Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][CH:3]1OC.[C:22]1([S-:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+].CN([CH:33]=[O:34])C>>[CH3:9][O:8][C:7]1[CH:2]=[CH:12][C:13]2[C:5](=[CH:4][CH:3]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:34][CH3:33])[CH:17]=3)[CH:14]=2)[C:6]=1[S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C=O
Reactant: COC1=CC=CC(OC)C1(Br)c1cccc2ccccc12
Reactant: [S-]c1ccccc1
Agent: [Na+]
Product: COc1cccc(-c2ccc3c(Sc4ccccc4)c(OC)ccc3c2)c1
Temperature: 25 °C

Procedure:
A mixture of 1-bromo-2-methoxy-6-methoxyphenylnaphthalene (850 mg, 2.47 mmol, 1 eq), sodium benzenthiolate (391 mg, 2.96 mmol, 1.2 eq) and anhydrous DMF (10 ml) was refluxed under nitrogen for 11 hours. After cooling to room temperature, the mixture was poured onto ice. The precipitate was filtered off, washed with water and dried. Yield: 385 mg, 42%.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([NH:23][C@H:24]([C:32]([OH:34])=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[NH:35]([CH3:54])[C@H:36]([C:38]([NH:40][C@H:41]([C:50]([O:52][CH3:53])=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH3:37]>C(OC(=O)C)C>[NH:23]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:24]([C:32]([N:35]([CH3:54])[C@H:36]([C:38]([NH:40][C@H:41]([C:50]([O:52][CH3:53])=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH3:37])=[O:34])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
The procedure of Example 1 is followed using 1 liter of ethylacetate, 30.68 ml of isobutyl chloroformate, 26.00 ml of N-methylmorpholine, 62.72 grams of BOC-phenylalanine and 68 grams of N-Me-Ala-Tyr-OMe affording 3 crops of product as follows:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]O)#[N:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:31]([C:33]1[CH:34]=[C:35]([CH2:36][O:13][C:14]2[CH:15]=[C:16]([O:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:38]=[CH:39][CH:40]=1)#[N:32]
Reactant: N#Cc1cccc(CO)c1
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Diethyl azodicarboxylate (174 mg, 1.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285 mg, 1.0 mmol), as prepared in the preceding step, 3-cyanobenzyl alcohol (133 mg, 1.0 mmol)(Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofyiran (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated NaHCO3 (2×30 mL), brine (2×30 mL) and dried over Na2SO4. The solvent was removed in vacuo the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (375 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 5.02 (s, 2 H), 6.78 (m, 2H), 6.85 (dd, 1H, J=4.2, 1.3 Hz), 7.20 (t, 1H, J=8.2 Hz), 7.38 (t, 1H, J=5.8 Hz), 7.51 (t, 1H, J=7.7 Hz), 7.59-7.68 (m, 5 H) and 7.93 (dd, 1 H, J=4.0, 0.7 Hz).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[CH:21][C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[CH:15][C:14]([C:23]3[CH:28]=CC(C(Br)Br)=[CH:25][CH:24]=3)=[N:13]4)[N:10]=2)=[CH:5][CH:4]=1.[OH-:33].[Na+].[C:35]([OH:39])(=O)[CH2:36][CH3:37]>>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[CH:21][C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[CH:15][C:14]([C:23]3[CH:28]=[CH:37][C:36]([CH:35]=[O:39])=[CH:25][CH:24]=3)=[N:13]4)[N:10]=2)=[CH:5][CH:4]=1)=[O:33]
Reactant: [OH-]
Reactant: CCC(=O)O
Reactant: BrC(Br)c1ccc(-c2ccc3ccc4ccc(-c5ccc(C(Br)Br)cc5)nc4c3n2)cc1
Agent: [Na+]
Product: O=Cc1ccc(-c2ccc3ccc4ccc(-c5ccc(C=O)cc5)nc4c3n2)cc1
Reaction time: 1 h

Procedure:
Compound (3) (2.00 g, 2.96 mmol) and powdered NaOH (0.71 g, 17.7 mmol) were refluxed in propionic acid (15 mL) for 6 h under argon. The propionic acid was evaporated under reduced pressure and replaced with THF (25 mL) and 2M NaOH (5 mL). The solution was stirred for 1 h, and then the THF was evaporated. Water (20 mL) was added and the pH adjusted to ~8 with HCl. The solution was extracted with CH2Cl2 (3×100 mL). Yield 0.92 g (80%). 1H NMR (CDCl3) δ8.38 (s, 2H), 8.64 (d, J=8.4 Hz, 4H), 8.42 (d, J=8.4 Hz, 2H), 8.25 (d, J=8.4 Hz, 2H), 8.13 (d, J=8.4 Hz, 4H), 7.89 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].F[C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:18])=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1>CC(N(C)C)=O>[OH:5][CH2:4][CH2:3][O:6][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:18])=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: Oc1ncnc2cc(F)ccc12
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: OCCOc1ccc2c(O)ncnc2c1
Temperature: 60 °C
Yield: 45.1 %

Procedure:
A mixture of sodium hydride (60% in oil, 7.67 g, 189.6 mmol) and dimethylacetamide (160 ml) were cooled in an ice-bath under a nitrogen atmosphere and then ethylene glycol (18.2 g, 284 mmol) was slowly added. The reaction mixture was warmed to 60° C. for 10 minutes and then 7-fluoroquinazolin-4-ol (7.75 g, 47.3 mmol) was slowly added. The reaction mixture was heated to 110° C. for 16 hours and then the mixture was concentrated to approximately half volume. The mixture was poured into water and the pH of the solution was adjusted to 5 with dilute hydrochloric acid. The resultant precipitate was filtered and then dried in a vacuum oven at 65° C. for 16 hours. The residue was triturated with diethyl ether to give 7-(2-hydroxyethoxy)quinazolin-4-ol (4.4 g) as an off white solid which was used in subsequent steps without further purification: MS (+ve ESI): 207 (M+H)+ MS (−ve ESI): 205 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([Br:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[C:33]([CH2:35][C:36](OCC)=[O:37])#[N:34]>CN1C(=O)CCC1>[Br:32][C:16]1[CH:17]=[C:18]([F:31])[C:19]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:23])=[CH:20][C:15]=1[C:7]1[C:8](=[O:14])[N:9]([CH2:12][CH3:13])[C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:1][C:36](=[O:37])[CH2:35][C:33]#[N:34])[CH:11]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(N)cc21
Reactant: CCOC(=O)CC#N
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(NC(=O)CC#N)cc21
Temperature: 125 °C
Reaction time: 48 h
Yield: 8.5 %

Procedure:
A suspension of Example 57 (135 mg, 0.272 mmol) in ethyl cyanoacetate (2.307 g, 20.40 mmol) was heated at 105° C. for 4.5 h, then at 125° C. for 2 days. The mixture was treated with NMP (0.3 mL), heated at 125° C. for 5 h, then cooled to RT and purified via silica gel chromatography (EtOAc/Hex). The material was re-purified via silica gel chromatography (THF/Hex), dissolved in 4:1 MeCN/H2O, frozen and lyophilized. The material was treated with MTBE, the resulting solid collected via filtration and dried to afford N-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (13 mg, 8.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.10 (s, 1H), 8.74 (m, 2H), 8.23 (d, J=8.5 Hz, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.70 (d, J=10.7 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 565.1 [M+H]+.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1OC)[CH2:6][NH2:7].C(=C(O)[C@H](O)[CH:18]=[O:19])(C)C.S([O-])([O-])(=O)=[O:23].[Mg+2].COC1C=C(C=CC=1OC)CN=C[C@H](C(=C(C)C)O)O.C(N(CC)CC)C>C(Cl)Cl>[C:18]1(=[O:19])[NH:7][C:6](=[O:23])[C:5]2=[CH:8][CH:9]=[CH:10][CH:3]=[C:4]12
Reactant: CC(C)=C(O)[C@H](O)C=O
Reactant: COc1ccc(CN)cc1OC
Reactant: O=S(=O)([O-])[O-]
Agent: COc1ccc(CN=C[C@@H](O)C(O)=C(C)C)cc1OC
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 3,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4 Å and after 20 minutes 0.7 g (5.4 mmol) of isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for 1 hour. The resulting organic solution of isopropylidene-L-glyceraldehyde (3,4-dimethoxybenzyl)imine is cooled to -20° under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. Then, a solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is added dropwise thereto within 1 hour and the mixture is subsequently stirred overnight at room temperature. The mixture is worked-up as described in Example 1 and there are obtained after chromatography 1.56 g (62%) of N-(3S,4S)-cis-1-(3,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [α ]D =+16.2° (c=1.0 in methanol); MS: 466 (M+).
Reaction SMILES: [Li]CCCC.[Si]([CH:10]=[N+:11]=[N-:12])(C)(C)C.[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:16][CH2:15]1>C1COCC1>[C:22]([O:21][C:19]([NH:18][C@@H:17]([CH2:16][CH2:15][C:14](=[O:13])[CH:10]=[N+:11]=[N-:12])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC(=O)C=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
n-BuLi was added dropwise to a solution of TMSCHN2 (690 mL, 1.38 mol) in dry THF (3 L) (600 mL, 1.5 mol) at −78° C., and the mixture was stirred at −78° C. for 30 min. The mixture was then transferred to a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (300 g, 1.17 mol) in dry THF (3 L) via cannula, and the mixture was stirred at −78° C. for 30 min. The reaction mixture was then quenched with sat. NH4Cl solution, and extracted with DCM three times. The combined organic layer was concentrated in vacuum and the crude product was purified by silica gel column chromatography (3:1 petroleum ether:EtOAc) to afford (S)-ethyl 2-((tert-butoxycarbonyl)amino)-6-diazo-5-oxohexanoate (262 g, 75%) as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]([C:26]([OH:28])=[O:27])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2].CO.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:3]([C:26]([OH:28])=[O:27])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCC(C(=O)O)N(CCCCc1ccc([N+](=O)[O-])cc1)c1cccc(C#N)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C(=O)O)N(CCCCc1ccc(N)cc1)c1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Part D. A solution of ethyl N-[4-[4-nitrophenyl]butyl]-N-[3-cyanophenyl]glycine (0.31 gm, 0.81 mmol) and 20 mL methanol:ethyl acetate (v:v, 50:50) was degassed with nitrogen in a Parr shaker bottle, then 10% palladium on carbon was added. The reaction was charged to 50 PSI hydrogen and shaken for 1/2 hr. The catalyst was filtered off over celite, the filtrate concentrated and the product purifed by flash chropmatography on silica gel eluting ethyl acetate:methylene chloride (v:v, 10:90) to give ethyl N-[4-[4-aminophenyl]butyl]-N-[3-cyanophenyl]glycine as a semisolid 0.27 gm (94%). MS 352(M+H)+ 1 H NMR (CDCl3): 7.2(m, 1H), 7.0(m, 3H), 6.8(m, 2H), 6.6(d, 2H), 4.2(q, 2H), 4.0(s, 2H), 3.6(bs, 2H), 3.4(m, 2H), 2.6(m, 2H), 1.6(m, 4H), 1.2(t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.[CH2:27]([OH:33])[CH2:28][O:29][CH2:30][CH2:31][OH:32]>>[OH:33][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:25][CH:24]([CH2:22][O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[OH:26]
Reactant: OCCOCCO
Reactant: ClCC1CO1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOCC(O)COCCOCCO
Yield: 65.1 %

Procedure:
14.9 g (50 millimole) of 3,7,11,15-tetramethylhexadecanol, 18.5 g (200 millimole) of epichlorohydrin and 106 g (1 mole) of diethylene glycol were treated by following a procedure similar to that of Working Example 4, and purification by silica gel column chromatography (Merck Co., Art. 7734, 400 g, Eluant: hexane-ethyl acetate-acetone=3:1:1-2:1:1) was carried out, to give 15 g (65%) of the above-captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[CH:12]([O-:14])=O.[NH4+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>O1CCCC1.CO.C(OCC)C.[Pd]>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:4]([C:3]2[CH:2]=[N:8][C:7]3[C:6]([C:12]=2[OH:14])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=3[F:1])=[O:11])=[CH:19][CH:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(O)cc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 10% Pd/C and 2.0 g of 3-fluoro-4-nitrophenol in 10 mL of tetrahydrofuran and 10 mL of methanol is added 4.817 g of ammonium formate. After the reaction stirred at room temperature for 1 h, it is filtered through celite and condensed. To the residue is then added 2.57 mL of diethylethoxymethylenemalonate and 10 mL xylene. The mixture is heated to 135 ° C. for 1 h with a Dean-Stark trap to remove formed ethanol. The reaction is cooled. The resulting solid is collected, washed with hexanes, and dried. The solid is then dissolved in 50 mL of diphenyl ether and heated to 250° C. for 3 h with a Dean-Stark trap to collect ethanol. The solution is cooled and diluted with hexanes. The resulting solid is collected and dried to yield 0.527 g. A solution of 0.415 g of that solid in 4 mL of 4-chlorobenzylamine is heated to 180° C. for 1 h. The solution is cooled and diluted with diethyl ether. The resulting solid is collected and recrystallized from acetone/hexanes to yield 0.226 g of the title compound as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[NH:12]C(=O)C(F)(F)F)[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[NH2:12][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c(NC(=O)C(F)(F)F)ccc2ocnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCc1c(N)ccc2ocnc12
Temperature: 90 °C

Procedure:
A solution of 4-ethyl-5-trifluoroacetamidobenzoxazole (14.13 mmol) in a 20% mixture of water in methanol (20 mL) is treated with anhydrous potassium carbonate (56.52 mmol). A reflux condenser is attached and the mixture is heated to 90° C. with an oil bath for five hours. The mixture is cooled to room temperature and distributed between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a black residue. This material is purified by chromatography (silica gel, 50% ethyl acetate/hexanes) to afford 5-amino-4-ethylbenzoxazole.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].[Cl:10][CH:11]([C:15]1[O:20][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:17]=2[N:16]=1)[CH2:12][CH2:13][CH3:14]>O1CCCC1.C([Li])CCC.CCCCCC>[Cl:10][CH:11]([CH2:12][CH2:13][CH3:14])[C:15]([NH:16][C:17]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](=[O:21])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:20]
Reactant: CCCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 72.6 %

Procedure:
Using the procedure of Step A of Example 6, a solution of 6.94 g of N-(2-thiazolyl)-acetamide in 280 ml of tetrahydrofuran and 70 ml of a butyllithium-hexane solution and a solution of 7.8 g of the product of Step A in 40 ml of tetrahydrofuran were reacted to obtain 8.3 g of 2-[(2-chloro-1-oxo-pentyl)-amino]-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene propanamide melting towards 184°-186° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])[CH2:17][CH2:16]2)[CH:10]=3)[CH2:3][CH2:2]1.[CH2:26](N(CC)CC)C.[S:33](Cl)(Cl)(=[O:35])=[O:34].Cl>C1COCC1>[CH3:26][S:33]([O:25][CH:23]([CH3:24])[CH2:22][CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([N:11]2[CH:10]=[C:9]3[C:13]([CH:14]=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:7]=[CH:8]3)=[N:12]2)[CH2:16][CH2:17]1)(=[O:35])=[O:34]
Reactant: CC(O)CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: CC(CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1)OS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 4-{trans-4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]cyclohexyl}butan-2-ol (2.45 g) and triethylamine (1.50 mL) in THF (50 mL) was added dropwise a solution of sulfonyl chloride (0.83 mL) in THF (50 mL) under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. The reaction mixture was poured into 1N hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.98 g).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[CH3:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](/[CH:19]=[C:20](/[C:23](=O)[CH3:24])\[C:21]#[N:22])[CH:17]=2)[NH:12][N:11]=1.C([O-])(=O)C.[NH4+:30]>C(O)(=O)C>[CH3:24][C:23]1[NH:30][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[CH3:9])[C:20]=1[C:21]#[N:22]
Reactant: O=C1CCCC(=O)C1
Reactant: [NH4+]
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(CCCC2=O)N1

Procedure:
273 mg (2.442 mmol) cyclohexane-1,3-dione, 500 mg (2.222 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A) and 205 mg (2.664 mmol) ammonium acetate in acetic acid (5 ml) were heated to 50° C. overnight. Then, additional ammonium acetate (102 mg, 1.332 mmol) was added, and the mixture was heated to reflux for 24 h. After cooling, the mixture was evaporated to dryness, and the residue was taken up in ethyl acetate and washed with water twice. The combined aqueous phases were extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate. After filtration and evaporation to dryness, the remaining solid was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 55 mg (8% of th.) of the title compound.
Reaction SMILES: C[N:2]([C@@H:10]([CH3:26])[C:11](=[O:25])[NH:12][C@H:13]1[CH2:19][O:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])[C:3](=O)OC(C)(C)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:15]2[C:14](=[O:24])[C@@H:13]([NH:12][C:11](=[O:25])[C@@H:10]([NH:2][CH3:3])[CH3:26])[CH2:19][O:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]2=3)=[CH:30][CH:31]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2ccc(Cl)cc2)C1=O
Yield: 61.2 %

Procedure:
In a similar manner to that described for Example 45 except in Step 2 the material obtained after chromatography was not triturated, tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate (173 mg, 476 iumol) and 1-(bromomethyl)-4-chlorobenzene (103 mg, 500 μmol) were converted to the title compound (113 mg) as an off-white foam. HRMS: calcd. for C20H22N3O3Cl: (MH+) 388.1422. found 388.1423.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O)C.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1C=O>C(OCC)(=O)C>[S:14]1[CH:15]=[CH:16][CH2:17][C:18]1=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: O=Cc1cccs1
Reactant: CCOP(=O)(CN)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN=C1CC=CS1)OCC
Yield: 100 %

Procedure:
A solution of 16.7 g. (0.1 mol) diethyl aminomethylphosphonate in 200 ml. absolute ethanol is treated with 11.2 g. (0.1 mol) thien-2-aldehyde and the resulting mixture is heated under reflux and then evaporated to give 26 g. diethyl N-thien-2-ylidene-aminomethylphosphonate (yield: about 100%) in the form of a yellow oil giving a single spot in TLC (silica plate; eluant: ethyl acetate).
Reaction SMILES: [CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.Cl>O1CCOCC1.C([O-])(O)=O.[Na+]>[CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COc1ccccc1
Product: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Yield: 97.3 %

Procedure:
To a suspension of 110 mg of 10o in 1 ml of dioxane, was added 75 μl of anisole and 500 μl of 4N HCl in dioxane. After 1 hr the reaction mixture was diluted with 10 ml of sat. NaHCO3 and the product was extracted with ethyl acetate. The organic layer was washed once with sat. NaCl, dried and concentrated. The residue was triturated with diethyl ether, to provide 90 mg of 10q as white crystalline material. Mp: 250-252° C.; Rf 0.60 (CH2Cl2/methanol 8/2);
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[CH:11]1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[CH:11]1
Reactant: O=c1ccn(CCOC2CCCCO2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1ccn(CCO)cc1
Yield: 71.2 %

Procedure:
A solution of 1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (500 mg, 2.23 mmol) in acetic acid (4 ml), THF (2 ml) and water (1 ml) was heated at 45° C. for 4 hours. The volatiles were removed by evaporation to give 1-(2-hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 71%) as an off-white solid. 1H NMR Spectrum: (DMSOd6) 3.70(t, 2H); 4.06(t, 2H); 6.95(d, 2H); 8.37(d, 2H)