Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=O)[N:10]([C:19]([C:21]3[CH:26]=CC=CC=3)=O)[C:11](=[O:18])[N:12](C(C)C=O)[CH:13]=2)[S:5][C:6]=1[CH3:7].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:35]=[CH:34][C:33]([C@:36]23[CH2:41][C@H:40]2[CH2:39][NH:38][CH2:37]3)=[CH:32][CH:31]=1.C(O)(=[O:46])C.[Na]>C(#N)C.CCOC(C)=O.ClCCCl>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13](=[O:46])[NH:12][C:11](=[O:18])[N:10]([CH2:19][CH2:21][CH2:26][N:38]3[CH2:39][C@H:40]4[C@:36]([C:33]5[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:42])[F:43])=[CH:35][CH:34]=5)([CH2:41]4)[CH2:37]3)[CH:9]=2)[S:5][C:6]=1[CH3:7]
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: CC(=O)O
Reactant: Cc1nc(-c2cn(C(C)C=O)c(=O)n(C(=O)c3ccccc3)c2=O)sc1C
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC#N
Product: Cc1nc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)sc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
[5-(4,5-dimethyl-1,3-thiazol-2-yl)-2,4-dioxo-3-(phenylcarbonyl)-3,4-dihydro-1(2H)-pyrimidinyl]propanal (Prep18, 0.098 mmol from previous reaction considered quantitative) was dissolved in Acetonitrile (1.500 ml). (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Prep4, 0.022 g, 0.098 mmol) was added and to the resulting slurry 1,2-Dichloroethane (DCE) (1.5 ml) and Acetic acid (0.011 ml, 0.196 mmol) were added. The resulting clear and dark yellow solution was stirred at rt for 10 minutes then it was cooled to 0° C. and sodium triacetoxyborohydryde (0.023 g, 0.108 mmol) was added in one portion. The mixture was stirred while the temperature slowly rose to rt (ca 5 hrs). The mixture was diluted with EtOAc (20 mL) washed with aqueous saturated NaHCO3 and extracted with EtOAc (2×5 mL). The organics were combined and dried (Na2O4, rotary evaporator) to afford a crude that was purified by silica chromatography, eluting with DCM:MeOH 100:0 to 9:1 to afford a yellow foam that was purified by SCX (5 g) eluting with DCM, MeOH, Ammonia 1M in MeOH (10 mL each) to afford 36 mg of compound that was further purified by Fraction Lynx. Product fraction was dried to afford 5 mg of impure title compound that was filtered through an SCX cartridge (500 mg) eluting with DCM, MeOH, Ammonia 2M in MeOH. Fraction from ammonia was dried to afford the title compound as a white solid (3 mg)
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10](=[O:25])[CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][C:10]1=[O:25])[CH3:24]
Reactant: CCOC(=O)CN1C(=O)CN(C(=O)OC(C)(C)C)Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)CNCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-ethoxycarbonylmethyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (125 mg, 0.36 mmol) in dry DCM (5 mL) was added trifluoroacetic acid (1.08 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for one hour. After completion of the reaction, as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford trifluoroacetic acid salt of (2-oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl)-acetic acid ethyl ester (119 mg, 92%) as a gummy solid which was used as such without any further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.O=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(#[N:22])C>>[CH3:18][C:17]1[NH:22][C:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:7][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1ccc(CN)cc1
Reactant: CCOC(=O)C(=O)C(C)=O
Reactant: CC#N
Product: CCOC(=O)c1nc(-c2ccc(C)cc2)[nH]c1C

Procedure:
A mixture of 10.7 g of 4-methylbenzylamine, 12.7 g of 2,3-dioxobutyric acid, ethyl ester, (Z)-2-oxime and 160 ml of acetonitrile was stirred and refluxed for 3.5 hours. The mixture was cooled, the solid collected and recrystallized from ethanol, giving 6.2 g of 5-methyl-2-(4-methylphenyl)-1H-imidazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: [Na].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][OH:25]>>[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[CH3:21][O:22][CH2:23][CH2:24][O:25][C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1
Reactant: COCCO
Reactant: CN1CCC=C(c2nsnc2Cl)C1
Agent: O=C(O)C(=O)O
Agent: [Na]
Product: COCCOc1nsnc1C1=CCCN(C)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (120 mg, 5 mmol) in 2-methoxyethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)1,2,5,6-tetrahydro-1-methylpyridine oxalate (310 mg, 1 mmol). The mixture was stirred at 50° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The title compound was crystallized as the oxalate salt from acetone to yield 270 mg. (M.p. 152.1° C.; M+ : 253; Compound 15).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.[NH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[NH2:19]>CO>[ClH:1].[N:23]1[CH:24]=[CH:25][C:20]([NH:18][NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[N:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][CH:22]=1
Reactant: NNc1ccncc1
Reactant: CCOC(=O)c1cnc2ccncc2c1Cl
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cnc2ccncc2c1NNc1ccncc1

Procedure:
A solution of 2.36 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylate and 1.53 g of 4-hydrazinopyridine hydrochloride in 37 ml of methanol is stirred for 19 hours at room temperature, then refluxed for 4 hours. The reaction mixture is then cooled in an ice bath, and solid is collected by filtration, washed successively with methanol and ether to yield ethyl 4-[2-(4-pyridyl)hydrazino]-1,6-naphthyridine-3-carboxylate hydrochloride.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH3:8][CH2:9][CH2:10][CH2:11][SnH:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16].B(CC)(CC)CC.[F:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([F:36])=[C:31]([F:37])[C:30]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C1COCC1>[CH2:13]([Sn:12]([CH2:11][CH2:10][CH2:9][CH3:8])([CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:4][CH2:3][CH2:2][C:1]([O:7][C:30]1[C:29]([F:28])=[C:34]([F:35])[CH:33]=[C:32]([F:36])[C:31]=1[F:37])=[O:6])[CH2:14][CH2:15][CH3:16]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: C#CCCC(=O)O
Reactant: CCCC[SnH](CCCC)CCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCB(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCC[Sn](C=CCCC(=O)Oc1c(F)c(F)cc(F)c1F)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 4-pentynoic acid (308 mg, 3.1 mmol) in toluene (7.0 mL) under N2 was added Bu3SnH (1.7 mL, 6.3 mmol) followed by Et3B (0.30 mL, 1.0M solution in hexanes, 0.30 mmol). The resulting solution was stirred at room temperature for 13/4 hours after which the solvent was evaporated under reduced pressure. The resulting oil was dissolved in EtOAc and washed with saturated NaCl. The EtOAc layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford 2.0 gr of crude product. To a solution of the crude product in anhydrous THF (15 mL) was added a solution of 2,3,5,6-tetrafluorophenol (554 mg, 3.4 mmol) in THF (1.0 mL) followed by a solution of dicyclohexylcarbodiimide (652 mg, 3.2 mmol) in THF (1.0 mL). The resulting solution was stirred at room temperature overnight during which time a white precipitate formed. The THF was evaporated under reduced pressure and the residue was suspended in CH3CN. The insoluble precipitate was filtered off and the filtrate was purified via flash chromatography (silica gel, 25 mm×90 mm, 5% EtOAc/hexanes) to afford 833 mg (50%) of 2,3,5,6-tetrafluorophenyl 5-(tri-n-butylstannyl)-4-pentenoate as a mixture of isomers. 1H NMR (200 MHz, CDCl3) S 6.90 (m, 1H), 6.20 (m, 2H), 2.78 (bq, 2H, J=7 Hz), 2.60 (m, 2H), 1.65-1.20 (m, 18H), 1.90 (t, 9H, J=8 Hz); 13CNMR (50.3 Hz, CDCl3) S 169.75, 145.95, 145.80, 132.14, 130.77, 106.70 (t, J=23 Hz), 103.63 (t, J=23 Hz), 34.04, 33.13, 32.62, 32.23, 29.43, 27.63, 13.96, 10.53, 9.71.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:36])=[C:4]([CH:22]2[CH2:25][N:24](C(OCC3C=CC=CC=3)=O)[CH2:23]2)[C:5]([O:20][CH3:21])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.Cl.O>CO.[Pd]>[NH:24]1[CH2:25][CH:22]([C:4]2[C:5]([O:20][CH3:21])=[C:6]([CH:8]([NH:10][C:11]3[N:19]=[CH:18][N:17]=[C:16]4[C:12]=3[N:13]=[CH:14][NH:15]4)[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:36])[CH2:23]1
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reaction time: 8 h

Procedure:
Benzyl 3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate (255 mg, 0.503 mmol) and 5% palladium (125 mg) was combined in methanol (15 mL), to which was added 0.25 M HCl in water (5.0 mL, 1.2 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature overnight. The suspension was filtered and concentrated to give N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine. LCMS calculated for C18H22ClN6O (M+H)+: m/z=373.2. found: 373.1. The azetidine intermediate made above was combined with DIPEA (0.26 mL, 1.5 mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by the addition of 37% formaldehyde (0.19 mL, 2.5 mmol). The mixture was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (0.32 g, 1.5 mmol). The mixture was stirred at room temperature overnight, then diluted with MeOH and purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C19H24ClN6O (M+H)+: m/z=387.2. found: 387.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]([CH3:20])([CH3:19])[CH2:9][C:10]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH:11]([OH:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]([CH3:19])([CH3:20])[CH2:9][C:10]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:11](=[O:13])[CH3:12])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)=O)C(F)(F)F
Reaction time: 20 h
Yield: 71.7 %

Procedure:
1.46 g (4.5 mmol) of 5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)hexane-2,3-diol and 3.14 ml (22.5 mmol) of triethylamine in 16.3 ml of DMSO and 50 ml of methylene chloride are mixed in portions with 4.3 g (27 mmol) of pyridine-sulfur trioxide complex at room temperature. After 20 hours at room temperature, it is hydrolyzed with saturated ammonium chloride solution while being cooled with ice and extracted with diethyl ether. The combined extracts are dried (sodium sulfate) and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 1.04 g of the product.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F-].[CH2:10]([N+:14](CCCC)(CCCC)[CH2:15]CCC)[CH2:11]CC.Cl.[O:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:11][C:10]1[CH:29]=[CH:30][C:31]([CH:32]([OH:28])[C:2]([F:4])([F:3])[F:1])=[CH:15][N:14]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C1CCOC1
Agent: Cl
Agent: [F-]
Product: Cc1ccc(C(O)C(F)(F)F)cn1
Reaction time: 1 h
Yield: 50 %

Procedure:
6-Methylnicotinic acid N,O-dimethylhydroxylamide (737 mg, 4.09 mmol) was dissolved in dichloromethane. To this, diisobutylaluminum hydride (a 0.98 mol/L solution in hexane, 4.60 mL, 4.50 mmol) was added dropwise under a nitrogen atmosphere at −10° C. and the mixture was stirred at the same temperature for 10 minutes. To this, water (4.60 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give a 3:1 mixture (405 mg) of 2-methyl-5-formylpyridine and 6-methylnicotinic acid N,O-dimethylhydroxylamide. The mixture was dissolved in tetrahydrofuran (8.0 mL). To this, (trifluoromethyl)trimethylsilane (593 μL, 4.01 mmol) and tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 340 μL, 0.340 mmol) were added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a 1N aqueous hydrogen chloride solution (6.0 mL) was added and the mixture was further stirred for 10 minutes. Then, the reaction mixture was neutralized with a saturated sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 2-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CK) (387 mg, yield: 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Cl
Temperature: 25 °C

Procedure:
6-Chloro-3-nitroquinolin-4-ol (Compound of step 2, 5 g, 22.42 mmol) in POCl3 (150 mL, 493 mmol) was stirred for 45 min at 120° C. The mixture was cooled to RT and poured slowly into ice-water. The precipitate was filtered, washed with ice-cold water, and dissolved in CH2Cl2. The organic phase was washed with cold brine and dried over Na2SO4. The organic solvent was evaporated to dryness to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C@H:33]([CH3:36])[CH2:34][OH:35]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([NH:32][C@H:33]([CH3:36])[CH2:34][OH:35])[N:17]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: C[C@@H](N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@H](C)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 18 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and (R)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 230 for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a off-white amorphous solid. mp 90-95°, LC MS m/z=441 (MH+). Retention time=2.09 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][OH:18])[O:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[C:22]([CH3:32])[C:21]=1[OH:33]>>[OH:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][O:18][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][C:22]=2[CH3:32])[O:12][N:11]=1.[Si:1]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][O:33][C:21]2[C:22]([CH3:32])=[CH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:25][C:20]=2[CH3:19])[O:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCCO)on1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1O
Product: Cc1cc(-c2ccccc2)cc(C)c1OCCCc1cc(CO)no1
Product: Cc1cc(-c2ccccc2)cc(C)c1OCCCc1cc(CO[Si](C)(C)C(C)(C)C)no1

Procedure:
3-(Hydroxymethyl)-5-[3-[2,6-dimethyl-4-phenylphenoxy]-propyl]-isoxazole was prepared following procedures described in the literature; J. Med. Chem. (1994) 37 2421, thus 3-(t-butyldimethylsilyloxymethyl)-5-(3-hydroxypropyl)isoxazole (ibid.) and 2,6-dimethyl-4-phenyl-phenol were coupled by way of a Mitsunobu reaction to give the adduct, 3-(t-butyldimethylsilyloxymethyl)-5-[3-[2,6-dimethyl-4-phenylphenoxy]-propyl]-isoxazole in 82% yield. 1H nmr (CDCl3): δ=7.6-7.2 (m, 7H); 6.13 (s, 1); 4.75 (d, 2H); 3.86 (t, 2H); 3.07 (t, 2H); 2.33 (s, 6H); 2.23 (m, 2H) and 2.1 (t, OH). MS (ES): (M+H) 338.1748 (calc. C21H24NO3 338.1750). Removal of the silyloxy group under acidic hydrolysis gave the hydroxy compound, 3-(hydroxymethyl)-5-[3-[2,6-dimethyl-4-phenylphenoxy]-propyl]-isoxazole in 93% yield. 1H mm (CDCl3): δ=7.6-7.2 (m, 7H); 6.13 (s, 1H); 4.75 (d, 2H); 3.86 (t, 2H); 3.07 (t, 2H); 2.33 (s, 6H); 2.23 (m, 2H) and 2.1 (t, OH). MS (ES): (M+H) 338.1748 (calc. C21H24NO3 338.1750). Bromination of the hydroxy compound following the procedure of example 1 gave the bromomethyl compound, 3-(bromomethyl)-5-[3-[2,6-dimethyl-4-phenylphenoxy]-propyl]-isoxazole in 95% yield. 1H nmr (CDCl3): δ=7.6-7.2 (m, 7H); 6.17 (s, 1H); 4.41 (s, 2H); 3.86 (t, 2H); 3.07 (t, 2H); 2.33 (s, 6H) and 2.23 (m, 2H). MS(ES): (M+Na)+ 422.0725 (calc. C21H22BrNO2Na 422.0720).
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]2[S:14][C:15]3[CH2:20][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:17][C:16]=3[C:3]1=2.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)N1CCc2c(sc3nc(-c4cccnc4)[nH]c(=O)c23)C1
Product: CCOC(=O)N1CCc2c(sc3nc(-c4cccnc4)nc(Cl)c23)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
4.1 g of 5,6,7,8-tetrahydro-4-oxo-7-ethoxycarbonyl-2-(3-pyridyl)pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine was added to 40 ml of phosphorus oxychloride, and stirred at 80 to 100° C. for 3 hours. After phosphorus oxychloride was distilled off under reduced pressure, 50 ml of water was added to the reaction residue. The reaction solution was made alkaline with an aqueous saturated solution of sodium hydrogen carbonate while cooling, and extracted with chloroform. The organic layer was washed with saturated salt water and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off. The filtrate was concentrated under reduced pressure to give 5.0 g of 5,6,7,8-tetrahydro-4-chloro-7-ethoxycarbonyl-2-(3-pyridyl)pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN([CH:22]=[N:23][NH:24][C:25](OCC)=[O:26])C.CC(O)C>S1CCCC1>[O:26]=[C:25]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:22]=[N:23][NH:24]1
Reactant: CCOC(=O)NN=CN(C)C
Reactant: CCOC(=O)N1CCN(c2ccc(N)cn2)CC1
Solvent: CC(C)O
Solvent: C1CCSC1
Product: CCOC(=O)N1CCN(c2ccc(-n3cn[nH]c3=O)cn2)CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
A mixture of ethyl 4-(5-amino-2-pyridinyl)-1-piperazinecarboxylate (0.18 mol) and ethyl 2-[(dimethylamino)methylene]hydrazinecarboxylate (0.54 mol) in tetrahydrothiophene, 1,1-dioxide (50 ml) was stirred at 150° C. for 3 hours. The mixture was cooled till 100° C., 2-propanol was added until crystallization. The precipitate was filtered and recrystallized from methanol; yielding 30.5 g ethyl 4-[5-(2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl)-2-pyridinyl]-1-piperazinecarboxylate (53.3%); mp. 220.8° C. (interm. 1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[CH:14][C:13]([CH3:17])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([O:16][C:15]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)[N:12]=[C:13]([CH3:17])[CH:14]=1)(=[O:27])[CH3:26]
Reactant: Cc1cc(O)n(-c2ccc(C(C)(C)C)cc2)n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cc(C)nn1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.6 %

Procedure:
1-(4-t-Butylphenyl)-5-hydroxy-3-methyl-1H-pyrazole (21.7 g, 94.1 mmol) in tetrahydrofuran (600 mL) was mixed with triethylamine (26.2 mL, 188 mmol.) and acetyl chloride (7.4 mL, 104 mmol) at 0° C. and stirred at room temperature for 45 minutes. The reaction solution was mixed with water (300 mL), and the aqueous layer and the organic layer were separated. The solvent was removed from the organic layer by distillation, and the residue was mixed with ethyl acetate. The aqueous layer was extracted with ethyl acetate twice, and the extract was combined with the organic layer. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate once, with water twice and with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 22.2 g of the desired product (87% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])[CH:19]=[CH:20][C:21](O)=O>>[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)c(F)c3)nc2n(CC)c1=O
Yield: 48.6 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3 -diethyluracil and 2.79 g (15.2 mmol) of 3,4-difluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.12 g (yield 49%) of Compound 116 as gray plates.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(O)(O)O>O>[CH2:6]([NH:13][CH2:1][CH:2]([CH3:4])[CH3:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)C=O
Reactant: NCc1ccccc1
Agent: OP(O)O
Solvent: O
Product: CC(C)CNCc1ccccc1

Procedure:
To the imine from isobutyraldehyde and benzylamine (51.4 g; 0.3 mole) was added phosphorous acid (24.6 g; 0.3 mole). While stirring the mixture was slowly warmed to 65°-70° when a vigorous exothermic reaction was initiated. The reaction temperature reached 130°-145°. Upon cooling the reaction mixture became a glass. This glass was dissolved in water and basified. Extraction with benzene yielded benzylisobutylamine. The aqueous portion was acidified and after removal of sodium chloride yielded a phosphonic acid (20 g). Recrystallization gave a white solid (12 g) mp 186°-190° the N-benzyl α-aminophosphonic acid. ##STR35##