Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.N=C=N.C(N(CC)CC)C.Cl.[CH2:40]([O:47][P:48]([CH2:57][C@H:58]([OH:61])[CH2:59][NH2:60])([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH2:40]([O:47][P:48]([CH2:57][C@H:58]([OH:61])[CH2:59][NH:60][C:16](=[O:18])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:13]([CH3:14])[CH3:15])([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:49])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: N=C=N
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
To a solution of N-Cbz-L-valine (1.0 g, 3.98 mmol) dissolved in CH2Cl2 (80 mL) under nitrogen was added hydroxybenzotriazole (0.538 g, 3.98 mmol) and PS-Carbodiimide (2.25 g, 5.17 mmol). After stirring for 10 min, triethylamine (0.665 mL, 4.78 mmol) and ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (1.44 g, 3.98 mmol) were added. The reaction was stirred for 2 h, then filtered and concentrated in vacuo. The residue was purified by flash chromatography with methanol/dichloromethane on a 35 g RediSep disposable column to give [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester (0.60 g, 1.07 mmol) as a white foam. NMR and MS spectra were substantially similar to the product obtained via Method A set forth above.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccnc1Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ncccc3F)CC2)cc1
Yield: 9.6 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-chloro-3-fluoropyridine (74 μl, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (13 mg), a white solid, in 10% yield.
Reaction SMILES: [CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=C)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:31]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:31])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 75A, 0.015 g, 0.036 mmol) in dichloromethane (5.0 mL) at −78° C. was passed ozone from an ozone generator until the solution turned a deep blue. The reaction mixture was then purged with oxygen until the blue color disappeared and then with nitrogen for 5 minutes. The reaction mixture was allowed to warm to room temperature, and triethylamine (5.07 μl, 0.036 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. Concentration under vacuum provided 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde [0.014 g, 0.0.036 mmol, 98%] as a tan solid. The product had an HPLC ret. time=4.44 min. (condition B). LC/MS M+1=417.07.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([Br:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[Br:13].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Br:13])=[CH:7][C:8]([F:12])=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[Br:11]
Reactant: Fc1cc(Br)c(OCCCl)c(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)cc(Br)c(OCCCl)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 1-(2-chloroethoxy)-2,6-dibromo-4-fluorobenzene (65.8 g, 0.20 mol) in concentrated sulfuric acid (165 mL) maintained at room temperature using a water bath was slowly added a solution of nitric acid in sulfuric acid (10 mL HNO3 in 165 mL H2SO4). The reaction was allowed to stir at room temperature for 1 hour then poured into ice (1.5 L) and extracted with methylene chloride (2×300 mL). The combined organic layers were washed with aqueous sodium bicarbonate (150 mL) and dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to afford 73.3 g (97.1%) a white crystalline solid: mp 56°-57° C.; MS EI m/e 375/377/379/381; 1H NMR (CDCl3) δ 3.91 (2H, t, J=5.9 Hz), 4.29 (2H, d, J=5.9 Hz), 7.54 (8.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][Mg]Br.C(OCC)C>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]([OH:24])[CH3:25])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.5 g, 0.001457 mol) and THF (25 mL) was added and cooled to 0° C. To the flask was slowly added 1.5 M methyl magnesium bromide in diethyl ether (0.145 mL, 0.002186 mol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to provide the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 40% ethyl acetate in hexane [0.3 g, 57%]. 1H NMR (300 MHz, CDCl3): δ 8.05 (d, J=1.2 Hz, 1H), 7.83 (d, J=6.3 Hz, 1H), 7.71 (dd, J′=6.6, J″=1.2 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.40 (d, J=2.7 Hz, 1H), 4.91 (q, J=4.8 Hz, 1H), 3.89 (s, 8H), 1.63 (d, J=4.8 Hz, 3H). LC-MS (ESI): Calculated mass: 359. 1; Observed mass: 360.1 (RT: 1.58 min).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH3:13])[S:8](=[O:15])(=[O:14])[C:7]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:6]1=2)(=O)[CH3:2].S(C)C.Cl>O1CCCC1>[CH2:1]([NH:4][C@H:5]1[CH2:10][C@H:9]([CH2:11][CH2:12][CH3:13])[S:8](=[O:15])(=[O:14])[C:7]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:6]1=2)[CH3:2]
Reactant: CCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCC[C@H]1C[C@H](NCC)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A flask fitted with a short path distillation head was charged with a solution of 7 (53.3 g, 0.145 mol) in 1000 ml of tetrahydrofuran. After blanketing the system with argon, the solution was treated with 10.0M BH3.(CH3)2S (51 ml, 0.5 mol) at a rate sufficient to maintain reasonable gas evolution. Upon addition, the flask was gently warmed to collect (CH3)2S. After equilibrating to room temperature overnight, the solution was chilled to 0° C. and was then treated with 80 ml of absolute ethanol followed by equilibrating to room temperature. The resulting amber solution was concentrated to remove solvents. The dry solids were solublilzed in 500 ml of tetrahydrofuran and treated with 60 ml (0.36 mol) of 6N aqueous hydrochloric acid. The mixture was allowed to reflux for 1 hour, followed by stirring at room temperature for 2 hours. The solution was concentrated to remove tetrahydrofuran, and the resulting oil was treated with 500 ml of ethyl acetate and 200 ml of water. The aqueous phase was buffered to pH 8, and washed with an additional 50 ml of ethyl acetate. All organic extracts were then washed with 100 ml of saturated aqueous sodium chloride. The dried (Na2SO4) organic phase was filtered and concentrated to yield 45.12 g (0.128 mol, 88.3%) of 8 and 9 as a cis/trans isomeric mixture. The mixture was dissolved in 1500 ml ethyl acetate and treated with a solution of 5.6 g (0.134 mol) of maleic acid in 400 ml of hot ethyl acetate. A sufficient amount of hot methanol was added to solubilize all solids, and the solution was allowed to stand for 72 hours. The resulting white solid was collected and dried to give 12.50 g of the maleate salt. A second crop gave 2.26 g. The remaining liquor was concentrated and oil was solubilized in ethyl acetate and triturated slowly with diethyl ether to selectively give the trans isomer. The precipitation was repeated several times to give a total of 12.88 g of white solid. The total amount of pure trans maleate was 27.64 g (46.1% of 8). The remaining cis isomer enriched oil 9 was chromatographed (silica gel, 95:5:0.5, CHCl3 /MeOH/NH4OH followed by 90:10:1.0, CHCl3 /MeOH/NH4OH)) to give 0.9 g of 8. A total yield of 21.70 g (48.4% yield)* of 8 was obtained.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:14])[C:10](OC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>CO>[CH2:1]([O:8][C@H:9]([CH3:14])[C:10]([NH:16][NH2:17])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)[C@@H](C)OCc1ccccc1
Solvent: O
Solvent: CO
Product: C[C@@H](OCc1ccccc1)C(=O)NN
Yield: 64 %

Procedure:
A mixture of (R)-methyl 2-(benzyloxy)propanoate (1 g, 5.15 mmol), hydrazine monohydrate (250 ul) in MeOH (14 mL) was refluxed 3 hours. Solvent was removed under reduced pressure and the residue was purified on silica gel. Elution with EtOAc yielded title compound (640 mg, 64%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@:3]1([OH:19])[C:15]([O:17][CH3:18])=[O:16].Cl.[CH3:21][C:22]1[CH:31]=[C:30]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:19][C@@:3]1([C:15]([O:17][CH3:18])=[O:16])[C@H:2]([NH:1][S:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:21])[CH:31]=3)=[CH:35][CH:36]=2)(=[O:41])=[O:42])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: COC(=O)[C@@]1(O)CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@]1(O)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A suspension of 1-tert-butyl 3-methyl (3R,4R)-4-amino-3-hydroxypiperidine-1,3-dicarboxylate (1.63 g, 5.96 mmol), 4-((2-methylquinolin-4-yl)methoxy)benzene-1-sulfonyl chloride hydrochloride (4.6 g, 11.92 mmol, 2.0 eq), CH2Cl2 (100 mL) and saturated NaHCO3 (50 mL) was stirred at room temperature overnight, and then diluted with CH2Cl2. The organic phase was washed with water, then brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel eluting with 50-70% ethyl acetate/hexane to yield 1.65 g (47%) of 1-tert-butyl 3-methyl (3R,4R)-3-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-1,3-dicarboxylate as white solid. MS: (M+H)+=586.1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=O)[C:6]2=[CH:12][CH:13]=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[N:20]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:7](=[O:9])[C:6]2=[CH:12][CH:13]=1
Reactant: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(C(F)(F)F)cc2C1=O
Temperature: 140 °C

Procedure:
4-Trifluoromethyl-N-isobutylphthalimide is prepared as described in Example 2, starting with 14.8 g of 4-trifluoromethylphthalic anhydride, 7.2 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 160 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 5 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and the residue is taken up in 250 cm3 of ethyl acetate and 200 cm3 of saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is separated out after settling has taken place and then extracted twice with 250 cm3 of ethyl acetate. The organic extracts are combined, washed with saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 14.9 g of 4-trifluoromethyl-N-isobutylphthalimide are thus obtained in the form of a yellow powder (Rf=0.59, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[N:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:25])C=1.CO>C(Cl)(Cl)Cl>[N+:1]([C:4]1[S:8][C:7]([S:9]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[O:25])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc(Sc2cncc[n+]2[O-])s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnc(S(=O)c2cncc[n+]2[O-])s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred solution of 1.0 g (0.004 mol) of Compound 2 in 50 ml of chloroform was gradually added 2.0 g (0.010 mol) of 85% m-chloroperbenzoic acid. The reaction mixture was stirred overnight at room temperature and then filtered. The filtrate was washed with water, dilute bicarbonate and brine, and dried over MgSO4. Evaporation of the solvent afforded a yellow oil that solidified on standing. This crude product was recrystallized from CHCl3 /hexane and a second crop of crystals was recrystallized from methanol for a total yield of 0.3 g (28% yield) of yellow crystals, m.p. 139°-141° C.
Reaction SMILES: [NH2:1][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:17][C@H:16]3[N:13]([C:14](=[O:28])[C@@H:15]3[C@H:18]([O:20][Si](CC)(CC)CC)[CH3:19])[C:12]=2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])=[CH:7][CH:6]=1)=[O:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1>[NH2:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:17][C@H:16]3[N:13]([C:14](=[O:28])[C@@H:15]3[C@H:18]([OH:20])[CH3:19])[C:12]=2[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])=[CH:9][CH:10]=1)=[O:3]
Reactant: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(OC(N)=O)cc3)C[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(OC(N)=O)cc3)C[C@H]12
Reaction time: 0.75 h
Yield: 12.4 %

Procedure:
To a solution of 4-nitrobenzyl (5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (110 mg) prepared in the above step in THF (1.9 ml) was added under ice cooling acetic acid (11 mg). Then 1M tetrabutylammonium fluoride/THF solution (0.19 ml) was dropped thereto and the mixture was stirred at the same temperature for 45 minutes. The residue prepared by the same manner as step a) of example 11 was purified by silica gel thin-layer chromatography (chloroform/acetone=2/1) to give 4-nitrobenzyl (5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (11 mg).
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]#[CH:9].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH3:6])[C:3]([O:5][CH2:9][C:8]#[CH:7])=[O:4]
Reactant: CC(O)C(=O)O
Reactant: C#CCO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCOC(=O)C(C)O
Reaction time: 3 h
Yield: 45 %

Procedure:
52.99 g (0.50 mol) of an aqueous solution of 85% 2-hydroxypropionic acid and 45 mL of toluene were dissolved in 84.09 g (1.50 mol) of propargyl alcohol, and 1.0 mL of concentrated sulfuric acid was added thereto. Using a Dean-Stark device under normal pressure, the formed water was removed from the system, and this was further reacted under reflux under normal pressure. After 3 hours, the reaction liquid was analyzed through liquid chromatography, and the disappearance of the starting materials was confirmed. Then, the reaction liquid was neutralized with sodium acetate added thereto, filtered, and the filtrate was concentrated. The residue was purified through reduced pressure distillation to give 28.81 g (45% yield) of 2-propynyl 2-hydroxypropionate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[F-].[K+].O>C1(C)C=CC=CC=1>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Cl)nc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
To a solution of 6-Chloro-pyridin-3-ol (3.10 g, 23.9 mmol) in toluene (30 ml) is added 4-tert-butyl-phenylboronic acid (5.46 g, 30.6 mmol), potassium fluoride (2.82 g, 47.9 mmol), and palladium tetrakis triphenylphosphine (1.20 g, 1.20 mmol). Water (15 mL) is added and the reaction mixture is heated to reflux overnight. After cooling to rt, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and eluted using hexanes with an ethyl acetate gradient to give the title compound (2.06 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: CN1CCc2ccc(O)cc2C1=O
Product: CN1CCc2ccc(OCCCCCl)cc2C1=O

Procedure:
By a similar method as in Reference Example 9,7-(4-chlorobutoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one in the form of a brown oil was prepared from 7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one using 1-bromo-4-chlorobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]1[C@@H:35]2[CH2:36][O:37][CH2:38][CH2:39][N:34]2[CH2:33][C@H:32]([CH2:40]O)[O:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:40][C@@H:32]5[O:31][CH2:30][C@@H:35]6[CH2:36][O:37][CH2:38][CH2:39][N:34]6[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC[C@H]1CN2CCOC[C@H]2CO1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@H]1CN2CCOC[C@H]2CO1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-yl]methanol (prepared as described in WO 2004/006846) following General Procedure J.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:23][NH:24][C:25](=[O:37])[CH:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28]>>[CH2:30]([CH:26]([C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28])[C:25]([NH:24][CH2:23][C:22]1[CH:38]=[C:39]([F:41])[CH:40]=[C:20]([F:19])[CH:21]=1)=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)C(Cc1ccccc1)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CN1C(=O)C(NC(=O)C(Cc2ccccc2)C(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=539.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-benzyl-malonamic acid.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:9]=1[C:41]([O:43]CC)=[CH2:42].Cl>CCO>[C:41]([C:9]1[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)=[N:11][C:12]2[N:13]([N:14]=[CH:15][C:16]=2[C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[C:8]=1[NH2:7])(=[O:43])[CH3:42]
Reactant: C=C(OCC)c1c(CC2CCC(C(=O)OCC)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 20 mL scintillation vial containing ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4n, 113 mg, 0.144 mmol) was added EtOH (2 mL) followed by 4N HCl(aq). The resulting cloudy suspension was stirred at room temperature 1 hour, at which time the solution was now homogenous. The solvent was removed in vacuo and excess solvent was pumped off on high vacuum. The compound was taken on without further purification.