Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=1.[N:22]1[N:23]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])[N:24]=[CH:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:20][N:19]([CH3:21])[C:11]1[CH:10]=[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([C:29]([C:28]4[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=4[N:23]4[N:24]=[CH:25][CH:26]=[N:22]4)=[O:30])[CH2:8]3)[CH2:1]2)[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: CN(C)c1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)c1cc(N2CC3CN(C(=O)c4ccccc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 2-[1,2,3]triazol-2-yl-benzoic acid (34.5 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (34.0 mg, 43.4%). MS (ESI) mass calcd. for C22H23F3N8O, 472.47; m/z found 473.2 [M+H]+. 1H NMR (CDCl3): 7.98 (d, J=8.1, 1H), 7.70-7.69 (m, 2H), 7.56-7.49 (m, 1H), 7.45-7.37 (m, 2H), 5.20-5.10 (m, 1H), 3.90-3.66 (m, 4H), 3.60-3.28 (m, 4H), 3.08 (s, 6H), 3.02-2.89 (m, 2H).
Reaction SMILES: [C:1](/[C:3](=[C:8]1/[C:9](=[O:22])[NH:10][C:11]2[C:16]/1=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)/[C:4]([O:6][CH3:7])=[O:5])#[N:2].[C-:23]#[N:24].[K+]>>[C:1]([CH:3]([C:8]1([C:23]#[N:24])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:19])([F:21])[F:20])[CH:15]=2)[NH:10][C:9]1=[O:22])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(OC(F)(F)F)cc21
Reactant: [C-]#N
Agent: [K+]
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(OC(F)(F)F)cc21
Yield: 90 %

Procedure:
Following the general method as outlined for Intermediate 5, starting from methyl (2Z)-cyano[2-oxo-5-(trifluoromethoxy)-1,2-dihydro-3H-indol-3-ylidene]acetate (intermediate 3) and potassium cyanide, the title compound was isolated, after evaporation, as a pale brown solid in 90% yield. This was a mixture of diastereomers.
Reaction SMILES: [SH:1][C:2]1[C:3]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=[O:21])[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[N:5]([CH3:9])[C:6](=[O:8])[N:7]=1.[CH3:28]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:9][N:5]1[C:4]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11](=[O:21])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13](=[O:14])[C:3]=2[C:2]([S:1][CH3:28])=[N:7][C:6]1=[O:8]
Reactant: CN(C)C=O
Reactant: Cn1c(=O)nc(S)c2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CSc1nc(=O)n(C)c2c1c(=O)n(-c1ccccc1)c(=O)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To crude 5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 24 (100 mg) obtained in Step 5 was added N,N-dimethylformamide (0.5 ml). Under a nitrogen atmosphere, potassium carbonate (44 mg) and methyl iodide 25 (20 μl) were successively added, and the mixture was stirred at room temperature for 3 hrs. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=4:1→3:1) to give 8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 26 (91 mg, yield 89%) as brown crystals.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[CH3:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:23]=[CH:22][CH2:21][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC=Cc1ccccc1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OCC=Cc1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 1.0 g (3.6 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 10 g (85 mmol) of β-methylstyrene under a nitrogen atmosphere is heated at 120° C. for 36 hours. The reaction mixture is concentrated in vacuo and the title compound is isolated after column chromatograph as a white solid, melting at 115-116° C.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH:9]2[CH2:13][O:12][C:11](=[O:14])[C:10]2([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[H-].[Na+].C(CC(C)(C)C)(C)C>[CH:1]1([N:7]2[CH2:8][CH:9]([CH2:13][OH:12])[C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1OCC(CNC2CCCCC2)C1(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)CC(C)(C)C
Product: O=C1N(C2CCCCC2)CC(CO)C1(c1ccccc1)c1ccccc1
Yield: 73 %

Procedure:
To 90.0 g. (0.26 mole) of 4-cyclohexylaminomethyl-4,5-dihydro-3,3-diphenylfuran-2-(3H)one in 500 ml. of isooctane was added 1.0 g. of sodium hydride (57% in mineral oil) as a catalyst and the mixture was refluxed overnight. Upon cooling a solid precipitated and the isooctane was decanted from the solid. The solid was recrystallized from isopropyl alcohol, weighed 66.0 g. (73% yield) and melted at 148°-150° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].P(Br)(Br)[Br:18].O>CCOCC>[Br:18][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1ccccc1CCCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)Cc1ccccc1CCCBr

Procedure:
To a solution of ethyl [2-(3-hydroxypropyl)-phenyl]acetate (44.4 g., 0.20 mole) in ether (300 ml.) is added dropwise during 40 minutes a solution of phosphorus tribromide (20.7 g., 0.075 mole) in ether (100 ml.). The temperature is maintained at 25°-28° C. during this time by means of a cold water bath. The reaction solution is then heated a reflux for 4 hours. It is cooled and poured into iced-water. The ether layer is separated, washed with water, dried over magnesium sulfate, and evaporated in vacuo to yield ethyl [2-(3-Bromopropyl)phenyl]acetate.
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[C:4]=1[F:13].Br[C:16]1[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[C:4]=2[F:13])=[CH:17][N:18]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1ncc(-c2ccc(C(=O)O)c(F)c2F)cn1
Temperature: 110 °C

Procedure:
A mixture of 4-(dihydroxyboryl)-2,3-difluorobenzoic acid (0.47 g, 2.3 mmol), 5-bromopyrimidin-2-amine (0.44 g, 2.6 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.1 mmol), and potassium carbonate (0.96 g, 7.0 mmol) in toluene (4.0 mL), ethanol (2.0 mL) and water (2.0 mL) was heated at 110° C. for 3 h. After cooling to RT, the mixture was washed with ether to remove impurity. The aqueous layer was adjusted to pH 6 with 1N HCl. The solid was filtered, washed with water and ether to give the desired product. LCMS: (M+H)=252.9.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:9][OH:10])[CH2:7][CH3:8].[Li+].CC([N-]C(C)C)C.[C:19]([O:26][CH2:27][CH3:28])(=[O:25])[C:20]([O:22]CC)=O>C1COCC1>[OH:10][N:9]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:7]([CH3:8])[C:20](=[O:22])[C:19]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCC(=NO)c1cccs1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=NO)c1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
1-(Thiophen-2-yl)propan-1-one oxime (6.3 g, 40.6 mmol) was dissolved in 100 mL of THF and cooled to 0° C. LDA solution (46.7 mL, 93.5 mmol, 2M in heptane/THF/ethyl benzene) was added dropwise, and the reaction mixture was stirred at 0° C. for 1 hour and then warmed to room temperature. The mixture was then transferred to an addition funnel and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (27.6 mL, 203 mmol) and THF (100 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 150 mL of 10% hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-20% EtOAc/hexanes) to give 7.7 g of the title compound. MS: (+) m/z 256.33 (M+1).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1.[OH-].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[N:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OC1CCC(Nc2nc(Cl)nc(Cl)n2)CC1
Temperature: 2.5 °C

Procedure:
To cyanuric chloride (1.2209 g, 6.6 mmol) dissolved in acetone (15 mL) stirring at 0-5° C., was added a solution of trans-4-aminocyclohexanol hydrochloride (1.0044 g, 6.6 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (5.3 mL, 13.2 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 hour under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine solution and dried over sodium sulfate. The filtered sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. The product was used with no further purification, (155a, 1.49 g, 86%), mp 120° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 6.1 min, 92.6% purity.
Reaction SMILES: C(OC[C@H](C1C(Br)=[C:17]2[C:22](=CC=1C)[N:21]=[C:20](CN(C)C)[CH:19]=[CH:18]2)OC(C)(C)C)(=O)C(C)(C)C.[C:31]([O:35][C@@H:36]([C:45]1[C:46]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[C:47]2[C:52](=[CH:53][C:54]=1[CH3:55])[N+:51]([O-])=[C:50]([CH3:57])[CH:49]=[CH:48]2)[CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:34])([CH3:33])[CH3:32].N1CCCCC1>>[C:39]([O:38][CH2:37][C@@H:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])[C:45]1[C:46]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[C:47]2[C:52](=[CH:53][C:54]=1[CH3:55])[N:51]=[C:50]([CH2:57][N:21]1[CH2:22][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH:49]=[CH:48]2)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(CN(C)C)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: C1CCNCC1
Product: Cc1cc2nc(CN3CCCCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)quinolin-6-yl)ethyl pivalate was prepared following the procedure used to prepare compound (S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate of Example 9, except that (S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide was used instead of (S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide, and piperidine was used instead of N,N-dimethylamine solution. LCMS-ESI+ (m/z): 551.3, 553.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:6](=[O:11])[CH2:7][CH2:8][C:9]#[CH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N[CH:16]([CH3:18])[CH3:17])(C)C>CN(C=O)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:6](=[O:11])[CH2:7][CH2:8][C:9]#[C:10][C:3]2[CH:2]=[C:1]([CH3:5])[C:6]([OH:11])=[CH:18][C:16]=2[CH3:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)NC(C)C
Reactant: C#CCCC(=O)C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C#CCCC(=O)C2CCCC2)c(C)cc1O
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 1-cyclopentyl-pent-4-yn-1-one (0.33 g, 2.2 mmol) from example F(7), Step 2,4-iodo-2,5-dimethyl-phenol (0.54 g, 2.2 mmol), copper (I) iodide (33 mg, 0.18 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol), and diisopropylamine (2.2 mL) in DMF (2.2 mL) was heated to 100° C. for 30 minutes. The reaction was cooled to room temperature and diluted with 10 mL of EtOAc. The resulting slurry was filtered, and the mother liquor was concentrated to a black oil. The oil was then purified by flash chromatography to give the desired product (112 mg, 19% yield). 1H NMR (CDCl3) δ: 1.58-1.84 (m, 8H), 2.15 (s, 3H), 2.29 (s, 3H), 2.68-2.70 (m, 2H), 2.75-2.79 (m, 2H), 2.90 (p, J=8.08 Hz, 1H), 6.57 (s, 1H), 7.10 (s, 1H).
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.[CH2:19](Br)[CH:20]=[CH2:21]>CN(C)C=O.C(N(CC)CC)C.C(OCC)C>[CH2:21]([N:2]1[CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]3[CH:16]=[CH:17][CH:18]=[C:7]3[CH:6]2[CH2:1]1)[CH:20]=[CH2:19]
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCN1CCN2c3ccccc3Cn3cccc3C2C1
Reaction time: 1 h

Procedure:
To the solution of 4.8 g of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine in 20 ml of dimethyl formamide and 2.44 g of triethylamine, 2.91 g of allyl bromide are added dropwise while stirring. After one hour, the mixture is diluted with diethyl ether, washed with water and saturated aqueous sodium chloride and the aqueous phase is once more extracted with diethyl ether. The combined organic solutions are washed with saturated aqueous sodium bicarbonate, dried, evaporated and the residue triturated with diethyl ether, to yield the 2-allyl-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine melting at 130°-132°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6]C(O)=O.[H][H].[C:18]([OH:21])(=[O:20])C>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]([CH3:6])[C:18]([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(C(C)C(=O)O)c1OC

Procedure:
2,3-Dimethoxycinnamic acid (50 g, 0.24 m) was suspended in a mixture of 120 ml of ethanol and 40 ml of glacial acetic acid, then treated with 0.8 g of 10% palladium-on-charcoal. The mixture was warmed on a steam bath before putting on the Paar shaker. Hydrogenation was continued until the uptake of hydrogen stopped (45 minutes). The catalyst was filtered off and the resulting filtrate was evaporated to dryness. The resulting residue solidified on standing. A quantitative yield of the desired 2,3-dimethoxyphenylpropionic acid was isolated.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH:14]N=[C:16]3[C:20]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=N[N:18]=[C:17]3N)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C[O:31]CC1.NN.[K]>CCO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:31]=[C:20]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:16][C:17]#[N:18]
Reactant: NC1=NN=C(c2ccncc2)C1=NNc1cccc(CN2CCOCC2)c1
Reactant: C1CCOC1
Agent: NN
Agent: [K]
Solvent: CCO
Product: N#CCC(=O)c1ccncc1
Product: Nc1cccc(CN2CCOCC2)c1

Procedure:
In a similar manner, 4-[(3-morpholin-4-ylmethylphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine was prepared according the procedure described above in Paragraphs A and B with the following modifications: THF was used as the solvent to replace EtOH and the temperature was 55° C. for the hydrazine reaction. 3-Morpholin-4-ylmethylphenylamine (0.192 g, 1.0 mmol) and potassium salt of 3-oxo-3-pyridin-4-ylpropionitrile (0.276 g, 1.5 mmol) yielded 0.117 g of the product (32%). MS (m/z, ES+): 364.4 (M+1. 100%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][C:8]2=[O:15])=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(C(F)(F)F)C(F)(F)F>[CH2:18]([N:25]=[C:13]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:15])[CH2:9]1)[NH2:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CN1CCN(Cc2ccc(F)cc2)C(=O)C1
Reactant: NCc1ccccc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: NC(=NCc1ccccc1)N1CCN(Cc2ccc(F)cc2)C(=O)C1

Procedure:
A solution of 4-(4-fluorobenzyl)-3-oxopiperazine-1-carbonitrile (0.56 g, 2.40 mmol) and benzylamine (0.53 mL, 4.80 mmol) in 1,1,1,3,3,3-hexafluoroisopropanol (10 mL) was heated to reflux overnight. The solvent was removed in vacuo and the residue was purified by prep HPLC on a C18 column eluting with a water/acetonitrile/TFA gradient. The pure fractions were concentrated to an oil. The oil was partitioned between aqueous sat. NH4Cl and chloroform. The layers were separated and the aqueous layer was extracted twice more with chloroform. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give an oil for the title compound. 1H NMR (400 MHz, d6 DMSO) before work-up δ 8.29 (t, 1H, J=5.5 Hz), 7.81 (bs, 2H), 7.29-7.40 (m, 7H), 7.19 (t, 2H, J=8.8 Hz), 4.56 (s, 2H), 4.45 (d, 2H, J=5.7 Hz), 4.15 (s, 2H), 3.67 (m, 2H), and 3.39 (m, 2H). ES MS (M+1)=341.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[CH2:9][CH2:8][CH2:7][CH:6]=1.C([O-])(=[O:13])C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]1[CH2:9][CH:8]2[O:13][CH:7]2[CH2:6]1
Reactant: COC(=O)CC1=CCCC1
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CC1CC2OC2C1
Temperature: 35 °C
Yield: 424.1 %

Procedure:
43.46 g (0.31 mol) of cyclopentenylacetic acid methyl ester are dissolved in 80 ml of chloroform. After the addition of 4 g of sodium acetate, 82.51 g of a 40% solution of peracetic acid in acetic acid are added dropwise thereto, with stirring, the temperature being maintained at about 35° C. The reaction mixture is then stirred for a further 5 hours at 35° C. The reaction mixture is extracted with 5% sodium hydrogen carbonate solution and then twice with water. The organic phase is then separated off and dried and residual peroxide is destroyed with sodium sulfite. After distillation of the organic phase there are obtained 32.3 g of 3,4-epoxycyclopentylacetic acid methyl ester (66.5% of theory).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([NH:11][C:12](=S)[NH:13][NH2:14])[CH:8]([CH3:10])[CH3:9].O1CC[CH2:18][CH2:17]1>>[CH2:7]([NH:11][C:12]1[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:17]([CH3:18])[NH:14][N:13]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: C1CCOC1
Reactant: CC(C)CNC(=S)NN
Reactant: COC(=O)CCl
Product: COC(=O)c1c(NCC(C)C)n[nH]c1C
Reaction time: 0.5 h

Procedure:
15.1 g of methyl 2-chloroacetate is added to a suspension of 14.7 g of 4-isobutylthiosemicarbazide in 150 ml of tetrahydrofuran. The mixture is stirred for 30 minutes and then boiled. After stirring for a further hour at 65° C., the mixture is cooled, the precipitated solid is isolated and washed with acetone. The residue is dissolved hot in water, filtered off from the precipitated sulfur and, after cooling, aqueous ammonia solution is added. After suction filtering and drying the product, 3-isobutylamino-4-methoxycarbonyl-5-methylpyrazole is isolated; m.p. 100°-103° C.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:21]1([CH2:24][C:25]([NH2:33])([CH3:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C:25]([NH:33][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][O:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:32])[CH2:23][CH2:22]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)COC2)cn1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3(F)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 131b) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (42 mg, 54%); MS (ESI, m/z): 459.6 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:11][C:12]([NH:14][C@H:15]([C:20]([OH:22])=O)[CH2:16][C:17](O)=[O:18])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:23]([N:25](C(C)C)[CH:26](C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[CH2:4]([O:11][C:12](=[O:13])[NH:14][C@@H:15]([CH2:16][C:17]([N:25]([CH3:26])[CH3:23])=[O:18])[C:20]([N:2]([CH3:3])[CH3:1])=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a solution of 50% aqueous dimethylamine solution (2.16 g) and N-[(benzyloxy)carbonyl]-L-aspartic acid (2.13 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (4.12 g) in DMF (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.06 g) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (550 mg).