Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[C:17](=[N:21][OH:22])[CH2:16][CH2:15]4)=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:30][C:31]#[N:32].C(N(CC)CC)C>ClCCl.CN(C)C=O>[OH:22][N:21]=[C:17]1[C:18]2[C:14](=[CH:13][C:12]([C:10]3[O:11][C:7]([CH:4]4[CH2:3][CH2:2][N:1]([CH2:30][C:31]#[N:32])[CH2:6][CH2:5]4)=[CH:8][C:9]=3[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: N#CCBr
Reactant: ON=C1CCc2cc(-c3oc(C4CCNCC4)cc3-c3ccncc3)ccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of the product of Example 40 Step 5 (0.13 g, 0.35 mmol) in dry dichloromethane (10 ml) and dry dimethylformamide (0.5 ml) was treated with bromoacetonitrile (0.027 ml, 0.39 mmol) and triethylamine (0.054 ml, 0.39 mmol) and stirred at ambient temperature overnight. The crude reaction mixture was poured onto an SCX column and eluted with methanol followed by a mixture of 0.880 ammonia/methanol (1:10). The basic fractions were combined, concentrated in vacuo and triturated with diethyl ether to afford the title compound (0.13 g, 90%); MS(ES+) m/e 413 [M+H]+.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCC1.[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].N1CCCC1>O>[N:17]1([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:19][CH2:16][CH2:15]1
Reactant: N#Cc1cccnc1F
Reactant: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: N#Cc1cccnc1N1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To an oven-dried, N2-purged, 50-mL flask containing a magnetic stir bar were added 2-fluoronicotinonitrile (1.22 g, 10.0 mmol), anhydrous tetrahydrofuran (5 mL), and triethylamine (3.04 g, 4.19 mL, 30.0 mmol). The flask was sealed with a septum and cooled to 0° C. in an ice bath. Neat pyrrolidine (1.04 g, 1.24 mmol, 15.0 mmol) was added via syringe. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature overnight. Water (10 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to a brown oil. The product was recrystallized from ethyl acetate/hexanes to give 1.29 g (75%) of the title compound as a tan powder. MS (ESI+) m/z 174.0 (M+H)+; 1H NMR (DMSO-d6) δ 1.91-1.95 (m, 4H), 3.63-3.68 (m, 4H), 6.68 (dd, J=7.6, 4.6 Hz, 1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 8.31 (dd, J=4.7, 2.0 Hz, 1H).
Reaction SMILES: OO.[OH:3][CH:4]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:5]=[CH:6][CH:7]1[C:11](=[CH:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10](=[O:22])[CH:9]=[CH:8]1.[OH-].[Na+].[Cl-:30].[NH4+].Cl.C(=O)([O-])O.[Na+]>CO.CC(C)=O>[Cl:30][C:9]1[C:10](=[O:22])[C:11](=[CH:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:7]([CH:6]=[CH:5][CH:4]([OH:3])[CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:8]=1
Reactant: COC(=O)CCCC=CC=C1C(=O)C=CC1C=CC(O)C1CCCC1
Reactant: [Cl-]
Agent: Cl
Agent: O=C([O-])O
Agent: OO
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)CCCC=CC=C1C(=O)C(Cl)=CC1C=CC(O)C1CCCC1
Yield: 38 %

Procedure:
0.2 ml of 30% aqueous hydrogen peroxide was added to a solution of 65 mg (190 micromol) of 4-(3-hydroxy-3-cyclopentyl-1-propenyl)-5-(6-methoxycarbonyl-2-hexenylidene)-2-cyclopentenone in 2 ml of methanol under ice cooling and stirring, and then 50 microliters of 1N sodium hydroxide was added. The mixture was stirred at 0° C. for 20 minutes. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with hexane. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered and concentrated to give an oily product. The product was dissolved in 3 ml of acetone, and 0.5 ml of concentrated hydrochloric acid was added. The mixture was stirred for one hour. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 10 g; eluent, cyclohexane:ethylacetate=4:1) to give 27 mg (yield 38%) of 2-chloro-4-(3-hydroxy-3-cyclopentyl-1-propenyl)-5-(6-methoxycarbonyl-2-hexenylidene)-2-cyclopentenone.
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>>[C:1]1([P:7]([N:20]=[N+:21]=[N-:22])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Following a previously [Paciorek et al, Inorg. Nucl. Chem. Letters, 2, 39 (1966)] developed procedure, diphenylphosphinyl chloride (14.87 g, 62.86mmol) was introduced into a tube (in the inert atmosphere enclosure). Trimethylsilyl azide (10.45 g, 90.69 mmol) was then condensed onto this material on a vacuum line at liquid nitrogen temperature. The tube was sealed in vacuo and heated at 60° C for 48 hr. Thereafter, it was cooled, opened to a vacuum system and the volatiles were collected in a liquid nitrogen trap (originally without pumping at room temperature, finally with pumping at 70° C). The total time required to remove the volatiles (excess (CH3)3SiN3 and the by-product (CH3)3SiCl) was 16 hr. A quantitative yield of pure diphenylphosphinyl azide was realized.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][CH3:23])[N:3]=1.O.[NH2:25][NH2:26].CCOC(C)=O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:25][NH:26]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][CH3:23])[N:3]=1
Reactant: NN
Reactant: CC[C@@H]1CCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H]1CCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To 4-{2-amino-6-[(2R)-2-ethyl-1-pyrrolidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (50 mg, 0.161 mmol) in ethanol (4 mL) was added hydrazine monohydrate (1 mL, 20.40 mmol), and the reaction mixture was stirred overnight at 100° C. into a sealed tube. The reaction was poured onto water and EtOAc, and the organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in ethanol (˜2 mL), and treated with hexanes until the solution became cloudy. The mixture was roto-evaporated (˜½ original volume) until a heavy precipitate was observed. The solution was decanted and the solid was dried under vacuum at 40° C. to afford the title compound (30 mg, 58%) as a pale yellow solid. LC-MS (ES) m/z=324 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (t, J=7.3 Hz, 3H), 1.37 (m, 1H), 1.7-2.0 (m, 5H), 3.40 (m, 1H), 3.50 (m, 1H), 4.00 (m, 1H), 5.38 (bs, 2H), 5.97 (bs, 2H), 6.23 (s, 1H), 7.51 (dd, J=8.6, 1.0 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.89 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](OCC4C=CC=CC=4)=O)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:39]([O:44][CH2:45][C@@H:46]1[O:48]C1)(=[O:43])CCC>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][C@H:45]([CH2:46][OH:48])[O:44][C:39]4=[O:43])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC=C(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 2, 0.500 g) in dry tetrahydrofuran (5.7 mL) at -78° C. under N2 is treated with n-butyllithium (0.73 mL, 1.6 M in hexanes) dropwise over five minutes. The resulting mixture is stirred at -78° C. for 45 minutes and is then treated with (R)-(-)-glycidyl butyrate dropwise. The resulting solution is allowed to warm to ambient temperature over approximately 45 minutes and is stirred for an additional 20 hours, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude produce which is chromatographed on silica gel (230-400 mesh, 40 g), eluting with methanol/methylene chloride (1/99). Pooling and concentration of those fractions with an Rf =0.37 by TLC (methanol/chloroform, 5/95) gives the titles compound, mp 131.5-133.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][C:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@:9]1([C:14](=[O:16])[NH:36][S:33]([C:30]2([CH3:29])[CH2:32][CH2:31]2)(=[O:35])=[O:34])[CH2:11][C@H:10]1[CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 85 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH˜2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58%) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS: MS m/z 343 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[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>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1
Yield: 89 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.30 mmol), benzeneboronic acid (110 mg; 0.901 mmol) and tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (1-10%) in heptane to give 100 mg (89%) of the title compound. ESI/APCI(+): 375 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][O:6][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: COC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A mixture of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (13.2 g, 100 mmol), 4-methyl-benzenesulfonyl chloride (18.1 g, 90 mmol), 4-dimethylamino pyridine (15.9 g, 130 mmol) in dichloromethane was stirred at room temperature for 1 h. Then the mixture was washed by aqueous HCl solution (1 N), brine and dried over Na2SO4. The solvent was removed in vacuum to give title compound (23 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)([O-:3])=[O:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I:27]I>C1COCC1>[I:27][C:8]1[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cn1
Reactant: II
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1I
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
In an oven-dried flask, 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.5192 g, 6.2432 mmol) was dissolved in 20 mL THF and cooled at −78° C. To this solution was slowly added 1.0M lithium hexamethyldisilazide in tetrahydrofuran (7.5 mL, 7.5 mmol). After stirring for 40 minutes at −78° C., a solution of iodine (1.7602 g, 6.9351 mmol) in 8 mL THF was slowly added. The reaction mixture was kept at −78° C. for an additional 1.5 hours, and then quenched with saturated aqueous ammonium chloride and warmed to room temperature. The reaction mixture was partitioned between ethyl acetate and half-saturated aqueous Na2S2O3. The organic layer was dried with magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 15% ethyl acetate in heptanes) to yield 2.2349 g (97%) of 5-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. 1H NMR (400 MHz, DMSO-d6) δ: 8.48 (s, 1H), 5.59 (s, 2H), 3.61 (t, J=8.0, 2H), 0.86 (t, J=8.0, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C.C(OCC)(=O)C>[CH2:14]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCBr
Reactant: OCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCOCCCCCCCCO
Temperature: 50 °C
Reaction time: 10 h
Yield: 33 %

Procedure:
At room temperature, a commercially available reagent of octane-1,8-diol (351.2 mg, 2.40 mmol) was dissolved in DMF (3.0 mL), and sodium hydride (60 wt %, 105.7 mg, 2.64 mmol) was added. The mixture was then warmed to 50° C., stirred for 10 hours while maintaining the temperature at 50° C., and cooled to room temperature. 1-Bromo-heptane (430.2 mg, 2.40 mmol) in DMF (1.5 mL) was then added, and the mixture was stirred at room temperature for 48 hours. The progress of reaction was stopped by adding water. Ethyl acetate was added, and the mixture was extracted. The organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was then purified with SP1 (SiO2 cartridge, 50% ethyl acetate/n-hexane, Rf=0.8) to obtain 8-heptyloxy-octan-1-ol (No. 6804253; 193.8 mg, 33% yield).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C1N(C2C=CC=C(OC)C=2)N=C(C)C=1)=O.[OH-].[Li+].COC1C=C(N2C(N3C[C@H](S(C4C=CC=CC=4C(F)(F)F)(=O)=O)C[C@@H]3C(O)=O)=CC(C)=N2)C=CC=1>>[CH3:36][O:35][C:31]1[CH:30]=[C:29]([N:24]2[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:21])([F:22])[F:20])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]2)[CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(OC)c1
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(OC)c1
Agent: COc1cccc(-n2nc(C)cc2N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2C(=O)O)c1
Agent: [Li+]
Product: COc1cccc(-n2nc(C)cc2N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)c1

Procedure:
In analogy to the procedure described in example 253e, a mixture of (2S,4R)-1-[2-(3-methoxy-phenyl)-5-methyl-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester and (2R,4R)-1-[2-(3-methoxy-phenyl)-5-methyl-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give a mixture of the title compound and (2R,4R)-1-[2-(3-methoxy-phenyl)-5-methyl-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid as orange solid which was used in the next step without further purification. MS (ESI): m/z=510.2 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[IH:11].[CH3:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15](SC)[NH:14]1>C(#N)C>[IH:11].[CH3:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:14]1
Reactant: CSC1=Nc2ccccc2C(C)N1
Reactant: NCCOc1ccccc1
Agent: I
Solvent: CC#N
Product: CC1NC(NCCOc2ccccc2)=Nc2ccccc21
Temperature: 80 °C
Yield: 79.4 %

Procedure:
2-Phenoxyethylamine (26 mg, 0.19 mmol) was added to a solution of 4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (50 mg, 0.16 mmol) in acetonitrile (1 ml), and the mixture was heated overnight (80° C.) in a screw-capped vial. The solvent was then evaporated and the mixture was suspended in diethyl ether. The title compound (52 mg, 62%) was obtained from this mixture by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH3:18])=[O:16])[CH:8]([CH3:19])[CH2:7][C:6]2=[O:20].[CH:21](OCC)=[O:22].[O-]CC.[Na+].[H-].[Na+]>C(O)C.C1C=CC=CC=1>[OH:22][CH:21]=[C:7]1[C:6](=[O:20])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([C:15]([O:17][CH3:18])=[O:16])[CH:8]1[CH3:19]
Reactant: CCOC=O
Reactant: COC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: COC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate (13.8 g.) in 140 ml. of benzene containing 19 ml. of ethyl formate is added to sodium ethoxide freshly prepared from 4.8 g. of sodium hydride and 6 ml. of ethanol over a period of 45 min. After stirring at room temperature for 4 hrs. the reaction mixture is poured onto 250 ml. of ice-water. The aqueous layer is retained and the organic layer washed with 1N aqueous sodium hydroxide. The washings are combined with the aqueous extracts and backwashed with benzene. The aqueous layer is then made acid with 12N hydrochloric acid and extracted with chloroform. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is employed in subsequent reactions without further purification.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[OH:31][C:6]1[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10](=[O:24])[N:11]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccc(OC)cc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Cn2c(=O)c(-c3ccccc3)cc3c(O)c(C(=O)NCCC(=O)O)ncc32)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 5-hydroxy-1-(4-methoxy-benzyl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.084 mmol), β-alanine (750 mg, 8.4 mmol) and NaOMe solution (13 mL, 6.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 31 mg of the title compound as a yellow solid. MS: (+) m/z 474.30 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][C:12](=C)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:16]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:16])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CC(CNC(=O)OC(C)(C)C)C1
Reactant: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CC(=O)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a round bottom flask were placed 9 g of the product from Step A of Example 9, 100 mL of methanol, and 400 mL of dichloromethane. The solution was cooled to -78° C., and ozone was bubbled through the reaction mixture until the solution was blue. The system was flushed with nitrogen for 2.5 h, and then treated with 34 mL of dimethylsulide. After 1 h at -78° C., 0° C. for 1 h, and room temperature for 1 h, the solution was stored in a refrigerator at 5° C. overnight before being concentrated. The crude material was purified by column chromatography to afford the title compound.