Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Br>C(O)C>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[N:6]2[CH2:28][CH:27]([OH:29])[CH2:25]2)=[CH:23][CH:22]=1
Reactant: BrCC1CO1
Reactant: COC(=O)c1ccc([C@@H](N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc([C@H](c2ccc(Cl)cc2)N2CC(O)C2)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
1-{(R*)-(4-Chlorophenyl)[4-methoxycarbonyl)-phenyl]methyl}azetidin-3-ol, A isomer form, may be prepared by carrying out the procedure in the following manner: 0.605 g of sodium hydrogen carbonate is added to a suspension of 2.0 g of methyl (+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate in 30 cm3 of ethanol followed by 0.60 cm3 of epibromohydrin. After stirring for 20 hours at 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3 cm, height 35 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume for fractions 6 to 10 and then 60/40 for fractions 18 to 27, and then 50/50) and collecting 60-cm3 fractions. Fractions 15 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 30 cm3 of ethanol and is then supplemented with 0.20 g of sodium hydrogen carbonate and 0.2 cm3 of epibromohydrin. After stirring for 48 hours at 20° C. and then 24 hours at 35° C., the mixture is filtered and the filtrate is concentrated to dryness at 60° C. under reduced pressure (2.7 kPa). 1.76 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azetidin-3-ol, A isomer form, are obtained in the form of a pasty solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][N:13]([CH3:27])[C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:51])[CH3:50])=[N:46][CH:47]=2)O1>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:27][N:13]1[CH2:12][C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:42]4[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:51])[CH3:50])=[N:46][CH:47]=4)=[N:3][C:4]=3[C:5]=2[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14]1=[O:26]
Reactant: CN1Cc2cnc3ccc(Cl)nc3c2N(c2cccc(C(F)(F)F)c2)C1=O
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2ccc3ncc4c(c3n2)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
9-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-2(1H)-one (314 mg, 0.80 mmol), tetrakis(triphenylphosphine) palladium (15 mg, 0.013 mmol) and 2N aqueous sodium carbonate solution (1.3 mL) were added sequentially to a solution of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (225 mg, 0.858 mmol) in 1,4-dioxane (15 mL), and reacted under nitrogen at 90° C. for 16 h, cooled to room temperature, filtered, the organic layer was concentrated under reduced pressure, dissolved in 50 mL of dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (ethyl acetate) to give 267 mg of the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH:6]1[CH2:9][O:8][CH2:7]1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:28])C=CC=CC=1.[Cl-].[NH4+].Cl>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([OH:28])[CH:6]1[CH2:9][O:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1COC1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)C1COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a stirred solution of oxetan-3-yl-acetic acid ethyl ester (obtained from Activate Scientific GmbH), (1.04 g, 7.21 mmol) in anhydrous tetrahydrofuran (72 mL) at −78° C. under nitrogen was added dropwise sodium hexamethyldisilazide (0.6 M in toluene, 14.4 mL, 8.66 mmol) to give a yellow orange solution. The reaction mixture was stirred at −78° C. for 30 min and then a solution of 2-(phenylsulfonyl)-3-phenyl-oxaziridine (2.83 g, 10.8 mmol) in tetrahydrofuran (7 mL) was added over 2 min. The reaction mixture was stirred at −78° C. for 90 min and then saturated ammonium chloride solution (10 mL) was added via syringe. The reaction mixture was allowed to warm to ambient temperature and after 5 min further saturated ammonium chloride solution (10 mL) was added and then stirred at ambient temperature for 1 h. The reaction mixture was neutralised to pH 7 with hydrochloric acid (2 M) and the mixture diluted with water and extracted with ethyl acetate (4×). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and partially evaporated to about ˜10 mL. The mixture was diluted with dichloromethane and the solids were filtered off, the filtrate was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/diethyl ether 1:0 to 1:3 to give the title compound (688 mg, 60%) as a white gum. 1H NMR (300 MHz, CDCl3) δ 1.30 (t, J=7.2 Hz, 3H), 2.95 (d, J=5.1 Hz, 1H), 3.26-3.38 (m, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.42 (dd, J=7.4, 5.1 Hz, 1H), 4.67-4.81 (m, 4H). LCMS (m/z) 161.2 [M+H] Tr=0.72 min
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:36]([O:38]CC)=[O:37])=[C:21]([C:23]3[CH:28]=[N:27][C:26]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[CH:25][N:24]=3)[N:22]=2)[CH2:14][C@H:13]1[O:41][CH3:42])=[O:10].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:36]([OH:38])=[O:37])=[C:21]([C:23]3[CH:28]=[N:27][C:26]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[CH:25][N:24]=3)[N:22]=2)[CH2:14][C@H:13]1[O:41][CH3:42])=[O:10]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(N2CCN(C)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CO[C@@H]1CN(c2nc(-c3cnc(N4CCN(C)CC4)cn3)c(C(=O)O)s2)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
Ethyl 2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate (Example 60, 92 mg, 0.144 mM) was dissolved in methanol (15 mL). To this was added 2N sodium hydroxide (7 mL) and the reaction mixture was stirred at room temperature for 4 h. The methanol was completely evaporated and water (20 mL) was added. The aqueous layer was washed with diethyl ether (2×20 mL) and the aqueous layer was acidified to pH 6 with 2N hydrochloric acid (1.0 mL). The solid that precipitated out of solution was filtered and dried to afford 2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylic acid 60 mg (82%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][O:6][C:5]([CH2:15][S:16][CH2:17][C:18]([O:20]CC)=[O:19])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:4][CH2:3]1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1([CH3:23])[CH2:7][O:6][C:5]([CH2:15][S:16][CH2:17][C:18]([OH:20])=[O:19])([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[O:4][CH2:3]1
Reactant: CCOC(=O)CSCC1(c2ccc(C)cc2)OCC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2(CSCC(=O)O)OCC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Ethyl ({[5,5-dimethyl-2-(4-methylphenyl)-1,3-dioxan-2-yl]methyl}thio)acetate (10.1 g, 29.8 mmol) was dissolved in THF (150 ml) and cooled to 0° C. LiOH (3.76 g, 89.5 mmol) in water (50 ml) was added and the mixture was stirred for two hours at room temperature. The mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with diethyl ether. The aqueous layer was acidified using 2M HCl to pH 3 and extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (Na2SO4) and concentrated under reduced pressure to afford 8.7 g (94%) of the title compound as a white solid. 1H-NMR(CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 2.4 (s, 3H), 3.0 (s, 2H), 3.4 (s, 2H), 3.4 (s, 4H), 7.2-7.4 (m. 4H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20]Br>C(C(CC)=O)C>[Br:18][CH2:19][CH2:20][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: BrCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: BrCCOc1ccc2ccccc2c1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
A mixture of 144 g (1 mole) of 2-naphthol, 600 ml of diethyl ketone, 275 g (2 moles) of potassium carbonate and 850 g (4.5 moles) of 1,2-dibromoethane is refluxed for 48 hours. Diethyl ketone and excess dibromoethane are then distilled off under reduced pressure and the residue is taken up in 500 ml of methylene chloride and 200 ml of 10% strength sodium hydroxide solution. After the aqueous phase has been separated off, the organic layer is washed with 100 ml of water, dried over sodium sulfate and concentrated under reduced pressure. The solid residue is stirred with 100 ml of n-pentane for 10 minutes at -5° C., filtered and washed with 50 ml of cold pentane. There is obtained 195 g (78% of theory) of pure 1-bromo-2-(2-naphthyloxy)-ethane; m.p.: 93°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:18])=[CH:15][CH:14]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:43]1[C:51]2[N:50]=N[NH:48][C:47]=2[CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:48][C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:51]=2[NH2:50])=[O:26])=[O:18])=[CH:15][CH:14]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
6-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid (396 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (394 mg, 81% yield) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.[C:12](Cl)(Cl)=[S:13].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:4]1[CH:3]=[C:2]([N:1]=[C:12]=[S:13])[CH:9]=[C:8]([Cl:10])[C:5]=1[C:6]#[N:7]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1c(Cl)cc(N)cc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Yield: 71.3 %

Procedure:
A suspension of 4-amino-2,6-dichlorobenzonitrile (500 mg, 2.67 mmol, Eq: 1.00), thiophosgene (1.35 g, 900 μl, 11.7 mmol, Eq: 4.39), triethylamine (875 mg, 1.2 ml, 8.64 mmol, Eq: 3.23) in benzene (30 ml) was heated at reflux overnight. The brown reaction mixture was concentrated and chromatographed (80 g Analogix, 0 to 5% ethyl acetate/hexane) to give 436 mg (71%) of desired product as a light brown solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:20]=[C:19]([OH:21])[C:18]([C:22]([CH3:26])([CH3:25])[CH:23]=[CH2:24])=[CH:17][C:14]=1[CH:15]=O.Cl.O>C(O)C>[CH3:26][C:22]([C:18]1[CH:17]=[C:14](/[CH:15]=[CH:1]/[C:2]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[O:3])[C:13]([O:12][CH3:11])=[CH:20][C:19]=1[OH:21])([CH:23]=[CH2:24])[CH3:25]
Reactant: C=CC(C)(C)c1cc(C=O)c(OC)cc1O
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C=CC(C)(C)c1cc(/C=C/C(=O)c2ccc(O)cc2)c(OC)cc1O
Reaction time: 2 h
Yield: 35.2 %

Procedure:
A solution of 150 mg (1.1 mmol) of 4-hydroxyacetophenone and 220 mg (1.0 mmol) of 2-methoxy-4-hydroxy-5-(1,1-dimethylprop-2-enyl)benzaldehyde in 3 ml of ethanol was left on an ice bath, and 1.1 ml of ethanol saturated with dry hydrogen chloride was added. The solution was left for 2 hours and poured into 10 ml of water. The mixture was concentrated in vacuo and extracted with two 10 ml portions of ethyl acetate, and the extract was dried and concentrated in vacuo to give 281 mg of an oil from which 119 mg of licochalcone A was isolated by column chromatography over silica gel 60 (Merck 0.063-0.200 mm, 23 g) using petroleum ether-ethyl acetate (1:1, 1000 ml) as an eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH2:27]([NH2:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:29][CH2:27][CH3:28])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CCN
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CCNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to ethylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-ethylterephthalamide. MS (Q1) 415 (M)+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].Cl.[CH2:16]([NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[ClH:14].[NH2:29][C:27]1[NH:26][C:24]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:25][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:28]=1
Reactant: CCCCCCCCCCCC=O
Reactant: N=C(N)NC(=N)NCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCC1N=C(N)NC(NCc2ccccc2)=N1

Procedure:
160 ml of ethanol, 13.0 g (70.5 mmol) of 1-dodecanal and 1.5 ml of concentrated hydrochloric acid were added to 8.0 g (35.1 mmol) of N1-benzyl-biguanide hydrochloride. The mixture was refluxed for 16 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography, and the first main fraction eluted with a mixture of chloroform and methanol (9:1.5) was recrystallized from 80% aqueous ethanol to obtain 3.1 g of colorless crystals (1) having a melting point of 152 to 155° C. The second main fraction was recrystallized from 80% aqueous ethanol to obtain 0.9 g of colorless crystals (2) having a melting point of 153 to 156° C.
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[F:12][C:13]1[C:18]([C:19]2[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=C[C:23]=2[F:24])=[CH:17][CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>ClCCl>[F:24][C:23]1[C:7]([CH:6]=[O:10])=[CH:21][NH:20][C:19]=1[C:18]1[C:13]([F:12])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(F)c1-c1cccnc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1c[nH]c(-c2cccnc2F)c1F
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a solution of N,N-dimethylformamide (717 mg) in dichloromethane (20 mL) was added oxalyl chloride (1.13 g) under ice-cooling under an argon atmosphere, and the mixture was stirred for 10 min. To the obtained suspension was added a solution of 2-fluoro-3-{3-fluoro-1-[tris(1-methylethyl)silyl]-1H-pyrrol-2-yl}pyridine (1.50 g) in dichloromethane (5 mL) and the mixture was stirred under refluxing conditions for 10 hr. The reaction mixture was cooled under ice-cooling, 1 mol/L aqueous sodium hydroxide solution (30 mL) was added and the mixture was stirred for 15 min. The solvent was evaporated to a half volume under reduced pressure and the residue was partitioned by adding ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual solid was washed with diisopropyl ether (30 mL) and filtered by suction to give the title compound as a colorless solid (yield 726 mg, 78%).
Reaction SMILES: [NH3:1].[C:2]([O:8][CH2:9][C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])(=[O:7])[CH2:3][C:4]([CH3:6])=O>CO>[NH2:1]/[C:4](/[CH3:6])=[CH:3]\[C:2]([O:8][CH2:9][C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])=[O:7]
Reactant: CC(=O)CC(=O)OCC1(C)OCCO1
Reactant: N
Solvent: CO
Product: C/C(N)=C/C(=O)OCC1(C)OCCO1
Yield: 84 %

Procedure:
Ammonia gas was passed through a mixture of 19 g of 2,2-ethylenedioxypropyl acetoacetate and 100 ml of methanol for 2.5 hours under ice-cooling while stirring. The solvent was then distilled off and the residue was distilled under reduced pressure to obtain 16 g (84% yield) of 2,2-ethylenedioxypropyl 3-aminocrotonate as a pale yellow oil having a boiling point of 120° C. (5 mmHg).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:23])[C@H:8]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([F:21])=[C:16]([CH3:22])[CH:15]=1)[CH2:9][CH2:10][CH2:11][CH3:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:5][NH:6][C:7](=[O:23])[CH:8]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([F:21])=[C:16]([CH3:22])[CH:15]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@@H](Nc1cc(C)c(F)c(C)c1)C(=O)NOC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(Nc1cc(C)c(F)c(C)c1)C(=O)NO
Temperature: 25 °C
Reaction time: 87 h
Yield: 29.8 %

Procedure:
To a solution of (R)-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid tert-butoxy-amide (0.737 g, 2.273 mmol) in 1 mL of dichloromethane, was added trifluoroacetic acid (9 mL). After stirring at room temperature for 87 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-10% methanol/dichoromethane to give the title compound as a white solid (0.182 g, 30% yield). Pure analytical sample was obtained by RP-HPLC purification. LC-MS: tR=6.8 min; m/z 269 (M+H)+;)+; 1H NMR (500 MHz, CD3OD) δ 0.92 (t, J=7.05 Hz, 3H), 1.33-1.45 (m, 4H), 1.71-1.79 (m, 2H), 2.13 (d, J=2.02 Hz, 6H), 3.65 (t, J=7.05 Hz, 1H), 6.36 (d, J=5.88 Hz, 2H); 13C NMR (125.75 MHz, CD3OD) δ 14.24, 14.80, 23.50, 29.18, 33.99, 58.94, 115.65 (d, J=3.14 Hz), 125.69 (d, J=18.74 Hz), 143.30, 155.19 (d, J=233.14 Hz), 172.75; 19F NMR (470.58 MHz, CD3OD) δ −135.79.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH:36]([CH3:38])[CH3:37])=[N:13][C:14]2[C:15]([CH3:35])([CH3:34])[CH2:16][N:17](C(=O)C(F)(F)F)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CC#N.O>CO>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH:36]([CH3:38])[CH3:37])=[N:13][C:14]2[C:15]([CH3:35])([CH3:34])[CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(C(=O)C(F)(F)F)CC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Yield: 32.8 %

Procedure:
A solution of methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 4) (0.483 g, 0.897 mmol) and 1N NaOH (4.48 ml) in MeOH (10 mL) was stirred at room temperature overnight (15 h) and then 8 h at reflux. After cooling the product was purified by preparative-HPLC (CH3CN/H2O, 10 mmol NH4OAc) to provide 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (0.126 g, 31% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.37 (2H, d, J=6.7 Hz), 7.31 (2H, d, J=6.7 Hz), 4.67 (1H, s), 3.59 (1H, d, J=16.2 Hz), 3.51-3.57 (1H, m), 3.33 (2H, br. s.), 3.10 (1H, d, J=16.2 Hz), 2.72-2.82 (2H, m), 1.28 (6H, s), 1.19 (3H, d, J=6.4 Hz), 1.07 (3H, d, J=6.7 Hz), 0.87 (9H, s). LCMS (M+H) calcd for C25H34FN2O3: 429.26. found: 429.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:21])[NH:11][CH2:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:21][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][N:11]=1
Reactant: COC(=O)CCCCCCC(=O)NCC(=O)c1ccccc1
Agent: BrC(Br)(Br)Br
Agent: CN(C)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCc1ncc(-c2ccccc2)o1
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Add a solution of 7-(2-oxo-2-phenylethylcarbamoyl)heptanoic acid methyl ester (7.05 g, 23.1 mmol) and carbon tetrabromide (11.3 g, 34.3 mmol) in methylene chloride over 40 minutes to a mixture of triphenylphosphine (9.0 g, 34.3 mmol) and DMAP (5.51 g, 45.1 mmol) in methylene chloride (500 mL) at room temperature under nitrogen. Stir the mixture for 30 minutes and add additional triphenylphosphine (2.6 g, 9.92 mmol) and carbon tetrabromide (3.35 g, 10.1 mmol). Stir the mixture for an additional 20 minutes, filter through Celite and wash with ethyl acetate (3×100 mL). Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (70:30), to provide 7-(5-phenyloxazol-2-yl)heptanoic acid methyl ester (2.75 g, 41%).