Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:50][CH:51]1[CH2:54][NH:53][CH2:52]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:53]3[CH2:54][CH:51]([OH:50])[CH2:52]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 1, 150 mg (0.297 mmol) of the compound from Example 3A and 139 mg (0.445 mmol) of the compound from Example 8A were used to obtain 68 mg (46% of theory) of the title compound. The reaction time in the first component step of the process here was 1 h. The crude product was purified by means of preparative HPLC (method 13). The free base was obtained from the resulting formate salt of the title compound by percolation of a methanolic solution of the salt through a hydrogencarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). The final purification was effected by extractive stirring in a mixture of 3 ml of pentane and a few drops of diisopropyl ether.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].Cl>C(OCC)C>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18](=[NH:3])[NH2:19]
Reactant: N#Cc1ccccc1Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: N=C(N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
According to literature reference (Huang, Y.; Luedtke, R. R.; Freeman, R. A.; Wu, L.; Mach, R. H. Bioorg. Med. Chem. 2001, 9, 3113–3122), to a solution of hexamethyldisilazane (36.7 mL, 175 mmol) in of diethyl ether (300 mL) at 0° C. is added n-butyl lithium (114 mL of 1.6 M solution in hexanes, 182 mmol) and the reaction mixture is stirred at 0° C. for 30 minutes after which time 2-chlorobenzonitrile (10.0 grams, 72.7 mmol) is added and the reaction mixture is warmed to 25° C. and stirred for 5 hours. Once complete, the reaction is poured into 2 N HCl and the aqueous phase was washed twice with diethyl ether. This aqueous phase is then made basic (pH=12) by addition of 6N sodium hydroxide. Subsequently, the aqueous phase is extracted with CH2Cl2 and the combined organic extracts are dried over sodium sulfate and concentrated to provide a crude solid. The crude product is then recrystallized from ethyl acetate to afford 5.4 g of 2-chlorobenzenecarboximidamide.
Reaction SMILES: [C:1]([C:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=1)([CH3:6])[CH3:5])([OH:3])=O.[N:18]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1)=[C:19]=[S:20].C(N(CC)CC)C>CCO>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:18]2[C:1](=[O:3])[C:4]([CH3:6])([CH3:5])[N:7]([C:8]3[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=3)[C:19]2=[S:20])=[CH:22][C:23]=1[C:29]([F:30])([F:31])[F:32])#[N:26]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CC(C)(Nc1ccc(C(=O)O)c(F)c1)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 2.2 %

Procedure:
4-(1-Carboxy-1-methyl-ethylamino)-2-fluoro-benzoic acid (241 mg, 1 mmol), 4-isothiocyanato-2-trifluoromethylbenzonitrile (342 mg, 1.5 mmol) and triethylamine (343 mg, 3.4 mmol) were mixed in EtOH (5 mL) and the solution was stirred for 10 days at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 1M aqueous HCl, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography eluting with ethyl acetate to obtain 4-[3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-2-fluoro-benzoic acid (10 mg) as an off white solid.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[OH:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42]>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: O=C1CCCN1CCO
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Product: CC1=C(C(=O)OCCN2CCCC2=O)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml 1-(2-hydroxyethyl)-2-pyrrolidinone. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH3:42])=[C:10]([CH:41]=2)[C@@H:11]([C:29]2[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=2[CH3:40])[O:12]C(=O)[C@H](C2C=CC3C(=CC=C(OC)C=3)C=2)C)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[OH:12][C@H:11]([C:29]1[C:30]([CH3:40])=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][C:38]=1[CH3:39])[C:10]1[CH:41]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=[CH:8][C:9]=1[CH3:42]
Reactant: COC(=O)c1cc(C)c([C@@H](OC(=O)[C@@H](C)c2ccc3cc(OC)ccc3c2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2ccnc2)cc1[C@H](O)c1c(C)cc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Methyl (S)-4-[5-(1-imidazolyl)-α-{(S)-2-(6-methoxy-2-naphthyl)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate (47 g) obtained in Example 1 was suspended in methanol (376 ml) and an aqueous solution (95 ml) containing sodium hydroxide (8 g) was added, which was followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated and to the residue were added dimethylformamide (300 ml) and water (300 ml), which was followed by neutralization with glacial acetic acid (23 ml). The precipitated crystals were collected by filtration, washed with water and acetone, and recrystallized from dimethylformamide to give 25.3 g of (S)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, melting point 286-288° C. (decomposition), optical rotation [α]D21 -261.5° (c=1.0, dimethylformamide).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:23][CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[O:3]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reaction time: 48 h
Yield: 29.6 %

Procedure:
293 mg of 5-acetyl-8-benzyloxycarbostyril are dissolved in 15 ml of chloroform, and 200 mg of N-bromosuccinimide are added thereto. The mixture is refluxed for 2 hours under stirring. 300 mg of N-bromosuccinimide are added to the mixture and 4 hours after the commencement of the reaction, 100 mg of N-bromosuccinimide are further added thereto. Six hours after the reaction is started, the mixture is cooled and is allowed to stand at 20° C. for 2 days. Precipitated crystals are collected by filtration. Then, the crystals are washed with methanol and ether and then dried. 110 mg of 5-bromoacetyl-8-benzyloxycarbostyril are thereby obtained as colorless crystals. On the other hand, the filtrate is concentrated to dryness, and the residue is treated in the same manner as above, whereby 60 mg of 5-bromoacetyl-8-benzyloxycarbostyril are further recovered from the filtrate. Total yield: 170 mg (45.8%)
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1c2cc(-c3ccnc4[nH]ccc34)sc2C(=O)NC1(C)C
Yield: 30 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (183 mg, 0.75 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with 2:1 EtOAc/THF (100 mL×3), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH). The obtained yellow solid was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (46.9 mg, 30%) as a pale yellow solid:
Reaction SMILES: C[C:2]1([O:22][C@H:21]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C@@H:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C@H:5]1[O:6]C(=O)C)[O:3][CH3:4]>C(=O)([O-])[O-].[K+].[K+]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][O:11][C@@H:10]1[C@@H:21]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[O:22][CH:2]([O:3][CH3:4])[C@@H:5]1[OH:6]
Reactant: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O

Procedure:
The compound prepared in Step 3 above (85.75 g, 0.1636 mol) in 820 mL of saturated methanolic potassium carbonate was stirred at ambient temperature for 45 minutes and then concentrated in vacuo. The oily residue was suspended in 820 mL of CH2Cl2, washed with water (493 mL+5×328 1 mL) and brine (328 mL), dried (NaSO4), filtered, and concentrated to give the product. The oil (75.93 g, 0.1573 mol) was immediatedly used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:18][CH2:17]1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH2:30]([N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([O:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][N:10]=4)[N:4]=3)[CH2:21][CH2:20]2)[CH2:29][CH2:28]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cn1c(OC2CCN(CCC3CCNCC3)CC2)nc(-c2ccncn2)cc1=O
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(OC2CCN(CCC3CCN(Cc4ccccc4)CC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 710 %

Procedure:
To a mixture of 1-methyl-2-[1-(2-piperidin-4-yl-ethyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one (40 mg, 0.10 mmol), benzaldehyde (16 mg, 0.15 mmol) and acetic acid (one drop) in 1,2-dichloroethane (0.5 ml) was added sodium triacetoxyborohydride (53 mg, 0.25 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=20/80) to afford 2-{1-[2-(1-benzyl-piperidin-4-yl)ethyl]piperidin-4-yloxy}-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (35 mg, 0.71 mmol, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=[S:22])[CH2:13][N:14]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCc1cc2c(s1)NC(=O)CN=C2c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Yield: 99.7 %

Procedure:
5-(2-Chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one (40 g) was dissolved in chloroform (600 ml) and phosphorus pentasulfide (117 g) was added thereto with stirring. The mixture was refluxed for 3 hours. After the reaction, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and precipitated crystals were collected by filtration with diisopropyl ether and recrystallized from ethanol-chloroform to give 42 g of 5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione having a melting point of 198°-199° C. The thione compound obtained (42 g) was suspended in methanol (300 ml) and 100% hydrazine hydrate (19 ml) was added thereto under cooling. The mixture was stirred at room temperature for 2 hours. After the reaction, the precipitated crystals were collected by filtration and recrystallized from ethanol-dimethylformamide to give 34 g of 5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-hydrazine, melting point 214°-216° C. The hydrazone compound (20 g) was dissolved in chloroform (200 ml) and cyclohexylcarbonyl chloride (10 g) was added thereto with stirring. The mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was dissolved in toluene (200 ml) and acetic acid (5.4 ml) was added thereto. The mixture was refluxed for 3 hours. After the completion of the reaction, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. The objective fraction was concentrated under reduced pressure to give 15 g of 4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine, melting point 116°-119°πC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22]CC)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([OH:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of intermediate 6, ethyl 3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (0.300 g, 0.91 mmol) in ethanol (10 ml) was treated with 3 ml (3.0 mmol) of 1 N sodium hydroxide and stirred at 25° C. for 30 min. The solution was then acidified with 1 N hydrochloric acid, extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.264 g (96% yield) of the title acid as white crystals; mp 171° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 4.03 (2H, t, J=5.3 Hz, CH2), 4.12 (2H, t, J=5.3 Hz, CH2), 4.73 (2H, s, OCH2), 5.53 (2H, s, OCH2), 7.35–7.42 (3H, m, aromatics), 7.53 (2H, m, aromatics). Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found: C, 59.35; H, 4.69; N, 9.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16]O)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][N:48]4[C:44](=[O:54])[C:45]5[C:46](=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:47]4=[O:49])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1Cc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 6. 68 mg, 0.213 mmol), triphenyl phosphine (168 mg, 0.64 mmol) and phthalimide (63 mg, 0.43 mmol) are dissolved in dry THF (3 mL). The stirred solution is cooled to 0° C. and diethyl azodicarboxylate (105 mg of 85% grade, 0.51 mmol) is added dropwise. The solution is stirred at 0° C. for 2 h during which time a white solid deposits and then stirred for 16 h at room temperature. The solution is then diluted with ether (20 mL) and the deposited solid filtered off. The solid is washed with ether and dried to give the first batch of product (20 mg). The ether solution is then washed with water and then extracted with dilute hydrochloric acid. A portion of the product deposits and is filtered off, washed twice with ether and dried to give the product as the hydrochloride salt (16 mg). The acidic phase is washed with ether and then made alkaline with sodium bicarbonate solution. Extraction with ethyl acetate (50 mL×3) followed by drying (MgSO4) and concentration gives the product as an off-white solid (32 mg). 1H NMR (d6-DMSO) δ 4.83 (s, 2H), 6.91 (dd, J=1.8, 7.2 Hz, 1H), 7.22 (t, J=8.9 Hz, 2H), 7.26 (d, J=5.9 Hz, 2H), 7.49 (dd, J=5.6, 8.6 Hz, 2H), 7.71 (s, 1H), 7.81–7.89 (m, 4H), 8.54 (d, J=4.7 Hz, 2H), 8.72 (d, J=7.1 Hz, 1H); APESI-MS m/z 449 (M+1)+
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([CH3:17])[CH:4]=1)=[O:2].[Si]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(C(C)(C)C)(C)C>>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][C:5]=2[CH3:17])=[CH:28][CH:27]=1
Reactant: Cc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Product: Cc1cc(C=O)ccc1-c1ccc(O)cc1

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 4-formyl-2-methyl-phenyl ester (9.3 mmol) with 4-tert-butyl-dimethylsilyoxyphenylboronic acid (2.35 g, 9.3 mmol) according to Method B to yield 1.12 mg (57%, over two steps) of yellowish solid: mp 94-96° C.; 1H NMR (DMSO-d6): ): δ 2.33 (3H, s), 6.86 (2H, d, J=8.55 Hz), 7.22 (2H, d, J=8.51 Hz), 7.39 (1H, d, J=7.81 Hz), 7.61 (1H, d, J=7.82 Hz), 7.81 (1H, s), 9.65 (1H, s), 10.00 (1H, s); IR 1670 cm−1; MS (ESI) m/z 211 (M−H)−, 213 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:7])[CH2:5][CH3:6].[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=O>C1COCC1>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH2:3][C:4](=[O:7])[CH2:5][CH3:6]
Reactant: CCC(C)=O
Reactant: COC(=O)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)CCCCCl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil: 8.88 g) in THF (250 mL) was added a mixture of 2-butanone (7.98 g) and methyl 5-chlorovalerate (50.0 g) in THF (100 mL) dropwise via cannula at 0° C. The mixture was stirred at 0° C. for 10 min and at rt for 24 h. After the reaction was quenched with 2 N—HCl (200 mL), the aqueous layer was extracted with EtOAc (3×). Concentration of the combined organic phase gave a brown colored oil, which was purified by fractional vacuum distillation. The title compound was collected in the temperature range between 95° C. and 110° C. at 10 mmHg. 1H NMR (500 MHz, CDCl3) δ 1.14 (t, 3H, J=7.4 Hz), 1.65-1.90 (m, 4H), 2.30-2.60 (m, 4H), 3.50-3.60 (m, 2H), 5.51 (s, 1H).
Reaction SMILES: [C:1](=[NH:20])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:21]([CH:23]([CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=1)[C:24](OC)=O)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([CH2:28][C:23]2[C:21](=[O:22])[N:20]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:24]=2)=[CH:34][N:33]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: Cc1cccc(Oc2ccc(CCOC(=N)N)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cccc(C)n4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 4.6 %

Procedure:
To the solution of 2-{4-[(6-methyl-2-pyridinyl)oxy]phenyl}ethyl imidocarbamate (200 mg, 0.737 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (182 mg, 0.811 mmol) in NMP (3 mL) was added K2CO3 (408 mg, 2.95 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (15 mg, 4.57% yield). LCMS: rt=2.54 min, [M+H+]=447
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:18])[CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:7]=1[F:19])(=O)C>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:18])[CH2:13][NH:14][CH:15]([CH3:16])[CH3:17])=[CH:8][C:7]=1[F:19]
Reactant: CC(=O)Nc1ccc(C(O)CNC(C)C)cc1F
Agent: Cl
Product: CC(C)NCC(O)c1ccc(N)c(F)c1

Procedure:
m.p. of the hydrochloride: 156°-158° C. (decomp.), was prepared from 1-(4'-acetylamino-3'-fluoro-phenyl)-2-isopropylamino-ethanol analogous to Example 4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[N:7][OH:8])[NH2:6].[C:12](Cl)(=O)[CH3:13]>N1C=CC=CC=1>[CH3:12][C:13]1[O:8][N:7]=[C:5]([C:4]2[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: CC(=O)Cl
Reactant: NC(=NO)c1cccc(O)c1
Solvent: c1ccncc1
Product: Cc1nc(-c2cccc(O)c2)no1

Procedure:
3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenol was prepared using 3-hydroxybenzamidoxime (1 g, 6.6 mM) and acetyl chloride (0.52 g, 6.7 mM) in pyridine (4 mL) according to Preparation 62 to provide 0.66 g of a white powder; m.p., 87-89° C.