Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=[O:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH3:22][N:8]1[C:3]([C:2]([F:1])([F:20])[F:21])=[CH:4][C:5](=[O:19])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7]1=[O:9]
Reactant: COc1ccc(Cn2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
A solution of 3.0 grams (0.01 mole) of 6-trifluoromethyl-3-(4-methoxy-phenylmethyl)-2,4(1H,3H)-pyrimidinedione in 25 mL of N,N-dimethylform-amide was stirred and 1.4 grams (excess) of potassium carbonate was added. To this was then added 0.7 mL (0.01 mole) of methyl iodide. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours, then poured into a mixture of 100 mL of ice and 100 mL of aqueous 10% hydrochloric acid. The resultant solid was collected by filtration and washed with water. The solid was then dissolved in 200 mL of ethyl acetate and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure, yielding 2.1 grams (66.9% yield) of 1-methyl-6-trifluoromethyl-3-(4-methoxyphenylmethyl)-2,4(1H,3H)-pyrimidinedione, mp 79°-80° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CN(C)CCO[C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl:23]C1C2C(=O)C3C(=CC=CC=3)NC=2C=CC=1.ClC1C=C(NC2C=CC=CC=2C(O)=O)C=CC=1.S(=O)(=O)(O)O>C(O)C>[Cl:23][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1cccc2c1c(=O)c1ccccc1n2C
Reactant: O=c1c2ccccc2[nH]c2cccc(Cl)c12
Agent: O=C(O)c1ccccc1Nc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1c2ccccc2c(=O)c2c(Cl)cccc21

Procedure:
1-(2-dimethylaminoethoxy)-10-methyl-9(10H)-acridinone [IV; R' is CH3, R" is H, --O--Y--N=Z is 1--O--CH2CH2N(CH3)2 ], hydrochloride salt, m.p. 237°-241° C. (tan granules from methanol-ether). The intermediate 1-chloro-10-methyl-9(10H)-acridinone, m.p. 183°-186° C. (pale yellow granules from ethanol) was prepared by N-methylation of 1-chloro-9(10H)-acridinone, in turn prepared by cyclization of 2-(m-chlorophenylamino)benzoic acid with sulfuric acid.
Reaction SMILES: C([O:5][C:6](=[O:50])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[C@@:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[C@@:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[N:18]=[C:17]2[C:37]2[CH:38]=[N:39][C:40]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][C:42]=2[O:43][CH2:44][CH3:45])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.[OH-].[Li+].Cl>CO.O1CCCC1>[ClH:28].[C:46]([C:40]1[N:39]=[CH:38][C:37]([C:17]2[N:16]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:50])=[O:5])[CH2:13][CH2:12]3)=[O:15])[C@@:20]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([CH3:21])[C@@:19]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([CH3:29])[N:18]=2)=[C:42]([O:43][CH2:44][CH3:45])[CH:41]=1)([CH3:47])([CH3:48])[CH3:49]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1

Procedure:
{4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid tert-butyl ester was either reacted with lithium hydroxide (2N solution) in methanol and tetrahydrofuran at 50° C. for 4 h or with 1N hydrochloric acid at 50° C. for 2.5 h to give the title compound. HR-MS (ES, m/z) calculated for C35H42Cl2N5O4 [(M+H)+] 666.2609, observed 666.2611.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=O)=[N:6][CH:7]=1.O.[NH2:35][NH2:36]>C(O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:4]2[C:5]([C:8]3[C:10]4[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:12](=[O:14])[NH:36][N:35]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:21])=[O:22])=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc12
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 2-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-benzoic acid (18 mg, 0.0347 mmol) and 2.3 mg of hydrazine hydrate in 1.0 ml of ethanol was refluxed for 4 hours. After cooled to room temperature the mixture was concentrated and the residue was purified via preparative TLC to afford 12 mg of title compound as a white powder. MS: (M+H)/z=515.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:33]([O:38]C)(OC)[O:34]C.Cl>O1CCCC1>[C:5]1([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]([C:22]3[CH:23]=[CH:24][C:25]([B:33]([OH:38])[OH:34])=[CH:26][CH:27]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Temperature: -78 °C
Yield: 84 %

Procedure:
In a 500 mL three-neck flask were added 20 g (49 mmol) of 9-(4-bromophenyl)-10-phenylanthracene obtained by the above Steps 1(1) to 1(4) of Synthesis Example 3 and 300 mL of tetrahydrofuran (abbr.: THF), and the mixture was stirred under a nitrogen stream at −78° C. Then, 34 mL (54 mmol) of n-butyllithium (1.6 mol/L hexane solution) was dropped, and this mixture was stirred for 2 hours at the same temperature. After the stirring, 13 mL (110 mmol) of trimethyl borate was added to this solution, and the mixture was stirred for 24 hours at room temperature. After the stirring, this mixture was brought back to room temperature, 200 mL of (1.0 molL) hydrochloric acid was added therein, and this mixture was stirred for 1 hour. After that, the organic layer thereof was washed with water and separated into the organic layer and the aqueous layer, and the obtained aqueous layer was extracted with ethyl acetate. After this extracted solution was washed together with the organic layer with saturated saline, magnesium sulfate was added therein for drying. The mixture was subjected to suction filtration, and the obtained filtrate was concentrated to obtain a solid. The obtained solid was recrystallized from a mixed solvent of chloroform and hexane, whereby 15 g of a white powdered solid of 4-(10-phenyl-9-anthryl)phenylboronic acid, which was the object of the synthesis, was obtained in a yield of 84% (synthesis scheme (X-5)).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([NH2:17])=[O:16].[Cl:18][CH2:19][C:20](=O)[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>>[Cl:18][CH2:19][C:20]1[N:17]=[C:15]([CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[O:16][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1oc(-c2ccccc2)nc1CCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)co1
Temperature: 130 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (10.0 g) and 1,3-dichloro-2-propanone (5.35 g) was stirred at 130° C. for 2 hrs. An aqueous potassium carbonate solution was added to alkalize the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was subjected to silica gel column chromatography to give crystals (2.30 g, 18%) of 4-[2-(4-chloromethyl-2-oxazolyl)ethyl]-5-methyl-2-phenyloxazole from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 71-72° C.
Reaction SMILES: [NH:1]([C:56]([O:58]C(C)(C)C)=O)[C@H:2]([C:18]([NH:20][C@@H:21]([C:34]([NH:36][C@H:37]([C:45]([N:47]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH3:48])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]=[O:33])[CH:24]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[CH2:64](Cl)Cl>>[NH:1]([C:56]([CH3:64])=[O:58])[C@H:2]([C:18]([NH:20][C@@H:21]([C:34]([NH:36][C@H:37]([C:45]([N:47]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH3:48])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]=[O:33])[CH:24]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: ClCCl
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of Boc-Lys(Z)-D-Trp(CHO)-Phe-NMeBzl (1.04 g) in methylene chloride (10 ml) was added 4N-HCl/DOX (10 ml) under ice-cooling. The mixture was stirred for an hour at room temperature. After evaporation, the residue was pulverized with diisopropyl ether, filtered, washed with diisopropyl ether and dried. The obtained HCl.H-Lys(Z)-D-Trp(CHO)-Phe-NMeBzl (0.94 g) was dissolved in methylene chloride (15 ml) and cooled in an ice-bath. To the solution were added triethylamine (0.34 ml) and Ac2O (0.11 ml) and the mixture was stirred for an hour at the same temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with water, 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water and saturated sodium chloride, and then dried over magnesium sulfate. The evaporated residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (50 ml). The fractions containing the object compound were combined and evaporated. The residue was pulverized with n-hexane, filtered, washed with n-hexane and dried to give Ac-Lys(Z)-D-Trp(CHO)-Phe-NMeBzl (0.82 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([O:35][CH3:36])[C:24]([NH:27]C(=O)OC(C)(C)C)=[N:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:37])=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([O:35][CH3:36])[C:24]([NH2:27])=[N:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:37])=[N:7]1
Reactant: COc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)c3c2)cnc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)c3c2)cnc1N
Yield: 12.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl (5-(3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (100 mg, 0.178 mmol) was deprotected in TFA/DCM (2/5 ml) to afford 10 mg (9.8% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.56 (s, 1H), 8.14-8.13 (d, 1H), 7.70-7.69 (d, 2H), 7.53 (s, 1H), 6.91-6.86 (td, 1H), 6.79-6.76 (d, 2H), 5.36 (s, 2H), 4.07 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H). MS: m/z=461.3 (M+1), HPLC: 95.61% in method B.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH2:44]([C:48]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:49]=1[CH2:50][NH:51][CH:52]1[CH2:54][CH2:53]1)[CH2:45][CH:46]=[CH2:47]>C(#N)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:51]([CH2:50][C:49]4[CH:55]=[CH:56][C:57]([F:59])=[CH:58][C:48]=4[CH2:44][CH2:45][CH:46]=[CH2:47])[CH:52]4[CH2:54][CH2:53]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCCc1cc(F)ccc1CNC1CC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCCc1cc(F)ccc1CN(Cc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (53.3 mg, 0.091 mmol) in acetonitrile (2 mL) at 0° C. was added Hunig's Base (0.016 mL, 0.091 mmol) and N-(2-(but-3-en-1-yl)-4-fluorobenzyl)cyclopropanamine (20 mg, 0.091 mmol). It was stirred at 0° C. for 2 h and then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)(cyclopropyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (45 mg, 0.067 mmol, 73.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=8.3, 6.1 Hz, 1H), 6.89-6.78 (m, 2H), 6.41 (s, 1H), 6.06-5.95 (m, 2H), 5.80 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.17 (d, J=11.0 Hz, 1H), 5.03-4.92 (m, 2H), 4.30-4.13 (m, 2H), 4.01 (d, J=4.9 Hz, 2H), 3.88 (s, 2H), 3.80 (s, 2H), 2.76-2.69 (m, 2H), 2.63 (s, 3H), 2.33-2.22 (m, 2H), 2.10-1.87 (m, 4H), 1.72 (br. s., 1H), 1.36 (br. s., 3H), 1.27-1.21 (m, 12H), 0.48-0.31 (m, 4H), 4 protons from piperidine were missing. LCMS (M+1)=676.5.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>CO.O1CCCC1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:12])[CH3:11]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reaction time: 8 h
Yield: 91 %

Procedure:
5-Acetyl-2-benzyloxybenzoic acid methyl ester (5.69 g, 20 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (20 mL). 2N Sodium hydroxide (11 mL) was added dropwise, and the mixture was stirred for 8 hours. The solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to the residue, and it was extracted with dichloromethane. After the dichloromethane layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was washed with isopropyl ether to give the title compound (4.92 g, 91.0%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15]CC)=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH2:21][CH3:22].[OH-].[Na+]>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:12]=[N:11][N:10]([CH2:21][CH3:22])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol) in DMF(10 mL) was carefully added sodium hydride (29.1 mg, 1.211 mmol). After 15 minutes stirring, iodoethane (0.077 mL, 0.951 mmol) was added and the mixture stirred at room temperature for 2 hr. Sodium hydroxide (1 mL, 1.000 mmol) was added and the mixture allowed to stir at room temperature for 1 h. The contents were concentrated in vacuo. The crude residue was diluted with water (50 mL) and acidified with acetic acid. The contents were then extracted with DCM (4×50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: hexanes to 100% EtOAc, then DCM to 20% MeOH:DCM). The final product was collected as 90 mg (45%). LCMS E-S (M+H)=232.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.17 (m, 4 H) 1.41 (t, J=7.33 Hz, 3 H) 2.35-2.45 (m, 1 H) 4.34-4.57 (m, 2 H) 7.62 (s, 1 H) 8.24 (s, 1 H) 13.83 (br. s., 1 H). Regiochemical assignment supported by 2D HNMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].O>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:14])[CH:15]=[CH:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cn1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 6-methoxy-pyridine-3-carbaldehyde (1 g, 7.29 mmol, 1 eq) in 50 ml of dry DCM was added portionwise (methoxycarbonylmethylene)triphenylphosphorane (1.05 eq, 2.56 g). The mixture was stirred at room temperature for 16 hours (overnight). The mixture was then poured into 200 ml of water and the organic substances were extracted with DCM (twice, 150 ml of DCM was used in total) The gathered DCM layers were dried and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 100 g normal phase silica SNAP coloumn and cyclohexane/EtOAc solvent system (gradient 3-22% of EtOAc in 20 coloumn volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(6-methoxy-pyridin-3-yl)-acrylic acid methyl ester (1.04 g, yield=73.8%, purity=95%). MS: [M+H]+=194.17 1H NMR (300 MHz; CDCl3) δ/ppm 3.81 (s, 3H), 3.97 (s, 3H), 6.34 (d, J=16.02 Hz, 1H), 6.77 (d, J=8.79 Hz, 1H), 7.65 (d, J=16.02 Hz, 1H), 7.77 (dd, J=8.70 Hz, J=2.40 Hz, 1H), 8.27 (d, J=2.40 Hz, 1H)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[N+:16]([C:19]1[C:20](=O)[NH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1)([O-:18])=[O:17].C(=O)(O)[O-].[Na+]>O>[Cl:3][C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)nc1Cl
Temperature: 140 °C
Yield: 87 %

Procedure:
To phosphorous oxychloride (11 ml, 117 mmol) was added quinoline (8.4 ml, 70 mmol) followed by 3-nitro-6-trifluoromethyl-2(1H)-pyridone (24.0 g, 115 mmol), and the resulting solution heated at 140° C. for 18 h. The solution was then cooled to 100° C., when water (50 ml) was carefully added. After cooling to room temperature, saturated sodium bicarbonate (200 ml) was added and the mixture extracted with ethyl acetate (2×200 ml). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as a brown oil (22.7 g, 0.1 mol, 87% yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2c(F)cccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1c(F)cccc1F
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 90.3 %

Procedure:
Trans-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.399 g, 1.04 mmol) (from example 127, step 1) was dissolved in MeOH (3.5 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.306 mL, 1.04 mmol) was added over 5 min. After 45 min with stirring, hydroxylamine (50% by weight in water, 0.064 mL, 1.04 mmol) was added over one minute and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5.36 mL, 32.16 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and the crude mixture redissolved in DCM and washed with water. The organic phase was dried and concentrated to give crude trans-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.331 g, 90%). MS m/z 353 (M+H)+
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])C.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][C:19]#[N:20])=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:19]([C:18](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:17]1[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=1)#[N:20]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC1(OCC)CCCN1C
Solvent: c1ccccc1
Product: CN1CCCC1=C(C#N)c1ccc(Cl)cc1

Procedure:
Boil 22.7 g of 2,2-diethoxy-1-methylpyrrolidine, 19.8 g of 4-chlorobenzylcyanide and 90 ml of benzene for 1 hour under reflux and with stirring. Distil off the volatile constituents under a vacuum. After trituration with a little diethyl ether, filter off the residue to obtain 20.8 g (68% of theory) and the title compound (m.p. 71° to 72° from isopropanol).
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([P:21](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][O:12][P:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(C2CCCCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=P(OCc1ccc(C2CCCCC2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a stirred solution of 4-cyclohexylbenzyl alcohol (1 g, 5.26 mmol) in 45 ml of dry dichloromethane, 5 ml of triethylamine and 41 mg of dimethylaminopyridine was added 1.05 ml (1.25 g) of diphenylphosphinic chloride. The mixture was stirred at room temperature for 3 h after which it was concentrated to approximately 10 ml. The mixture was diluted with dichloromethane, washed with cold 10% sodium bicarbonate, water, dried (sodium sulfate), filtered and concentrated to approximately 10 ml. The resulting solution was chromatographed on silica gel, eluting with ethyl acetate/heptane to provide 1.92 g of the title compound.