Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]([O:21][CH3:22])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH2:19][OH:20])[CH:7]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH2:19][O:20][CH3:29])[C:5]([O:21][CH3:22])=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1
Reactant: COc1c(/C=C/c2ccc([N+](=O)[O-])cc2CO)cc(Br)cc1C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1cc([N+](=O)[O-])ccc1/C=C/c1cc(Br)cc(C(C)(C)C)c1OC
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
step 2—To a solution of 312 (116 mg, 0.276 mmol) in DMF (5 mL) was added sodium hydride (0.022, 0.550 mmol, 60% mineral oil dispersion). After 20 min, methyl iodide (0.040 mL, 0.643 mmol) was added and the resulting suspension was stirred overnight. The reaction mixture was diluted with EtOAc, thrice washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5% to 15% EtOAc) to afford 81 mg (68%) of 5-bromo-1-tert-butyl-2-methoxy-3-[(E)-2-(2-methoxymethyl-4-nitro-phenyl)-vinyl]-benzene (314) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=O)=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:41]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([OH:41])=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(NC(=O)OCc4ccccc4)c(C=O)c3O2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(NC(=O)OCc4ccccc4)c(O)c3O2)cc1
Reaction time: 8 h
Yield: 41.4 %

Procedure:
A solution of {(2R)-7-{[(benzyloxy)carbonyl]amino}-8-formyl-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.45 g, 8.95 mmole) in methylene chloride (50 mL) was added dropwise to a solution of m-chloroperoxybenzoic acid (6.45 g, 22.4 mmole) in methylene chloride (120 mL). The reaction was stirred under nitrogen overnight. After dilution to 300 mL in volume, it was washed with saturated sodium bicarbonate (2×200 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated to dryness. A H1 NMR spectra was taken of the crude product and it was determined to be the formate ester. Cleavage was effected by stirring in methanol over basic alumina overnight. After filtration and evaporation, the product was purified by column chromatography on silica gel with hexane to remove the impurities, and the product eluted with methylene chloride to give the (R)-enantiomer of the title compound as a yellow oil (1.80 g, 40%). 1H (CDCl3) doublet 7.8 δ (2 H); multiplet 7.2-7.4 δ (7 H); broad singlet 7.0 δ (1 H); doublet 6.4 δ (1 H); singlet 5.2 δ (2 H); multiplet 4.4 δ (1 H); multiplet 4.2 δ (3 H); multiplet 4.0 δ (1 H); singlet 2.4 δ (3 H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].C(OC([NH:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=O)(C)(C)C>CS(C)=O>[NH2:30][C@H:31]1[CH2:35][CH2:34][N:33]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C@@H:14]3[CH2:16][C@@H:15]3[F:17])=[C:3]([CH3:22])[C:2]=2[F:1])[CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CS(C)=O
Product: Cc1c(F)c(N2CC[C@H](N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 68.6 %

Procedure:
A mixture of 100 mg of 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 120 mg of (S)-3-t-butoxycarbonylaminopyrrolidine, and 3 ml of anhydrous dimethyl sulfoxide was heated at 100° to 120° C. for 1 hour with stirring, and dimethyl sulfoxide was removed under reduced pressure. Water was added to the residue, and the precipitated yellow crystals were collected by filtration. Three milliliters of trifluoroacetic acid was stirred under ice-cooling, and the above-obtained yellow crystals were slowly added thereto, followed by stirring at room temperature for 30 minutes. The trifluoroacetic acid was removed under reduced pressure, and the residue was dissolved in a 1N sodium hydroxide aqueous solution (pH 12). The solution was neutralized with 1N hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and aqueous ammonia. The resulting crystals were collected by filtration, washed with ethanol, and dried to yield 83 mg of the titled compound as a pale yellow crystal.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH2:10][C:11](=[O:13])[N:12]=1.[N:14]1[C:23]2[C:18](=[N:19][C:20]([CH:24]=O)=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[N:19]1[C:18]2[C:23](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:22]=[CH:21][C:20]=1[CH:24]=[C:10]1[S:9][C:8]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:12][C:11]1=[O:13]
Reactant: O=C1CSC(NCc2cccs2)=N1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1N=C(NCc2cccs2)SC1=Cc1ccc2ncccc2n1
Temperature: 120 °C
Yield: 34.9 %

Procedure:
To a suspension of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one (34.0 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 120° C. with microwave for 5 min, then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 5-[1,5]naphthyridin-2-ylmethylene-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a light brown solid (19.7 mg, 34.9%). HR-ES (+) m/e calcd. for C17H12N4OS2: (M+H)+ 353.0526. Found: 353.0526.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:17](=[N:20][OH:21])[C:18]#[N:19])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C([N:24](CC)CC)C.NO.O>C1COCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:17]3[C:18]([NH2:24])=[N:19][O:21][N:20]=3)[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CCN(CC)CC
Reactant: N#CC(=NO)c1nc2cnc(Br)cc2n1-c1ccccc1
Agent: NO
Solvent: O
Solvent: C1CCOC1
Product: Nc1nonc1-c1nc2cnc(Br)cc2n1-c1ccccc1
Temperature: 120 °C
Yield: 60 %

Procedure:
The product from Step 6 (2.7 g, 7.93 mmol) in THF (5 mL) and triethylamine (1.1 mL, 7.93 mmol) was treated with a 50% solution of hydroxylamine in water (0.24 mL, 7.93 mmol). The mixture was heated at 120° C. in a sealed tube for 10 h and the reaction allowed to cool to room temperature. The resulting precipitate was filtered and dried in vacuo to afford the title compound (1.7 g, 60%). MS (ES+) m/e 357/359 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[C:3]1=[O:28].CCN(CC)CC.[C:36](Cl)(=[O:40])[CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[C:36]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:13][N:4]3[C:5](=[O:12])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]([CH3:1])[C:3]3=[O:28])[CH2:15][CH2:16]2)=[O:21])[CH2:23][CH2:24]1)(=[O:40])[CH2:37][CH2:38][CH3:39]
Reactant: CCCC(=O)Cl
Reactant: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)N3CCNCC3)CC2)c(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCN(C(=O)[C@H]2CC[C@H](Cn3c(=O)c4ccccc4n(C)c3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.26 mmol) of 1-Methyl-3-[trans-4-(piperazine-1-carbonyl)-cyclohexylmethyl]-1H-quinazoline-2,4-dione was dissolved in DCM (3 ml). 75 μL (0.52 mmol) of Et3N and then 41 μL (0.39 mmol) of butyryl chloride were added and the mixture was stirred at room temperature overnight. The solution was washed with a 0.4 M solution of Na2CO3, the organic phase was separated and dried over Na2SO4. The solvent was removed under reduced pressure and the crude material purified by column chromatography using acetone as eluent. In total 28 mg (yield 24%) of the titled compound were isolated.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH:16]3[NH:19][C:20](=[O:41])/[C:21](=[CH:26]/[C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]4)=[C:29]([O:39][CH3:40])[CH:28]=3)/[CH2:22][CH2:23][CH2:24]Cl)=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.O.C(OCC)(=O)C>CN(C=O)C>[CH3:40][O:39][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1)/[CH:26]=[C:21]1/[C:20](=[O:41])[N:19]([CH:16]2[C:17]3[C:12](=[CH:11][CH:10]=[C:9]([N:3]4[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[CH:18]=3)[CH2:13][CH2:14][CH2:15]2)[CH2:24][CH2:23][CH2:22]/1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC2CCCc3ccc(N4CCOCC4)cc32)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C2\CCCN(C3CCCc4ccc(N5CCOCC5)cc43)C2=O)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Sodium hydride (containing mineral oil at 40%, 37.8 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-benzylidene)valeric acid (7-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-1-yl)amide (213 mg) in DMF (5.0 mL) at 0° C., and the reaction solution was stirred for 30 minutes. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 195 mg of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-1-(7-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-2-one as a racemate.
Reaction SMILES: Cl[CH:2]([C:7]1[O:8][C:9]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=2[C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:9]2[O:8][C:7]([CH:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])=[C:11]([CH3:12])[C:10]=2[CH:13]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc2oc(C(Cl)CC(C)C)c(C)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2oc3ccc(OC)cc3c2C)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
A mixture of 2-(1-chloro-3-methylbutyl)-5-methoxy-3-methyl-1-benzofuran (380 mg) synthesized in Example A92(2), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (370 mg) synthesized in Example 2(2), sodium iodide (443 mg), sodium carbonate (314 mg) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% ethyl acetate/hexane) to give the title object compound (350 mg, 51%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10](Br)[CH:11]=1)=[O:5])[CH3:2].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[CH:31][CH:32]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2ccc(OC3CCCCO3)cc2)nc2c1c(C)nn2C1CCCCO1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a mixture of 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (6.00 g), 4-(tetrahydro-2H-pyran-2-yloxy)-phenylboronic acid (4.34 g) and potassium carbonate (2.93 g) in DME/water (v/v=2/1, 200 mL) was added at r.t. under Ar-atmosphere palladium(0) bis(tri-tert-butylphosphine) (0.42 g) and the mixture was stirred at 85° C. for 90 min. To the mixture water was added and it was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to give 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (7.00 g, 92%). This material was dissolved in isopropanol (30 mL), and 1N sodium hydroxide solution (15 mL) was added. The solution was stirred overnight, then the mixture was contentrated in vacuo to about a third of its volume. The precipitated solid was isolated by filtration and dried in air giving the sodium salt of 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (6.2 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:12])[CH:3]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].N1CCCC1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CCOC(C)=O>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:15]2[CH2:16][CH2:17][CH2:14][CH2:13]2)=[O:8])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: O=C(c1cc(F)c(Br)cc1Cl)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirring solution of 4-bromo-2-chloro-5-fluorobenzoic acid (50 g, 0.25 mol) in 200 mL of EtOAc at 0° C. (ice/water bath) was added triethyl amine (237 mL, 0.50 mol), pyrrolidine (41.2 mL, 0.5 mol), followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (CAS #68957-94-8) (237 mL, 0.37 mol, 50 wt %, EtOAc). After 1 hr, the reaction was quenched with a saturated solution of NaHCO3, and extracted with EtOAc, and CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification of this material was accomplished by flash column chromatography using a Biotage™ 75 L column, eluting with a gradient of 2%-50% EtOAc/hexanes. The product containing fractions were collected and concentrated to give the title compound (52 g, 68% yield) as a white solid: Rf=0.23 (40% EtOAc/hexanes); LRMS m/z Calcd for C11H10BrClFNO, 306.6, found, 306, 308, 310 (M+1) APCI; 1H NMR (300 MHz, CDCl3): δ 7.53 (d, J=6.2 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 3.54 (apt t, J=6.6 Hz, 2H), 3.13 (apt t, J=6.6 Hz, 2H), 1.92-1.83 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 164.5, 158.1 (d, JC-F=249.5 Hz), 138.2, 134.3, 126.0, 115.5 (d, JC-F=25.5 Hz), 110.3 (d, JC-F=22.5 Hz), 47.0, 45.8, 26.0, 24.6.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].OB(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:21]([C:17]1[CH:16]=[C:15]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a mixture of 3-bromopyridine (2.6 ml) and tetrakis(triphenylphosphine)palladium(0) (0.93 g) in toluene (50 ml) was added 2M aqueous solution of sodium bicarbonate (27 ml) and a solution of dihydroxy(3-nitrophenyl)borane (5.0 g) in methanol (12 ml). The mixture was stirred at 80° C. for 6 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:7)) to give 3-(3-nitrophenyl)pyridine (3.57 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:14])=[CH:12][S:13][C:7]2=[N:6][C:5]=1[CH3:15].Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:14])=[CH:12][S:13][C:7]4=[N:6][C:5]=3[CH3:15])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A mixture of 3.75 parts of 6-(2-chloroethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5 -one, 3.6 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 12 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone was stirred and refluxed for 22 hours using a water-separator. The reaction mixture was filtered hot over Hyflo and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 5 parts of 6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 199.7° C. (compound 4).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][CH2:27][CH:28]([NH2:31])[CH2:29][CH3:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[NH:31][CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCC(N)CC
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC(CC)CC)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and pentan-3-amine as a pale-yellow solid (78%). 1H NMR (400 MHz, DMSO-d6) δ 0.68 (t, J=8.0 Hz, 6H), 1.27 (s, 6H), 1.31 (t, J=8.0 Hz, 3H), 1.37-1.42 (m, 4H), 2.54 (s, 3H), 3.56-3.61 (m, 1H), 4.16 (s, 2H), 4.30 (q, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.06 (s, 2H). MS 416 (MH+).
Reaction SMILES: Br[C@H:2]([C@H:5]1[CH2:7][O:6]1)[CH2:3][CH3:4].[CH:8]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:15]1([CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:21]2[CH2:7][C@H:5]([OH:6])[C@@H:2]2[CH2:3][CH3:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC[C@H](Br)[C@H]1CO1
Reactant: NC(c1ccccc1)c1ccccc1
Product: CC[C@H]1[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Yield: 28.8 %

Procedure:
The same operation as in Example (234b) was performed using (2R*)-2-[(1S*)-1-bromopropyl]oxirane obtained in Example (235a) (1.50 g, 9.09 mmol) and benzhydrylamine (1.57 mL, 9.09 mmol), to obtain 699 mg of the title compound as a pale yellow solid (29%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:9][C:8](=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][CH:21]=1)[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: Cc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccc(C)cc1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a suspension of sodium hydride (a 60% dispersion in liquid paraffin, 15.0 g, 375 mmol) in N,N-dimethylformamide (160 ml) was added at 0° C. a solution of triethyl 2-phosphonopropionate (87.7 g, 368 mmol) in N,N-dimethylformamide (10 ml) and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction solution was added 4-methylbenzaldehyde (43.3 g, 361 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 66.7 g (91% yield) of the oily title compound.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[O:6])[CH:2]=[CH2:3].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].B(OC)(OC)OC.[Cl-].[NH4+]>[Zn].OCC(CO)O.O1CCCC1>[CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]([OH:6])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCC(C=O)CCCC
Reactant: COC(=O)CBr
Agent: COB(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: OCC(O)CO
Product: C=CCC(CCCC)C(O)CC(=O)OC
Temperature: 70 °C

Procedure:
2-Allylhexanal (J. Org. Chem. 46, 1980, 5250) (5 g, 33.7 mmol), methyl bromoacetate (3.7 mL, 40 mmol), and zinc (2.6 g, 40 mmol) were added to tetrahydrofuran (30 mL) and trimethyl borate (15 mL), and the mixture was vigorously stirred. Then, the reaction vessel was placed in an oil bath and heated to 70° C., and the mixture was stirred for 2 hours. The mixture was allowed to cool, and glycerin (20 mL) and a saturated aqueous solution of ammonium chloride (100 mL) were then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest (diastereomeric mixture) as a colorless oil substance (6.8 g, 94%).