Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[NH:4][N:3]=1.Cl.[CH3:12]O>>[CH3:12][O:9][C:8](=[O:10])[CH2:7][C:5]1[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1cc(CC(=O)O)[nH]n1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cc(C)n[nH]1
Yield: 70 %

Procedure:
A solution of 3-methyl-5-pyrazoleacetic acid (5.0 g, 35.7 mmol) [see C. Ainsworth, J. Amer. Chem. Soc., 76, 3172 (1954)] in methanol (50 mL) is saturated with HCl gas. The mixture is warmed to reflux for 5 hours, after which the solution is concentrated. The solid residue is taken up in chloroform and washed with 0.5N aqueous sodium bicarbonate, dried over MgSO4, and evaporated to afford 3-methyl-5-pyrazoleacetic acid methyl ester (3.9 g, 70%) sufficiently pure for further use.
Reaction SMILES: [NH2:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[H-].[Na+].O=[CH:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@H:2]([NH:1][CH2:13][CH2:14][N:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1)[CH2:3]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COC(=O)c1cccc2ccn(CC=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc2ccn(CCN[C@@H]3CN4CCC3CC4)c12
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred suspension of (S)-(−)-3-aminoquinuclidine (1.4 g, 7.0 mmol) in methylene chloride (50 mL) was added sodium hydride (562 mg, 14.0 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.6 mL) was added dropwise, followed by methyl 1-(2-oxoethyl)-1H-indole-7-carboxylate (1.3 g, 5.9 mmol) from Step B above and the reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (4.2 g, 19.6 mmol) was then added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.39 g, 66%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 7.79 (dd, J=4.5, 1.0 Hz, 1H), 7.69 (dd, J=4.3 Hz 1H), 7.18 (d, J=1.8 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.57 (d, J=1.8 Hz, 1H), 4.51 (t, J=6.5 Hz, 2H), 3.96 (s, 3H), 3.46 (s, 1H), 3.07-3.03 (m, 1H), 2.90-2.85 (m, 1H), 2.82-2.70 (m, 5H), 2.63-2.60 (m, 1H), 2.29-2.25 (m, 1H), 1.68-1.59 (m, 3H), 1.40-1.39 (m, 1H), 1.25-1.22 (m, 1H); MS (ESI+) m/z 328 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([NH2:13])=[O:12].[CH2:16]([N:23]=[C:24]=[S:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:26](Br)[CH:27]=[CH2:28]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:16]([NH:23][C:24](=[N:13][C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[C:4]([F:3])([F:14])[F:15])=[O:12])[S:25][CH2:28][CH:27]=[CH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C=NCc1ccccc1
Reactant: NC(=O)c1cnccc1C(F)(F)F
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCSC(=NC(=O)c1cnccc1C(F)(F)F)NCc1ccccc1

Procedure:
Sodium hydride (0.09 g, 60% dispersion in mineral oil) was added to a solution of 4-trifluoromethyl-3-pyridinecarboxamide (0.40 g) in N,N-dimethylformamide at 20° C. and stirred for an hour. Benzyl isothiocyanate (0.31 ml) was added to the mixture and stirred at 20° C. for 2 hours, then allyl bromide (0.30 ml) added with stirring at 20° C. for 5 hours. Ethyl acetate and water were added and the organic phase dried (magnesium sulfate), evaporated and purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (3:1) to give 1-benzyl-S-(2-propenyl)-3-(4-trifluoromethyl-3-pyridylcarbonyl)isothiourea (0.55 g, Compound A-724).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[S:25][C:16]=12
Reactant: N#Cc1cnc2cc(-c3ccccc3)sc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccccc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (336 mg, 1.75 mmol) and 60% sodium hydride (69 mg, 1.73 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 40 minutes. The solution is cooled and 7-chloro-2-phenylthieno[3,2-b]pyridine-6-carbonitrile (270 mg, 1.0 mmol) is added. The reaction mixture is heated at reflux for 5.5 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The aqueous layer is acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is treated with ethyl acetate and hexane and the insoluble material is collected by filtration. The solid is suspended in hot methanol and ethyl acetate and the mixture is filtered while warm to provide 50 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-phenylthieno[3,2-b]pyridine-6-carbonitrile as a light brown solid, mp 274–276° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.44–7.53 (m, 3H), 7.73 (d, J=7 Hz, 2H), 7.78 (s, 1H), 7.94 (s, 1H), 8.63 (s, 1H), 9.78 (s, 1H); MS 426.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:47][CH3:48])[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41](F)(F)[CH:42]([F:44])[F:43])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:49][CH3:50])[N:27]=1.[CH2:51](N(S(F)(F)F)CC)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:47][CH3:48])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]([F:44])([F:43])[CH3:51])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:49][CH3:50])[N:27]=1
Reactant: CCc1cc(NC(CC)c2ccc(OC(F)(F)C(F)F)cc2)nc(Cl)n1
Reactant: CCN(CC)S(F)(F)F
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc(NC(CC)c2ccc(OCC(C)(F)F)cc2)nc(Cl)n1
Yield: 61.9 %

Procedure:
To a solution of 1.0 g of dl-5-chloro-6-ethyl-4-(α-ethyl-4-acetonyloxybenzyl)aminopyrimidine obtained in Example 17 dissolved in 50 ml of dried benzene was added 0.5 g of diethylaminosulfur trifluoride, and the mixture was refluxed by heating for 5 hours while stirring. After completion of the reaction, the mixture was poured into ice-cold water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene: ethyl acetate=7:1) to give 0.6 g of the desired product as pale yellow oily liquid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 3-chloro-6-trifluoromethylpyridazine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1.[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]3[N:15]=[N:16][NH:17][N:14]=3)[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Temperature: 90 °C
Yield: 55 %

Procedure:
To a solution of 2-(1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (50 mg, 0.36 mmol) in 2 mL of DMF was added sodium azide (65 mg, 1 mmol) and ammonium chloride (54 mg, 1 mmol). The reaction mixture was heated at 90° C. for 20 hrs with vigorous stirring. It was then purified by ISCO flash column chromatography (MeOH/DCM=0-100%) to give the title compound as light pink solid (45 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 3.73 (3H, s), 7.71 (1H, dd, J=1.5 Hz and 5.1 Hz), 7.74 (2H, s), 8.46 (1H, s), 8.51 (1H, d, J=5.0 Hz). [M+H] Calc'd for C10H9N7, 228. Found, 228.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:33][O:34][C:35]1[CH:45]=[CH:44][C:43](/[CH:46]=[CH:47]/[C:48](=[O:61])[C:49]2[CH:54]=[C:53]([O:55][CH3:56])[C:52]([O:57][CH3:58])=[C:51]([O:59][CH3:60])[CH:50]=2)=[CH:42][C:36]=1[O:37][CH2:38][C:39](O)=[O:40]>ClCCl.O>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:39](=[O:40])[CH2:38][O:37][C:36]3[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](=[O:61])[C:49]4[CH:50]=[C:51]([O:59][CH3:60])[C:52]([O:57][CH3:58])=[C:53]([O:55][CH3:56])[CH:54]=4)[CH:44]=[CH:45][C:35]=3[O:34][CH3:33])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2c(C)cccc2s1
Yield: 802 %

Procedure:
To a solution of 4-methyl-2-aminobenzothiazole (164 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9k) (440 mg, 80% yield)
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][N:23]=1>CN(C)C=O.O>[CH3:9][C:10]([C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][N:23]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Clc1cnc(-c2ccccc2)cn1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C(C)(C(=O)OCC)c1cnc(-c2ccccc2)cn1
Temperature: 50 °C

Procedure:
A sodium hydride-mineral oil suspension (54%; 3.1 g., 0.069 mole) is stirred with three 50 ml. portions of dry hexane, each portion being pipetted out to remove the mineral oil. Dimethylformamide (30 ml., previously distilled and dried over a molecular sieve) is added through a pressure equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is cooled in an ice-bath while diethyl methylmalonate (12 g., 0.069 mole) is added dropwise to the stirred mixture. After the addition is complete, the ice-bath is replaced by an oil bath and the temperature is raised to 50° C. To the mixture is added dropwise 2-chloro-5--phenylpyrazine (10 g., 0.053 mole) in warm dimethylformamide (55 ml.). After this addition is complete, the mixture is heated for 31/2 hours during which time the temperature is raised to 120° C. The reaction mixture is cooled to about 80° C. and water (4 ml.) is added. The mixture is concentrated to a small volume, and the residual liquid is diluted with 50 g. of ice and extracted with ether several times. The combined ether extracts are washed with 5% hydrochloric acid, then with water, and then dried and evaporated. The resulting oil is chromatographed on a column of 500 g. of Merck acid-washed alumina. Elution with benzene-hexane (4:1) through ethyl acetate-benzene (1:3) yielded diethyl α-methyl-5-phenylpyrazinylmalonate.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N:10]([O-])=O.[Na+]>C(O)(=O)C.O>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:10]=[CH:9]2
Reactant: O=N[O-]
Reactant: Cc1cc(I)ccc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Ic1ccc2[nH]ncc2c1
Reaction time: 6 h
Yield: 99.3 %

Procedure:
A solution of 4-iodo-2-methylaniline (10.0 g, 42.9 mmol) in glacial acetic acid (400 mL) was treated with a solution of NaNO2 (2.96 g, 42.9 mmol) in water (10 mL). After stirring for 6 hours, the mixture was concentrated to dryness and dissolved in ethyl acetate (EtOAc). Filtration through a pad of silica gel (EtOAc) provided the title compound (10.4 g, 99%) as a deep purple solid: ESI MS m/z 245 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[O:20][CH2:19][CH2:18][N:17]([C@@H](C3C=CC=CC=3)C)[CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])=O.[NH4+].CO.O>O1CCCC1.[Pd]>[CH3:1][N:2]([C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)c3ccccn3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1ccc([C@H]2CNCCO2)cc1)c1ccccn1
Temperature: 95 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of N-Methyl-N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)-phenyl)pyridin-2-amine (0.57 g, 1.5 mmol) and ammonium formate (0.48 g, 7.6 mmol) in tetrahydrofuran (15 ml)-methanol (30 ml)-water (16 ml) was added 10% palladium on carbon (wet, 200 mg) and stirred at 95° C. for one hour. After filtration, the solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure to give N-Methyl-N-(4-((2S)-morpholin-2-yl)phenyl)pyridin-2-amine (0.38 g, 94%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:10]([N:17]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C(Cl)Cl>[C:10]([N:17]1[CH2:21][CH2:20][C@H:19]([NH:22][CH:5]2[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4]2)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC1(C)CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: ClCCl
Product: CC1(C)CCC(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
To a solution of 4,4-dimethylcyclohexanone (3.8 g, 30 mmol) in DCM (200 ml) was added commercially obtained (3S)-1-Boc-3-aminopyrrolidine (5.6 g, 30 mmol), and NaBH(OAc) (12.7 g, 60 mmol) was added, and stirred at rt for 6 h. After the reaction finished, the solvent was concentrated in vacuo, a NaHCO3 aqueous solution was added, and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=2/1) to give the title compound (8.4 g, 94.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.ClCCl.[OH:20]O>[Ti].CC(C1C=C(C(C)(C)C)C(=O)C(=CNCCCNC=C2C(=O)C(C(C)(C)C)=CC(C(C)(C)C)=C2)C=1)(C)C.C(#N)C>[O:20]1[C@H:7]2[C@@H:8]1[C:9]([CH3:12])([CH3:11])[O:10][C:5]1[C:4]([N+:14]([O-:16])=[O:15])=[CH:3][C:2]([F:1])=[CH:13][C:6]=12
Reactant: OO
Reactant: CC1(C)C=Cc2cc(F)cc([N+](=O)[O-])c2O1
Agent: [Ti]
Agent: CC(C)(C)C1=CC(=CNCCCNC=C2C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)C(=O)C(C(C)(C)C)=C1
Solvent: CC#N
Solvent: ClCCl
Product: CC1(C)Oc2c(cc(F)cc2[N+](=O)[O-])[C@H]2O[C@H]21
Reaction time: 0.5 h

Procedure:
6-Fluoro-2,2-dimethyl-8-nitro-2H-1-benzopyran (0.23 g, 1.0 mmol) was added to a dichloromethane solution (3 mL) of the optically active titanium-salan complex (E) (24 mg, 0.020 mmol) (2.0 mol % to a substrate) at 20° C. 30% hydrogen peroxide aqueous solution (0.12 g, 1.1 mmol) was divided into three equal portions and, while stirring the reaction solution, the first addition was conducted at 20° C., and after 30 minutes, the second addition was conducted, and after 1 hour, the third addition was conducted. The time of the first addition of 30% hydrogen peroxide aqueous solution was defined as the reaction start time. After stirring the solution for 24 hours from the reaction start time at 20° C., a reaction solution sample was taken. The reaction conversion rate of the taken sample was analyzed with HPLC. The conversion rate to the compound (VII′) was 96% and an optical purity was 99% ee or more. Analytical conditions; Column name: CHIRALPAK AD-RH (three columns are serially connected), Eluent: acetonitrile/20 mM (pH8) phosphate buffer solution=6/4 (v/v), Flow rate: 0.5 mL/min, Column temperature: 40° C., Retention time: product of the reaction 17.3 min, enantiomer 16.8 min, Measured wavelength: 220 nm.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[CH3:24][NH:25][NH2:26].C(O)(=O)C.[OH-].[Na+]>O.C(O)C>[CH3:24][N:25]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH2:5][C:4]([OH:3])=[O:23])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:26]1
Reactant: CNN
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1nc(-c2ccccc2)c(CC(=O)O)c1-c1ccccc1
Yield: 66.8 %

Procedure:
6.2 grams 3,3-dibenzoyl-propionic acid-ethyl ester, 1.0 gram methyl hydrazine and 4 grams glacial acetic acid were mixed and the mixture heated to the boiling temperature under reflux for 4 hours. The reaction mixture was then evaporated, the residue taken upon benzene and extracted with water. The benzene was then distilled from the benzene phase and the residue, constituting the crude ester reaction product, was heated with 2.0 grams sodium hydroxide, 20 milliliters ethanol and 20 milliliters water to the boiling temperature under reflux for 2 hours. The reaction mixture was then worked up and the reaction product was recovered by the general procedure set out in Example (2a). The recovered free acid was recrystallized from a mixture of benzene and petroleum ether boiling in a range from 50°-70° C. 3.9 grams 1-methyl-3,5-diphenyl-pyrazol-4-acetic acid, melting at 170°-172° C., were obtained, representing a yield of 67%.
Reaction SMILES: [CH:1]([OH:3])=O.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH3:9]
Reactant: CCCCCCC
Reactant: O=CO
Product: CCC=CCCCCCCCCCC=O
Yield: 67 %

Procedure:
The Grignard solution is then added to a mixture of 1-penten-3-yl isobutyrate ester (84 g, 0.538 mol) and LiCuBr2 reagent (1 M/THF, 63 mL) at a rate that maintains the reaction temperature between 25-30° C., with cooling as necessary. The mixture is stirred for 15 minutes then quenched with aqueous citric acid solution (1 L). The layers are separated and the organic portion is washed with water (2×) and dilute sodium hydroxide solution (until pH basic). The crude organic portion is then stripped of solvent and distilled to afford 98.1 g of the 11E-tetradecenal DEA product (b.p. 150° C., 0.1 mm Hg, Yld. 64%, m/z 284), which is subsequently deprotected using formic acid in heptane at room temperature to give 11-tetradecenal (67.3 g, Yld. 67%, E/Z 83:17).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][CH:11]([CH2:16][CH:17]=[CH2:18])[C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:19]([O:22][C:23]1([CH3:52])[CH2:28][CH2:27][N:26]([C:29]2[N:34]3[N:35]=[C:36]([CH2:38]I)[CH:37]=[C:33]3[N:32]=[C:31]([CH3:40])[C:30]=2[C@H:41]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:25][CH2:24]1)[CH:20]=[CH2:21].[H-].[Na+]>CN(C=O)C>[C:48]([O:47][C@@H:41]([C:30]1[C:31]([CH3:40])=[N:32][C:33]2[N:34]([N:35]=[C:36]([CH2:38][O:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:10][CH:11]([CH2:16][CH:17]=[CH2:18])[C:12]([F:13])([F:14])[F:15])[CH:37]=2)[C:29]=1[N:26]1[CH2:25][CH2:24][C:23]([CH3:52])([O:22][CH2:19][CH:20]=[CH2:21])[CH2:28][CH2:27]1)[C:42]([O:44][CH2:45][CH3:46])=[O:43])([CH3:51])([CH3:49])[CH3:50]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCC(Oc1cc(F)ccc1CO)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(F)cc4OC(CC=C)C(F)(F)F)nn23)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(4-Fluoro-2-((1,1,1-trifluoropent-4-en-2-yl)oxy)phenyl)methanol (66 mg, 0.25 mmol) and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (145 mg, 0.25 mmol) were dissolved in 1 mL of DMF at 0° C. and 60% (mineral oil) NaH (10 mg, 0.25 mmol) added. The resulting mixture was stirred at 0° C. for 3 hours then quenched with 1N HCl. The mixture was extracted with ethyl acetate. The organic fractions were combined and dried over Na2SO4, filtered and the solvent removed to yield the crude product which was used in the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CN(C)CCO
Reactant: CON(C)C(=O)c1ccc(O)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(OCCN(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of 5-hydroxy-N-methoxy-N-methylpicolinamide (1.0 eq), 2-(dimethylamino)ethanol (1.2 eq) and PPh3 (1.2 eq) in 5 mL anhydrous THF under nitrogen was added DIAD (1.2 eq) dropwise at 0° C. The reaction was stirred overnight at rt., quenched with water, and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (40% yield).