Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=1[C:21](Cl)=[O:22])([CH3:17])[CH3:16].N1C=CC=CC=1>O1CCOCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][C:21](=[O:22])[C:20]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:19]=1[O:18][CH:15]([CH3:16])[CH3:17])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: Cc1ccc(OC(C)C)c(C(=O)Cl)c1
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OC(=O)c2cc(C)ccc2OC(C)C)c(C(C)=O)c1
Yield: 113.6 %

Procedure:
Methyl 3-acetyl-4-hydroxy-benzoate (6 g) in dioxane (100 ml) was reacted with 2-isopropoxy-5-methyl-benzoyl chloride (10 g) in the presence of pyridine (10 ml) at room temperature for 16 hours. After dilution with water, the precipitate was extracted with ethyl acetate and the organic solution was washed with 5% NaHCO3 and water and then evaporated to dryness to give methyl 3-acetyl-4-(2'-isopropoxy-5'-methyl-benzoyloxy)-benzoate (13 g, oil), which was dissolved in methyl-ethyl-ketone (200 ml) and treated with anhydrous potassium carbonate (22 g) under stirring at the reflux temperature for 4 hours.
Reaction SMILES: [C:1]([N:11]([C:45]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[N:46]SC)[CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:59]([NH2:61])[CH3:60]>CN(C=O)C>[C:1]([N:11]([C:45]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[N:46][NH:61][CH2:59][CH3:60])[CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCN
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCN(C(=O)OCc2ccccc2)C(=NSC)C(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNN=C(C(=O)OCc1ccccc1)N(CCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@H](C)c1ccc(OC)cc1)C(=O)OCc1ccccc1
Yield: 65.6 %

Procedure:
A solution of (R)-N5 -(Cbz)-N5 -[methylthio(Cbz-iminomethyl)]-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide(0.5g; 0.63 mmol; from step (d) above) and ethylamine (70% wt. in water; 0.08 mL; 0.94 mmol) in DMF (10 mL) was stirred for 1 h at room temperature. The DMF was removed in vacuo and the residue dissolved in EtOAc. The EtOAc solution was washed with KHSO4 solution, then 0.5 N NaOH solution and then brine, dried over Na2SO4 and concentrated in vacuo to afford 0.33 g of the sub-title compound. The material was used directly in the next step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: Nc1cccc(I)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2cccc(I)c2)c1-c1ccccc1

Procedure:
m-Iodoaniline (5 mmol, 1.1 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The residual oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The solids were separated, and the solvents removed under vacuum. The resulting solid was recrystallized in ethanol. A portion of the material did not dissolve, and was separated by filtration. Both the recrystallized and filtered material yielded the named product (m.p. 142.6° C.-144° C).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:9])[CH3:8].[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:7]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:22][CH:21]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Pyridine (2 mL) was dissolved in 15 mL of CH2Cl2. The solution was cooled to about 5° C. and stirred while while acetyl chloride (393 mg, 5 mmol) was added slowly. Next, a suspension of p-phenylphenol (0.85 g, 5 mmol) in 20 mL of CH2Cl2 was added dropwise over a 15 min period. The cooling bath was removed and stirring continued for 30 min. The solvents were removed under reduced pressure and 50 mL of ethyl acetate was added to dissolve the solids. The solution was extracted with water, dried over Na2SO4 and evaporated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[CH3:10][C@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH3:20])=[CH:16][CH:17]=2)[C@@H:12]1[NH2:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([NH:21][C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=3)[CH2:19][C@@H:11]2[CH3:10])=[N:5][CH:6]=1
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Reactant: Nc1nc(Cl)ncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc2c(c1)[C@H](Nc1ncc(Br)c(N)n1)[C@@H](C)C2
Yield: 40.6 %

Procedure:
0.2 g (0.96 mmol) of 4-amino-5-bromo-2-chloropyrimidine, 0.196 g (1.15 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine and 0.399 g of potassium carbonate are heated in 1.5 ml of N,N-dimethylacetamide at 170° C. in a closed cell in a microwave for 60 minutes (Biotage initiator, http://www.biotage.com/DynPage.aspx?id=22001). The resulting crude mixture is absorbed on silica gel and purified by means of column chromatography using heptane/ethyl acetate as eluent. Following concentration by evaporation, 0.13 g of 5-bromo-N2-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]pyrimidine-2,4-diamine is obtained (yield 37% at 95% purity).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.ClC(OC(Cl)C)=O>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]([CH:14]2[CH2:15][NH:16][CH2:17]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sample of 2.25 g (5.5 mmole) of 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine (Step 2 of Example 76) was dissolved in 15 mL of THF and 1.1 mL (10 mmole) of 1-chloroethyl chloroformate was added. The solution was stirred at room temperature. After 2 h, the solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 h. The residue was dissolved in 20 mL of methanol and heated to reflux for 6 h. The solution was concentrated and the residue was partitioned between 100 mL ether and 50 mL of 1:1 saturated Na2CO3 solution-1M NaOH. The aqueous layer was washed with 3 portions of 100 mL ether and the combined organic extracts were washed with NaHCO3, then brine, then concentrated. The oily residue was applied to a silica gel column packed in 20% ethyl acetate-hexane and the column was washed with 5 column volumes of 20% ethyl acetate-hexane, then with dichloromethane, with 10% methanol in dichloromethane and finally with 80:20:2 dichloromethane-methanol-ammonium hydroxide. Homogenous fractions were concentrated to afford the title compound, which was not further purified but was used directly in the next step; Mass Spectrum: m/e=244 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.Cl.[Cl:17][C:18]1[C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:24]([C:23]1[C:18]([Cl:17])=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:25]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
As described in J. Med. Chem., 37, 519 (1994), a solution of 1.09 g of 2-aminophenol in 15 ml of tetrahydrofuran is added dropwise to a mixture of 2.1 g of triethylamine and 2.33 g of 2-chloropyridine-3-carbonyl chloride hydrochloride in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for one hour under argon and then refluxed for one hour. The solvent is removed under vacuum and the residue triturated with water: The solid is filtered off and washed with water to give 1.02 g of solid. Recrystallization from 2-propanol gives crystals, m.p. 145°-146° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22].Cl.CNC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:24][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)CN
Reactant: O=C(O)c1ccccc1Oc1ccc2[nH]ncc2c1
Agent: CNC
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)c1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.9 %

Procedure:
The 2-(1H-indazol-5-yloxy)benzoic acid (80.6 mg, 0.317 mmol) synthesized in Example 479 and isobutylamine (301 mg, 0.412 mmol) were dissolved in N,N-dimethylformamide (2 ml), and dimethylamine hydrochloride (72.5 mg, 0.380 mmol), hydroxybenzotriazole (47.1 mg, 0.349 mmol) and triethylamine (0.09 ml, 0.634 mmol) were added thereto at room temperature and then stirred for 2.5 hours. After the reaction, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to obtain 2-(1H-indazol-5-yloxy)-N-isobutylbenzamide (47 mg, 48%) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[NH:3]1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][NH:24][C:23]=1[CH:35]=O>C(O)C>[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])=[CH:25][NH:24][C:23]=1/[CH:35]=[C:10]1\[C:2](=[O:1])[NH:3][C:4]2[C:9]\1=[C:8]([C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]=[CH:6][CH:5]=2
Reactant: O=C(O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=O
Solvent: CCO
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)O)c3)c21
Yield: 53.2 %

Procedure:
[3-(2-Oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid (80.1 mg, 0.3 mmol) was condensed with 3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) in ethanol to give 75.3 mg of the titled compound.
Reaction SMILES: [CH2:1]1[O:31][C:4]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)([CH2:5][CH2:6][CH:7]([N+:19]([O-])=O)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[O:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:2]1[O:3][C:4]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)([CH2:5][CH2:6][CH:7]([NH2:19])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[O:31][CH2:1]1
Reactant: COc1ccc(CC(CCC2(CCc3ccc(C)cc3)OCCO2)[N+](=O)[O-])cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CC(N)CCC2(CCc3ccc(C)cc3)OCCO2)cc1OC
Yield: 96.1 %

Procedure:
In a 500 mL 3 necked rb flask equipped with a mechanical stirrer, condensor and addition funnel, a THF solution of 1-(3,4-dimethoxyphenyl)-2-nitro-7-(4-methylphenyl)-5-heptanone ethylene ketal (15.7 g; 0.037 mole) was added slowly to a suspension of LiAlH4 (14.2 g; 0.111 mole) in dry THF. The reaction was refluxed for 2 hours. Excess LiAlH4 was then decomposed with sat. Na2SO4, the salts filtered and the organic layer dried over MgSO4, filtered and concentrated to yield 14.2 g of a brown oil.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3][NH:2]1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=O)[CH2:22][CH2:21]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([N:2]1[CH2:3][C:4]3([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]3)[CH2:1]1)[CH2:22][CH2:21]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(Br)ccc31)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
In a dry 1 L flask was combined tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (6.53 g, 30.9 mmol) and 5-bromoindanone (7.00 g, 30.9 mmol) in 200 mL dichloroethane. Titanium (IV) isopropoxide (18.3 mL, 61.8 mmol) was added and the reaction was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (26.2 g, 123.6 mmol) was added and the reaction was stirred at room temperature for an additional 16 hours. The reaction was quenched with 400 mL saturated sodium bicarbonate and was stirred for 15 minutes. The mixture was passed through a thin layer of Celite®, resulting in a clear bi-phasic mixture. The two layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 17 g of a crude product as a brown oil. This material was purified via Analogix (Analogix Inc., Burlington, Wis.) chromatography eluting with 100:0→85:15 dichloromethane/methanol over 30 minutes to afford the desired product (9.82 g, 76%) as a brown foam. The enantiomers were separated via preparative chiral HPLC (Column chiralcel OJ-H, 250 mm×4.6 mm, flow-rate 2.5 ml/min, CO2/MeOH (80/20/) mobile phase with 0.1% isopropylamine) to afford the desired product (3-1a, 4.6 g, 36%). MS (ES+) 422.3 (M+H)+. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.67 (dd, 4H), 1.84-1.93 (m, 1H), 2.07-2.16 (m, 1H), 2.72-2.81 (m, 1H), 2.95-3.15 (m, 5H), 3.31 (dd, 4H), 3.85 (br s, 1H), 7.12 (d, 1H), 7.28 (br s, 1H), 7.35 (br s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([Cl:30])[N:21]=1.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33]>C1COCC1.CCOCC>[Cl:19][C:20]1[C:25]([Si:32]([CH3:34])([CH3:33])[CH3:31])=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([Cl:30])[N:21]=1
Reactant: C[Si](C)(C)Cl
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C[Si](C)(C)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: -20 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A dry 100 mL 3 neck rb flask was charged with diisopropylamine (2.15 mL, 15.3 mmol) and 40 mL of anhydrous THF. Reaction mixture was cooled at −20° C. under N2. A 2.5 M solution of n-BuLi in Hexane (5.90 mL, 14.8 mmol) was added dropwise via a syringe. The resulting reaction mixture was then cooled at −78° C. A solution of 2,6-dichloro-4-trifluoromethylpyridine (3.0 g, 14 mmol) in 5 mL of anhydrous THF was added slowly via an addition funnel to give a pale yellow solution. Reaction mixture stirred at −78° C. for 2 h. After which time, a solution of TMSCl (2.0 mL, 15.8 mmol) in 5 mL of THF was added dropwise via an addition funnel. The resulting reaction mixture was allowed to slowly warm up to room temperature and stirred over night. Reaction mixture was added to 150 mL of Et2O, washed with dilute HCl, then washed with aq. NaHCO3, dried over MgSO4, filtered and concentrated to give 3.80 g (95%) of 2,6-dichloro-4-trifluoromethyl-3-trimethylsilanylpyridine (Compound 8) as a brown oil:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:19]O>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2cccnc2c1
Reactant: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2cccnc2c1

Procedure:
To a solution of example 11A (1.98 g, 10.59 mmol) in 40 mL of anhydrous methanol was slowly added SOCl2 (1.5 mL, 31.7 mmol), and a drop of dimethylformamide as catalyst. The mixture was refluxed for 5 hrs and then concentrated under reduced pressure. The residue was dissolved in water (10 mL) and neutralized with aqueous sodium bicarbonate to pH 8. The product was extracted with methylene chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure to afford 2.13 g of the title compound. MS (ESI+) m/z 202 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][CH:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([OH:4])[CH2:6][CH2:7]2)[C:12]2[N:13]([N:37]=[CH:38][CH:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (4.0 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (20 mL)-tetrahydrofuran (20 mL), and sodium borohydride (0.28 g) was added at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (3.3 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].OS(O)(=O)=O.[CH3:20]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:20])=[O:11])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of p-nitrocinnamic acid (3.86 g, 20.0 mmol) in MeOH (50 mL) was treated with H2SO4 (2 mL) and was stirred at 25° C. for 24 h. Concentration afforded S31 (4.10 g, 19.8 mmol, 99%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) 8.26 (d, 2H, J=8.4 Hz), 7.12 (d, 1H, J=16.1 Hz), 7.68 (d, 2H, J=8.8 Hz), 6.58 (d, 1H, J=16.1 Hz), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]([CH3:32])([CH2:19][N:20]1[N:24]=[C:23]2[C:25]([Cl:31])=[CH:26][C:27]([Cl:30])=[C:28]([Cl:29])[C:22]2=[N:21]1)[C:17]#[N:18]>C1COCC1>[C:17]([C:16]([NH:15][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=1[F:1])([CH3:32])[CH2:19][N:20]1[N:24]=[C:23]2[C:25]([Cl:31])=[CH:26][C:27]([Cl:30])=[C:28]([Cl:29])[C:22]2=[N:21]1)#[N:18]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 2-fluoro-4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=494, RT=0.73 min.
Reaction SMILES: [OH-].[Na+].C([O:7][C:8](=O)[NH:9][C@H:10]([CH2:21][OH:22])[C@H:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12])(C)(C)C.F[C:25](F)(F)C(O)=O>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C1(C)C=CC=CC=1.O>[CH2:14]([O:13][C@@H:11]([C@@H:10]1[NH:9][C:8](=[O:7])[CH2:25][O:22][CH2:21]1)[CH3:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](OCc1ccccc1)[C@H]1COCC(=O)N1
Reaction time: 3 h

Procedure:
A 50% sodium hydroxide solution (400 mL) and tetrabutylammoniumbisulfate (24.1 g) were added to a toluene (400 mL) solution of ((1R,2R)-2-benzyloxy-1-hydroxymethylpropyl) carbamic acid t-butyl ester (83.1 g, CAS#133565-43-2). Under ice-cooling, t-butyl bromoacetic acid ester (125 mL) was added dropwise, and stirring was continued for 3 hours at the same temperature. Water (500 mL) and toluene (500 mL) were added, and the organic layer was partitioned, and the resultant was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and a crude material (122.5 g) containing ((2R,3R)-3-benzyloxy-2-t-butoxycarbonylaminobutoxy)acetic acid t-butyl ester was obtained. Dichloromethane (315 mL) and trifluoroacetic acid (315 mL) were added to the obtained crude material (118 q), and stirring was continued for 2 hours at room temperature. The solvent was removed under a vacuum, and methanol (350 mL) was added. Under ice-cooling, thionyl chloride (96.9 mL) was added dropwise, and the resultant was stirred at room temperature for 1 hour. The solvent was removed under a vacuum, and methanol (315 mL) was added, and under ice-cooling, sodium methoxide (165 mL, 28% methanol solution) was added dropwise. The solvent was removed under a vacuum, and ethyl acetate and water were added, and the organic layer was partitioned. The organic layer was washed with 1 N hydrochloric acid and brine in sequence, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the resultant was purified by silica gel column chromatography (ethyl acetate), and the title compound (61.57 g) was obtained. The physical property values are as follows.