CH:41][CH:40]=2)[CH2:7]1)=[C:2]=[O:3].[CH2:55](O)C1C=CC=CC=1>>[CH2:51]([O:50][C@H:48]([CH3:49])[CH2:47][O:46][CH2:45][C:42]1[CH:41]=[CH:40][C:39]([C@@H:8]2[C@@H:9]([O:12][CH2:13][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:10][NH:11][C@@H:6]([CH2:5][C:4]([NH:1][C:2](=[O:3])[CH3:55])([CH3:53])[CH3:54])[CH2:7]2)=[CH:44][CH:43]=1)[CH3:52]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)N=C=O)NC[C@@H]2OC(c2ccc3c(c2)N(CCCOC)CCO3)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCc1ccccc1
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)NC(C)=O)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 115 °C

Procedure:
A mixture of 1.0 mmol of 6-[(3R,4R,6R)-6-(2-isocyanato-2-methyl-propyl)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxy-propyl) -3,4-dihydro-2H-benzo[1,4]oxazine and 20.0 mmol of benzyl alcohol is heated at 115° C. for 14 h. The reaction mixture is directly purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on its Rf value.