Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](O)=[O:8].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[O:8]=[C:7]1[C@@H:6]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][O:4][C:3]2[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=[CH:21][C:2]=2[NH:1]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1C(F)(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2c(cccc2C(F)(F)F)NC1=O
Yield: 88.9 %

Procedure:
A solution of (S)-3-(2-amino-6-(trifluoromethyl)phenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (1.23 g, 3.38 mmol) and EDCI (803 mg, 4.19 mmol) in DMF (25 mL) was stirred at RT for 6 h, diluted with EtOAc and washed with H2O. The combined aqueous washes were extracted with EtOAc and the combined organic solutions were dried over MgSO4, filtered. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to afford the title compound (1.04 g, 89%) as a light brown oil. MS m/z 369 (M+Na)+
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH3:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[C:8]2[C:7]1=[O:23].I[CH3:26]>C1COCC1>[CH3:26][O:3][CH:4]([CH3:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[C:8]2[C:7]1=[O:23]
Reactant: CC(O)CN1CCn2nc(COc3ccccc3)cc2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)CN1CCn2nc(COc3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (8.6 mg, 0.21 mmol) was added to a solution of (rac)-5-(2-hydroxy-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (54 mg, 0.18 mmol) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes and then iodomethane (0.02 mL, 0.36 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with a saturated solution of NH4Cl and extracted with AcOEt, dried with (Na2SO4), filtered and the solvent evaporated in vacuo to yield a yellow oil which was purified by flash column chromatography (silica; AcOEt in heptane from 0:100 to 0:100) to yield a colourless oil which was triturated with DIPE to yield (rac)-5-(2-methoxy-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (28 mg, 49% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (d, J=6.4 Hz, 3H), 3.27 (dd, J=14.0, 7.9 Hz, 1H), 3.33 (s, 3H), 3.60-3.69 (m, 1H), 3.79-3.85 (m, 1H), 3.85-3.90 (m, 1H), 3.93-4.02 (m, 1H), 4.36 (t, J=6.2 Hz, 2H), 5.09 (s, 2H), 6.93 (s, 1H), 6.96 (t, J=7.4 Hz, 1H), 7.00 (d, J=8.1 Hz, 2H), 7.27-7.32 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)([CH3:3])[CH3:2].Cl.[O:13]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:16]2[CH2:17][C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[O:13][CH2:14][CH2:15]2)=[O:11])[N:8]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-isopropylthiazole-4-carboxylic acid (1 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.71 g) in DMF (30 mL) was cooled in an ice bath and treated with triethylamine (2.442 mL) followed by HATU (2.89 g). The ice bath was removed and the mixture was stirred at 20° C. for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 70% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 2 g.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[I:21]N1C(=O)CCC1=O.CCCCCC>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: CCCCCC
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reaction time: 0.08 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (prepared as described in EP 295 117 A1) (5.0 g) in acetonitrile (60 ml) at room temperature was added N-iodosuccinimide (3.52 g), portionwise over a period of five minutes. Stirring was continued for 1 hr and the mixture was then evaporated to dryness to provide the crude product (8.2 g), still containing succinimide. This may be used without further purification or, if desired, purified by partitioning between dichloromethane and water, separating, drying (MgSO4) and evaporating the organic layer to produce a yellow solid. Trituration with hexane provided the title compound as a white solid, m.p. 213° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])C=C[C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]([O:17][CH3:18])(C)[CH3:15]>CCOCC.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:12][O:13][CH:14]([O:17][CH3:18])[C:15]1[CH:4]=[CH:3][C:2]([F:1])=[C:9]([F:10])[C:8]=1[F:11]
Reactant: COC(C)(C)OC
Reactant: O=Cc1ccc(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: COC(OC)c1ccc(F)c(F)c1F
Yield: 71.7 %

Procedure:
A solution of 2,3,4-trifluorobenzaldehyde (25 g, 156.16 mmol), 2,2-dimethoxypropane (58.1 ml, 468.48 mmol), and 4-methylbenzenesulfonic acid (0.269 g, 1.56 mmol) was stirred at room temperature overnight. The reaction mixture diluted with ether and washed successively with aq. sodium bicarbonate solution, water, and brine. The organic layer dried over sodium sulfate and concentrated. The residue was distilled under high vacuum to give the title compound (23.07 g, 71.7%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:30][CH2:31][CH3:32])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C([Li])(C)(C)C.[O:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[NH2:15][C:6]1[C:5]2=[N:4][N:3]([CH2:30][CH2:31][CH3:32])[C:2]([CH2:1][C:41]3([OH:44])[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=C1CCOCC1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution of di(tert-butyl) 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (1.32 g, 3.00 mmol) in anhydrous tetrahydrofuran (THF) (30 mL) was cooled to −78° C. under an argon atmosphere. tert-Butyllithium (4.4 mL of a 1.7 M solution in pentane) was added over a period of five minutes, and the resulting dark-colored solution was stirred at −78° C. for 30 minutes. Tetrahydro-4H-pyran-4-one (901 mg, 9.0 mmol) was added, and reaction mixture was stirred for 10 minutes. The −78° C. bath was replaced with a 0° C. bath, and then saturated aqueous ammonium chloride (30 mL) was added. The aqueous layer was separated and extracted three times with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.3 g) was purified by automated flash chromatography (eluting with ethyl acetate) and heated in refluxing 1 M hydrogen chloride in ethanol (50 mL) for one hour. The solution was allowed to cool to room temperature and then made basic with the addition of 2 M aqueous sodium carbonate. The resulting solution was extracted four times with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.2 g) was purified by automated flash chromatography and recrystallized from acetonitrile to provide 430 mg of 4-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a white solid, mp 209-211° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(O[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])C.C(OCC)(=O)C>C(O)C>[NH2:22][C:21]1[N:12]([C:3]2[C:2]([Cl:1])=[C:6]([C:7]([F:10])([F:8])[F:9])[N:5]([CH3:11])[N:4]=2)[N:13]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: CCOC=C(C#N)C#N
Reactant: Cn1nc(NN)c(Cl)c1C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1nc(-n2ncc(C#N)c2N)c(Cl)c1C(F)(F)F

Procedure:
1.4 g (6.5 mmole) 4-Chloro-3-hydrazino-1-methyl-5-trifluoromethylpyrazole and 0.81 g (6.5 mmole) ethoxymethylenemalononitrile in 20 ml ethanol were stirred for 10 hours at room temperature and for 2 hours at 50° C. After addition of 100 ml ethyl acetate, the mixture was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (methylene chloride).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[H][H]>C(O)C.[Pd]>[CH:1]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CCCCc1ccc2c(c1)OCO2)N1CCCCC1
Yield: 78.5 %

Procedure:
Piperine (2 g, 7 mmol) was hydrogenated in ethanol (50 ml) over 5% Pd-C under a pressure of hydrogen at 10 psi for 30 mins to give tetrahydropiperine (1.59 g, 78% yield) as an oil2. Tetrahydropiperine (RV-C02)
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]2[C:19]#[N:20])=[O:7])=[CH:4][CH:3]=1.[NH2:23][OH:24]>CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]2[C:19](=[N:23][OH:24])[NH2:20])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C=CC(C#N)N2C(=O)c1ccc(Cl)cc1
Reactant: NO
Solvent: CO
Product: Cc1ccc2c(c1)C=CC(C(N)=NO)N2C(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 1-(4-chlorobenzoyl)-6-methyl-1,2-dihydroquinoline-2-carbonitrile (200 mg) in methanol (1 mL) was added cold 1M hydroxylamine in methanol (971 μL). The reaction mixture was warmed to ambient conditions and stirred overnight. The methanol is removed in vacuo and the crude product is purified by liquid chromatography (gradient elution of acetonitrile (0.02% trifluoroacetic acid)/water (0.02% trifluoroacetic acid) through a reverse phase C18 column) to give the titled compound (25 mg, 11% yield) as a pale yellow solid. (M+H)+−342.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:15]([C:12]1[CH:13]=[N:14][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)=[N:10][CH:11]=1)=[O:17])(=[O:30])=[O:31]
Reactant: O=C(O)c1cnc(-c2cc(F)cc(F)c2)nc1
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cc(F)cc(F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A mixture of 2-(3,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid (118 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) in dry DMF (5 mL) is treated with diisopropylethylamine (0.09 mL) and stirred at room temperature for 30 min. A solution of 3-methylsulfamoylbenzylamine (150 mg, 0.75 mmol.) in dry DMF (1 mL) is added and the mixture stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and water. The organic phase is separated and washed with saturated NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 30% EtOAc in DCM to afford 2-(3,5-difluorophenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (125 mg, 62%) as a solid. MS: 419 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.64 (d, 2H), 7.43-7.75 (m, 5H), 7.80 (s, 1H), 8.05 (d, 2H), 9.37 (s, 2H), 9.60 (t, 1H); IC50=49 nM.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)(Cl)Cl>[Cl:24][CH2:25][C:26]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:27]
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)NC(c1ccccc1)C(O)c1ccccc1
Yield: 76.8 %

Procedure:
To a stirred solution of 2-hydroxy-1,2-diphenylethylamine (95.5 g, 0.39 m) (obtained by catalytic reduction of benzoin oxime) and triethylamine (43.3 g, 0.429 m) in chloroform (1 liter) maintained under nitrogen was added dropwise chloroacetylchloride (46.2 g, 0.41 m) and the mixture heated to reflux for 1 hour. After cooling, the mixture was washed with 10% HCl (1 liter) and water and the organic phase dried over MgSO4. The solvent was evaporated to a solid residue which was recrystallized from methanol to give 91.0 g of N-chloroacetyl-2-hydroxy-1,2-diphenylethylamine, m.p. 166°-169°.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[O:10][C:9]=1[CH:19](Br)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([NH2:31])=[C:25]2[CH:24]=[N:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:22]([CH:19]([C:9]3[O:10][C:11](=[O:18])[C:12]4[C:17]([C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH3:20])[N:23]=[CH:24][C:25]=12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1Cc1ccccc1
Reactant: Nc1ncnc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1Cc1ccccc1)n1ncc2c(N)ncnc21
Yield: 35.4 %

Procedure:
The title compound was made in a similar way as that of the compound of example 15, 4-benzyl-3-(1-bromoethyl)-1H-isochromen-1-one (intermediate C13, 22 mg, 0.064 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (12.99 mg, 0.096 mmol), and K2CO3 (13.29 mg, 0.096 mmol) in DMF (1 ml) at 55° C. for 2 hrs to give the title compound (9 mg, 35%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9](=[O:18])[NH:8][C:7]1=[O:19].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>C(Cl)Cl>[CH3:17][C:16]1[CH:15]=[CH:14][S:13][C:12]=1[C:10]1[C:9](=[O:18])[NH:8][C:7](=[O:19])[N:6]([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])[CH:11]=1
Reactant: Cc1ccsc1-c1cn(CCCCO)c(=O)[nH]c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccsc1-c1cn(CCCC=O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
1-(4-Hydroxy-butyl)-5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 31, 30 mg, 0.11 mmol) was dissolved in dry DCM (2 mL), the solution was cooled to 0° C. and Dess-Martin periodinane (113 mg, 0.26 mmol) was added portionwise under nitrogen. The mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the solution washed with aqueous saturated Na2S2O3 (3 mL) and NaHCO3 (3 mL). The organic phase was dried (Na2SO4) and evaporated to give 30 mg of the title compound that was used in the next step without further purification (98% yield).
Reaction SMILES: CO[Na].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10])C.C([O:15][C:16](=O)[CH:17]=[CH:18][CH3:19])C>CO>[CH3:4][O:6][C:7]([C:8]1[CH:18]([CH3:19])[CH2:17][C:16](=[O:15])[CH2:10][C:9]=1[OH:11])=[O:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC=CC(=O)OCC
Agent: CO[Na]
Solvent: CO
Product: COC(=O)C1=C(O)CC(=O)CC1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a freshly prepared solution of MeONa (432 g, 7.99 mol) in MeOH (2 L) is added 3-oxo-butyric acid ethyl ester (1.04 kg, 7.99 mol) over 15 min and the mixture is stirred on an ice bath for an additional 15 min. But-2-enoic acid ethyl ester (912 g, 7.99 mol) is added dropwise at RT and the mixture stirred at RT for 1 h and then the reaction mixture is refluxed for 2 h. After cooling to RT, the precipitated solids are filtered off, dissolved in cold water (1.5 L), acidified with HCl (3 M) to pH to 7 and the resulting mixture is extracted with EtOAc (4×800 mL). The combined organic phase is dried over anhydrous Na2SO4, the solvents are evaporated in vacuo and the residue recrystallized from hexane to give 2-hydroxy-6-methyl-4-oxo-cyclohex-1-enecarboxylic acid methyl ester (672 g, 42% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:27]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccccc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (1.913 g, 5.74 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.230 g, 5.74 mmol) dissolved in water (1.500 mL) was added during 5 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.74 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 2 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (24 mL, 144.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase evaporated to yield a slightly yellow oil. The compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (1.344 g, 77%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.77-1.85 (m, 1H), 2.10-2.18 (m, 1H), 2.19-2.28 (m, 1H), 2.32-2.39 (m, 1H), 3.01-3.08 (m, 1H), 3.37 (ddd, 1H), 3.64 (s, 3H), 4.15 (ddd, 1H), 5.08-5.13 (m, 1H), 5.48 (s, 1H), 7.13-7.20 (m, 3H), 7.27 (t, 2H). MS m/z 303 (M+H)+
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:7])[CH3:6].[Br:18]Br>>[Br:18][C:16]1[CH:17]=[C:8]([C:5](=[O:7])[CH3:6])[CH:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Br)c2c(c1)CCCC2
Temperature: 25 °C

Procedure:
AlCl3 (9.9 g, 75 mmol) is added dropwise 6-acetyltetralin (5.25 g, 30 mmol) under al stirring at RT. After 20 minutes at 70° C. the reaction is cooled to RT and treated in small portions with Br2 (5.76 g [=1.86 ml], 36 mmol) over a period of 30 minutes. After that the mixture is stirred for further 60 minutes at 85° C. After cooling down to RT and addition of ice-water (450 ml) the compound is extracted with methylene chloride and purified on silica gel using a mixture of cyclo-hexane/ethyl acetate 2/1 to 1/1 obtaining the product as a pale yellow solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Si:11]([O:18][C@@H:19]1[C@H:23]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C@@H:22]([CH3:32])[O:21][C@H:20]1[N:33]1[CH:40]=[C:39]([F:41])[C:37]([NH2:38])=[N:36][C:34]1=[O:35])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>N1C=CC=CC=1>[Si:11]([O:18][C@@H:19]1[C@H:23]([O:24][Si:25]([C:28]([CH3:30])([CH3:31])[CH3:29])([CH3:27])[CH3:26])[C@@H:22]([CH3:32])[O:21][C@H:20]1[N:33]1[CH:40]=[C:39]([F:41])[C:37]([NH:38][CH:8]=[O:10])=[N:36][C:34]1=[O:35])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: O=CO
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(NC=O)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
To ice cooled acetic anhydride (0.57 ml) was added dropwise 99% formic acid (286 μl). The solution was stirred for 15 minutes at 0° C. and for 50 minutes at 50° C., and then cooled to 0° C. To the solution was added 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine (473 mg) obtained in Reference example (a) in dry pyridine (5 ml) at 0° C. The reaction mixture was stirred for 10 minutes at 0° C. and for 26 hours at room temperature. After removal of the solvent under reduced pressure the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane - ethyl acetate) followed by recrystallization from n-hexane - ethyl acetate to give 144 mg of 2',3'-bis-O-(tert-butyldimethylsilyl)-5 '-deoxy-5-fluoro-N4 -formylcytidine, mp 188° C. (dec.); MS 502 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19](/[C:22](=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])/[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone (320 mg, 1 mmol) in methanol (30 mL) was added semicarbazide hydrochloride (334 mg, 3.0 mmol). Triethyl amine was added dropwise to the reaction mixture to adjust the pH to 5˜6. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried over vacuum pump to afford 250 mg (yield: 66%) title compound as a white solid. 1H-NMR 400 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.85 (dd, 1H), 8.30 (d, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.94 (d, 1H), 7.77 (d, 1H), 7.66 (s, 1H), 7.47 (q, 1H), 6.73 (b, 2H), 4.56 (s, 2H), 2.23 (s, 3H). LCMS (method A): [MH]+=378, tR=4.64 min.