Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[CH2:8]=O.[CH3:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)=[CH:16][CH:15]=2>CCO>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)=[CH:16][CH:15]=2
Reactant: C=O
Reactant: Cc1cnc2ccc(-c3ccc(C#N)cc3)cc2n1
Reactant: C[C@@H]1CCCN1
Agent: Cl
Solvent: CCO
Product: C[C@@H]1CCCN1CCc1cnc2ccc(-c3ccc(C#N)cc3)cc2n1
Temperature: 85 °C

Procedure:
(2R)-2-Methylpyrrolidine hydrochloride 5 (973 mg, 8.0 mmol) and 37% aqueous solution of formaldehyde (0.57 mL, 7.0 mmol) were combined in EtOH (20 mL) and heated in a sealed tube at 85° C. for 1 hour. The mixture was allowed to cool to room temperature, treated with the products from Example 61C (500 mg, 2.0 mmol), and heated at 85° C. overnight. The mixture was allowed to cool to room and concentrated to dryness under vacuum. The residue was partitioned between IPAc (50 mL) and 20% brine (40 mL). The organic layer was separated, dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with heptane:acetone:CH2Cl2:Et3N (60:40:3:1) to provide the title compounds. MS 343 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.72 (s, 1H), 8.16 (m, 2H), 8.06 (m, 2H), 7.85 (m, 2H), 7.70 (m, 4H), 3.17 (m, 8H), 2.52 (m, 2H), 2.31 (m, 2H), 2.17 (m, 2H), 1.83 (m, 2H), 1.65 (m, 4H), 1.32 (m, 2H). 13C NMR (400 MHz, CDCl3) δ 156.63, 156.41, 146.45, 145.16, 143.73, 143.70, 141.75, 141.53, 140.81, 140.60, 139.89, 139.04, 132.38, 129.66, 129.36, 128.42, 127.68, 127.65, 127.55, 137.13, 126.86, 118.29, 111.48, 111.40, 59.87, 53.93, 52.89, 35.83, 32.90, 21.98, 19.25.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:8])=[CH:5][C:6]=1C.C=O.[ClH:11].CCO[CH2:15][CH3:16]>[Cl-].[Zn+2].[Cl-]>[Cl:11][CH2:6][C:5]1[C:15]([CH3:16])=[C:2]([Cl:1])[S:3][C:4]=1[Cl:8]
Reactant: CCOCC
Reactant: Cl
Reactant: Cc1cc(Cl)sc1Cl
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1c(Cl)sc(Cl)c1CCl
Temperature: 0 °C

Procedure:
A mixture of 61.59 g. (0.368 mol) of 2,5-dichloro-3-methylthiophene, 13.1 g. of paraformaldehyde and 3.1 g. of zinc chloride was heated to 55° C. Hydrogen chloride gas was passed through the mixture for 7.25 hours. The resulting mixture was cooled and poured into a mixture of ether and ice water. The organic phase was separated and washed with sodium chloride solution, sodium bicarbonate solution and sodium chloride solution again. Evaporation of the dried solvent gave a dark brown oil which was distilled under reduced pressure to yield 3-chloromethyl-2,5-dichloro-4-methylthiophene as a pale yellow liquid, b.p. 87°-92° C./0.75 mm.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.B(F)(F)[F:11].CCOCC.[F:19][B-:20]([F:23])([F:22])[F:21].[H+].FF>C(#N)C>[F:19][B-:20]([F:23])([F:22])[F:21].[F:19][B-:20]([F:23])([F:22])[F:21].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: FB(F)F
Reactant: [O-][N+]12CCN(CC1)CC2
Agent: FF
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CC#N
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 149.2 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (2.56 g, 20 mmole), boron trifluoride etherate (2.4 mL, 20 mmole), and tetrafluoroboric acid (50% solution, 3.66 g, 20 mmole) in acetonitrile (250 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 52 mmole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 4.8 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15](C2C=NC=CC=2)=[N:14]1.C[Si](C)(C)[C:32]1[CH:36]=[C:35]([C:37](OCC)=O)N[N:33]=1.Br[CH2:45]C(C1C=C(OC)C=CC=1OC)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]([C:45]2[CH:37]=[CH:35][CH:36]=[CH:32][N:33]=2)=[N:14]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Product: CCOC(=O)c1cc(-c2ccccn2)nn1CC(=O)c1cc(OC)ccc1OC

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(2,5-dimethoxyphenyl)ethanone (purchased from Aldrich). 1H-NMR δ 8.65 (dt, 1H), 7.94 (d, 1H), 7.72 (dd, 1H), 7.57 (s, 1H), 7.47 (d, 1H), 7.22 (dd, 1H), 7.13 (dd, 1H), 6.98 (s, 1H), 6.05 (s, 2H), 4.28 (q, 2H), 3.98 (s, 3H), 3.78 (s, 3H), 1.33 (t, 3H). Calculated mass for C21H21N3O5, 395.15, observed, 396.2 (M+1).
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:2][O:27][C:26](=[O:28])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:17]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with L-phenylalanine MS (m/z): 180 [M+1]+
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([N:9]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:5][CH:6]([CH3:8])[CH3:7].O.NN.Cl>CO>[CH3:1][O:2][CH2:3][C@H:4]([NH2:9])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC[C@@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COC[C@H](N)CC(C)C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of (R)-2-(1-methoxy-4-methylpentan-2-yl)isoindoline-1,3-dione (example 9b) (3.87 g, 14.84 mmol) in methanol (30 mL), was added hydrazine hydrate (0.866 ml, 17.81 mmol) and the reaction mixture was warmed up to 45° C. for about 3 hours. The mixture was acidified with 2N HCl and stirred at 45° C. for 30 min. The solution was cooled to room temperature, filtered and evaporated. The residue was taken up with 2N NaOH and extracted with ether, dried over MgSO4, filtered and evaporated to give 1.51 g of (R)-1-methoxy-4-methylpentan-2-amine. Yield 77%. 1H NMR (500 MHz, CDCl3): 0.91 (m, 6H); 1.17 (m, 2H); 1.58 (s, 2H); 1.71 (m, 1H); 3.02 (m, 1H); 3.10 (m, 1H); 3.32 (m, 1H); 3.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8]1([CH2:13][CH2:14][C:15](=O)[CH2:16][C:17](OC)=[O:18])[O:12][CH2:11][CH2:10][O:9]1>>[OH:18][C:17]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:15]([CH2:14][CH2:13][C:8]2([CH3:7])[O:9][CH2:10][CH2:11][O:12]2)[CH:16]=1
Reactant: COC(=O)CC(=O)CCC1(C)OCCO1
Reactant: Nc1cc[nH]n1
Product: CC1(CCc2cc(O)n3nccc3n2)OCCO1
Yield: 84.5 %

Procedure:
The same procedure as in Production Example 1 was followed using 0.9 g of 3-aminopyrazole and 1.9 g of methyl 2-methyl-β-oxo-1,3-dioxolane-2-valerate. As a result, 1.85 g of 7-hydroxy-5-[2-(2-methyl-1,3-dioxolane-2-yl)ethyl]pyrazolo[1,5-a]pyrimidine was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[N:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[CH:23][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:26]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([NH:36][CH2:35][CH2:34][C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)[CH3:21])=[CH:18][CH:19]=1)=[CH:7]3
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: NCCc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)NCCc4ccncc4)cc3)cc12

Procedure:
8-Methyl-2-(4-(1-(2-(pyridin-4-yl)ethylamino)ethyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and 2-(pyridin-4-yl)ethanamine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.94 (m, 2H), 8.92 (d, 2H), 8.73 (s, 1H), 8.43 (d, 1H), 7.60 (m, 2H), 7.40 (m, 2H), 7.16-7.26 (m, 3H), 4.55 (m, 1H), 3.55 (m, 4H), 2.56 (m, 4H), 2.12 (s, 3H), 1.73 (d, 3H) LRMS [M+H]=462.2
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N.[CH:15](O)=O>C=O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH3:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=CO
Reactant: O=[N+]([O-])c1ccc2ccncc2c1
Agent: C=O
Agent: N
Product: CN1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
A solution of 4.00 g (18.7 mmol) of 7-nitroisoquinoline in 10 ml of formic acid and 17 ml of 38% aqueous formaldehyde was heated at reflux for 1 h. The reaction mixture was cooled, poured onto ice and basified with aqueous ammonia. The gummy residue which precipitated was extracted twice with methylene chloride. The dried (magnesium sulfate) organic phase was concentrated to give crude 7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline as a thick oil. This oil was immediately taken up in ethanol (50 ml) and a solution of hydrochloric acid in ethanol was added until the solution was distinctly acidic to litmus. Ether was added to induce precipitation and the resulting solid was collected to give 3.99 g (93%) of the title compound as a yellow solid, m.p. 236°-8° C. (dec).
Reaction SMILES: Br[CH2:2][CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([CH:3]2[O:4][CH2:5][CH2:6][N:7]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH2:2]2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C(CBr)OCCNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cccc(C2CN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CCO2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
Dissolve N-[2-[2-bromo-1-(3-methoxyphenyl)ethoxy]ethyl]-4-nitro-benzenesulfonamide (14.22 g, 30.96 moles) in ACN (200 mL); add potassium carbonate (6.42 g, 46.44 mmol); and heat the mixture to reflux. Stir the mixture for 3 h while refluxing. Cool the resulting mixture to ambient temperature and dilute it with EtOAc. Filter through Celite®; concentrate the filtrate under reduced pressure to provide a residue. Purify the residue via flash column chromatography eluting with a 50-80% gradient of EtOAc in hexanes. Combine the product fractions and remove the solvents under reduced pressure to provide the title compound as an orange solid (11.2 g, 95.6%). MS (m/z): 379 (M+1).
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].C(OC(=O)C)(=O)C.[CH2:13]([C:15]1[O:16][C:17]([CH2:28][CH3:29])=[C:18]([CH2:25]CC)[C:19](=O)[C:20]=1[CH2:21]CC)[CH3:14]>O>[CH2:28]([C:17]1[O:16][C:15]([CH2:13][CH3:14])=[C:20]([CH3:21])[C:19](=[C:1]([C:4]#[N:5])[C:2]#[N:3])[C:18]=1[CH3:25])[CH3:29]
Reactant: N#CCC#N
Reactant: CCCc1c(CC)oc(CC)c(CCC)c1=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCC1=C(C)C(=C(C#N)C#N)C(C)=C(CC)O1
Yield: 47 %

Procedure:
To a solution of 0.33 g (5 mmol) of malonodinitrile in 2.4 ml (25 mmol) acetic anhydride 1.20 g (5 mmol) of 2,6-diethyl-3,5-dipropyl-pyran-4-one (prepared according to J. Chem. Soc (C), 1967, 828-830) was added. After addition of 150 ml of water the resulting solution was extracted twice with ether (50 ml). The combined organic phases were washed with water (2×50 ml) and with saturated NaCl-solution (1×30 ml). After drying (Na2SO4), the solvent was evaporated (HV) and the crude product was purified via FC (n-hexane/EtOAC 7:3) yielding 0.54 g (47%) of 2-(2,6-diethyl-3,5-dimethylpyran-4-ylidene)malononitrile as a brown solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[C:34]1([NH:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:40]([CH2:41][CH2:42][NH:43][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1)=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCCNc1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Product: CON=C1C[C@@H](C(=O)NCCNc2ccccc2)N(C(=O)c2ccc(-c3ccncc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and N1-phenyl-1,2-ethanediamine, the title compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=458.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-].[Na+].B(F)(F)F.CCOCC.CO>C1COCC1>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1c(CO)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (1.82 g, 10.0 mmol) in anhydrous THF (50 ml) was added sodium borohydride (770 mg, 20.0 mmol) followed by boron trifluoride diethyl etherate (2.5 ml, 20 mmol) and the mixture stirred at ambient temperature under a nitrogen atmosphere for 2 h. MeOH was cautiously added until gas evolution had ceased and the mixture reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO4) and reduced in vacuo to give 2-amino-3-nitrobenzyl alcohol (1.42 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7](=[O:9])C.[O-:11]Cl.[Na+].[OH-].[Na+]>>[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7]([OH:11])=[O:9]
Reactant: CC(=O)c1cc(Cl)sc1Cl
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Cl)sc1Cl
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A mixture of the 1-(2,5-dichloro-thiophen-3-yl)-ethanone (10 g, 51.26 mmol) and 9.5% NaOCl (150 mL, 230 mmol, 4.5 eq., commercial bleach) was treated with 5N NaOH (1 mL, 5 mmol, 0.1 eq.). The mixture was stirred vigorously and heated to 55° C. The internal temperature was monitored closely and heat was removed to control the exotherm. After 6 h at 61° C., starting material was completely consumed. The mixture was cooled to 0° C. and carefully quenched with 20% aq. NaHSO3 solution (20 mL). At 0° C., 6M HCl (12 mL) was added to adjust the pH to 1.5. The mixture was extracted with EtOAc (300 mL and 3×50 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to a white solid (8.8 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:26])[CH2:17][C:18]([O:20][CH2:21][CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:15])[CH3:26])[C:18]([O:20][CH2:21][CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:19]
Reactant: CC(=O)CC(=O)OCC1CCC1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CCC1

Procedure:
700 mg (3.72 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 760 mg (4.46 mmol) of cyclobutylmethyl 3-oxobutanoate, 53 μl (0.93 mmol) of acetic acid and 92 μl (0.93 mmol) of piperidine in 25 ml of anhydrous dichloromethane are heated under reflux after addition of 4 Å molecular sieves (1.5 g) for 24 h. After cooling, the suspension is filtered with suction and the filtrate is washed successively with saturated sodium bicarbonate solution and sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC. 962 mg (76% of theory) of the title compound are obtained as an E/Z mixture.
Reaction SMILES: [N:1]([CH:4]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH2:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]#[CH:25].C(O)(C(O)=O)C(O)C(O)=O>>[CH2:23]([C:24]1[N:1]([CH:4]2[CH2:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]([CH2:17][C:18]([OH:20])=[O:19])[C:7]=3[CH2:6][CH2:5]2)[N:2]=[N:3][CH:25]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CC(N=[N+]=[N-])CC2
Reactant: C#CCc1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Product: O=C(O)Cn1c2c(c3ccccc31)CC(n1nncc1Cc1ccccc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 7, Step 5 to 8 from ethyl (3-azido-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetate (J. Med. Chem., 2005, 48, 897) and prop-2-yn-1-ylbenzene. The resulting racemic acid was resolved by HPLC using a 4.6×250 mm Chiralcel OD column eluting with 40% MeOH, 30% iPrOH, 29.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm (retention times=8.9 and 18.3 min) to afford EXAMPLE 9.1 and 9.2 respectively. 1H NMR of EXAMPLE 9.1: 1H NMR (400 MHz, DMSO-d6): δ 12.99 (s, 1 H), 7.53 (s, 1 H), 7.39-7.29 (m, 4 H), 7.31-7.21 (m, 3 H), 7.08 (dd, 1 H), 6.99 (t, 1 H), 4.95-4.84 (m, 2 H), 4.75 (s, 1 H), 4.22 (s, 2 H), 3.20-3.08 (m, 1 H), 3.00 (dd, 1 H), 2.86 (dd, 1 H), 2.79-2.64 (m, 1 H), 2.36-2.27 (m, 1 H), 2.05-1.95 (m, 1 H). MS (+ESI) m/z: 387.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](SC)[N:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:34][C:35]1[C:36]([F:43])=[CH:37][C:38]([CH3:42])=[C:39]([OH:41])[CH:40]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:41][C:39]4[C:38]([CH3:42])=[CH:37][C:36]([F:43])=[C:35]([NH2:34])[CH:40]=4)[N:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1ccc(Cn2cc(-c3ccnc(SC)n3)cn2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(Oc4cc(N)c(F)cc4C)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine from Example A18 (200 mg, 0.64 mmol) in dichloromethane was added m-CPBA (220 mg, 1.28 mmol). The reaction was stirred for 2 hour at RT. Water was added, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine and concentrated in vacuo. The residue was combined with 5-amino-4-fluoro-2-methylphenol (180 mg, 1.28 mmol) and K2CO3 (176 mg, 1.28 mmol) in DMF (5 mL) and the resultant mixture was heated at 90° C. overnight. After filtration and concentration, the residue was purified by silica gel column chromatography to give 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine (210 mg, 84% yield). MS (ESI) m/z: 406.2 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][N:12]3[CH2:16][C:15]4([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[O:14][C:13]3=[O:22])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][N:12]3[CH2:16][C:15]4([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)[O:14][C:13]3=[O:22])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1OC2(CCCCC2)CN1Cc1ccc(C2=CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
3-(4-Cyclohex-1-enyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (Example 1.31, 15 mg, 0.046 mmol) was dissolved in ethanol (3 mL) in a round bottom flask. Pd/C (5 mg) was added and the flask was flushed with hydrogen and stirred at room temperature overnight. The reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated in vacuo to give the title product as a white powder (15 mg, quantitative yield). 1H NMR (300 MHz, CDCl3): δ (ppm)=7.19 (s, 4H), 4.4 (s, 2H). 3.11 (s, 2H), 1.82 (m, 10H), 1.45 (m, 11H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][OH:10])=[O:8])[CH2:3][CH:4](C)C.[CH:11](=O)[CH2:12][CH2:13][C:14](=O)[CH2:15][CH3:16].[OH-].[Na+].[CH3:21]O.O>>[CH:3]([C:2]1[C:7](=[O:8])[N:9]([OH:10])[C:14]([CH2:15][CH3:16])=[C:13]([CH2:12][CH3:11])[N:1]=1)([CH3:4])[CH3:21]
Reactant: CO
Reactant: CCC(=O)CCC=O
Reactant: CC(C)C[C@H](N)C(=O)NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(C(C)C)c(=O)n(O)c1CC
Temperature: -30 °C
Reaction time: 1 h

Procedure:
3-isopropyl-5,6diethyl-1-hydroxy-2-oxo-1,2dihydropyrazine is prepared by dissolving leucine hydroxamic acid (73 mg) in a mixture of methanol/water (1/1) (5 mL) and cooling to −30° C. and mixing with 1,4-hexanedione (57 mg) at −30° C. To this mixture, a very dilute solution of (˜0.5M NaOH) is added to maintain the pH above 7.0 but not greater than 8.5 for about one hour. The temperature is then slowly brought to room temperature, and the mixture is stirred at room temperature overnight. The solid that is formed is filtered and recrystallized from ethanol/water mixture. Yield 25 mg.
Reaction SMILES: C(Cl)Cl.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[C:23](Cl)(=[O:25])[CH3:24].[Cl-].[Na+]>C(N(CC)CC)C>[C:23]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:12]2=[O:22])=[CH:9][CH:10]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(N2CCN(c3cccnc3)C2=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(N2CCN(c3cccnc3)C2=O)cc1
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a 10 ml dried methylene chloride solution of 0.57 g (2.24 mmol) of 1-(4-aminophenyl)-3-(3-pyridyl)-2-imidazolidinone in a 100 ml round-bottomed flask were added 0.34 ml (1.1 eg.) of triethylamine, and, after stirred for 15 minutes, 0.17 ml (1.1 eg.) of acetyl chloride were added dropwise under cooling with ice. After dropwise addition, the mixture was stirred for 8 hours at room temperature. To this reaction mixture were added 10 ml of saturated aqueous solution of sodium chloride, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then solvent was distilled off under reduced pressure to obtain 0.16 g (yield 24%) of 1-(4-acetylaminophenyl)-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: N12CCCNC1CCC[CH:3]=[CH:2]2.[OH:12][C:13]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].Br[C:26]1C=C(C(O)=O)C=C[C:27]=1C(O)=O.BrCC>C1C=CC=CC=1>[OH:12][C:13]1[CH:21]=[C:20]([C:22]([O:24][CH2:26][CH3:27])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15]([O:17][CH2:2][CH3:3])=[O:16]
Reactant: O=C(O)c1ccc(C(=O)O)c(O)c1
Reactant: C1=CN2CCCNC2CCC1
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Solvent: c1ccccc1
Solvent: CCBr
Product: CCOC(=O)c1ccc(C(=O)OCC)c(O)c1

Procedure:
6.62 g of 1,8-diazabicyclo[5.4.0]undecene and 100 mL benzene were added to 3.76 g hydroxyterephthalic acid (synthesized from bromoterephthalic acid by a known method) and the mixture was heated. 6.76 g of bromoethane dissolved in 38 mL benzene was added dropwise in and the reaction mixture was heated under reflux for 19 hours. The salt product was filtered off, and purification by column chromatography then yielded 4.66 g diethyl hydroxyterephthalate.