Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1
Reactant: O=C(CBr)c1ccsc1
Reactant: O=c1ncc(Br)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Br)cnc1=O)c1ccsc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 5-bromopyrimidin-2-one (700 mg) and 3-bromoacetylthiophene (1.025 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1 h. the mixture was cooled to 3° C. and the precipitate collected. The dried solid was crystallised from ethanol to give the title pyrimidinone (475 mg), m.p. 180°-182° C. (dec), λmax (EtOH) 250.5 nm (ε 14,930), 334.5 nm (ε 3,260).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:24]2[CH:23]=[CH:22][C:21]3[O:16][CH2:17][CH2:18][O:19][C:20]=3[CH:25]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.26-7.16 (m, 3H), 7.07 (d, 1H), 6.85-6.78 (m, 3H), 4.24 (s, 4H), 3.75 (s, 2H), 3.68 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.62 (t, 2H); MS 342 (M+1).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][NH:5][CH2:4]1.Cl.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[C:19](=[O:20])[C:18]([N:21]3[CH:25]=[CH:24][N:23]=[N:22]3)=[CH:17][NH:16]2)[CH:10]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:2][CH:3]1[CH2:6][N:5]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([N:15]3[C:19](=[O:20])[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)=[CH:17][NH:16]3)[CH:10]=2)[CH2:4]1
Reactant: CC1CNC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1CN(c2cc(-n3[nH]cc(-n4ccnn4)c3=O)ncn2)C1

Procedure:
43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 12A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 25 mg (25% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([F:35])([F:34])([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:23]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([F:35])([F:31])([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Product: O=C(CC1(NC(=O)OCc2ccccc2)COC1)OCC(=O)c1ccc(S(F)(F)(F)(F)F)cc1

Procedure:
Prepared by Method E using (3-{[(benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 0.647 g, 2.44 mmol) and 2-bromo-1-[4-(pentafluoro-λ6-sulfanyl)phenyl]-ethanone (Preparation 40, 0.793 g, 2.44 mmol) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:31][C:30]1[CH:29]=[CH:28][C:27]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)[CH:35]=2)=[CH:26][C:25]=1[NH:24][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1N
Product: Cc1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 57 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpiperidin4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-piperidinobenzamide to give N-[2-methyl-5-(3-piperidinobenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 57% yield; NMR Spectrun: (DMSOd6) 1.39 (s, 9H), 1.54 (m, 4H), 1.62 (m, 4H), 1.91 (m, 2H), 2.19 (s, 3H), 3.2 (m, 4H), 3.65 (m, 2H), 4.64 (m, 4H), 7.09 (m, 1H), 7.19 (m, 2H), 7.27 (m, 2H), 7.41 (t, 2H), 7.58 (m, 2H), 7.79 (m, 1H), 9.83 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M—C3H7+ 557.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: Cc1noc(-c2sc(NC(=O)c3ccccc3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and benzoyl chloride.
Reaction SMILES: NC1SC(C(OCC)=O)=C(C)N=1.[NH2:13][C:14]1[S:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=1.Cl[CH2:29][CH2:30][N:31]=[C:32]=[O:33]>>[O:33]=[C:32]1[NH:31][CH2:30][CH2:29][N:13]1[C:14]1[S:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([C:19]([F:22])([F:20])[F:21])[N:18]=1
Reactant: O=C=NCCCl
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Agent: CCOC(=O)c1sc(N)nc1C
Product: CCOC(=O)c1sc(N2CCNC2=O)nc1C(F)(F)F
Yield: 30 %

Procedure:
Following the procedure as described in Example 3, making variations as required to replace ethyl 2-amino-4-methylthiazole-5-carboxylate with ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate to react with 2-chloroethyl isocyanate, the title compound was obtained as a colorless solid in 30% yield: mp 185-187° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 5.54 (s, 1H), 4.36-4.21 (m, 4H), 3.74-3.68 (m, 2H), 1.36-1.31 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 159.8, 157.0, 125.4, 122.6, 121.8, 118.2, 62.0, 44.2, 43.8, 14.0; MS (ES+) m/z 310.2 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:14]([O:16]C)=O)[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[N:5][N:4]=1.[CH2:18]([NH2:20])[CH3:19]>CO>[CH2:18]([NH:20][C:14]([C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2[N:7]([C:3]([NH2:2])=[N:4][N:5]=2)[N:8]=1)=[O:16])[CH3:19]
Reactant: COC(=O)c1nn2c(N)nnc2c(C)c1C
Reactant: CCN
Agent: Cl
Solvent: CO
Product: CCNC(=O)c1nn2c(N)nnc2c(C)c1C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Methyl 3-amino-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylate hydrochloride (W1.145; 200 mg) was dissolved in methanol, cooled to 0° C., slowly admixed dropwise with ethylamine (1.81 ml; 2 M in THF) and stirred at 0° C. for 6 h. Then a further equivalent of ethylamine was added and the mixture was left to stand at RT over the weekend. Subsequently, the mixture was concentrated and purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 149 mg of the title compound were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:31]1C=CN=C1)=O.[NH4+].[OH-]>CCOC(C)=O.C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH2:31])=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:23]([CH3:27])([CH3:28])[C:24]3([CH3:25])[CH3:26])=[O:21])=[CH:9]2)[CH2:5][CH2:6]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(N)=O)cc23)C1(C)C
Yield: 20 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114 B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and concentrated aqueous NH4OH (2 mL) in 5 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (20 mg, 0.052 mmol, 20% yield). 1H NMR (CDCl3, 300 MHz) δ ppm 1.32 (s, 6H), 1.36 (s, 6H), 1.39-1.58 (m, 4H), 1.92 (s, 1H), 2.08-2.23 (m, 1H), 3.34 (dt, J=11.4, 2.5 Hz, 2H), 3.94-4.04 (m, 2H), 4.08 (d, J=7.1 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.98 (dd, J=8.5, 1.4 Hz, 1H), 8.84 (d, J=1.0 Hz, 1H); MS (DCI/NH3) m/z 383 (M+H)+; Anal. Calculated for C23H30N2O3.0.4H2O: C, 70.89; H, 7.97; N, 7.19. Found: C, 70.77; H, 7.91; N, 7.32.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:6]=2[N:7]=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[O:30][CH2:31][C:32](O)=[O:33])([O-:26])=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:32](=[O:33])[CH2:31][O:30][C:29]3[CH:35]=[CH:36][CH:37]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)[CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:8][C:6]=2[N:7]=1
Reactant: O=C(O)COc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)oc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(C(=O)COc3cccc([N+](=O)[O-])c3)CC2)c2nc(-c3ccc(F)cc3)oc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-oxazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) and 2-(3-nitrophenoxy)acetic acid (0.22 mmol) in DMF (2 ml) was added TBTU (0.22 mmol) followed by diisopropylethylamine (0.22 mmol, 36 μL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound which was characterized by its mass spectrum: MS m/z (%): 522 ([M+H]+, 100).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:25])[CH2:8][CH:9]([C:13]2[CH:22]=[C:21]([CH3:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH3:24])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:24][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([CH3:23])=[CH:22][C:13]=1[CH:9]1[CH2:10][C:11](=[O:12])[C:6]([C:1](=[N:30][O:29][CH2:27][CH3:28])[CH2:2][CH2:3][CH3:4])=[C:7]([OH:25])[CH2:8]1
Reactant: CCCC(=O)C1=C(O)CC(c2cc(C)c3ccccc3c2C)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC(=NOCC)C1=C(O)CC(c2cc(C)c3ccccc3c2C)CC1=O

Procedure:
A mixture of 2-butyryl-5-(1,4-dimethylnaphth-2-yl)-3-hydroxycyclohex-2-en-1-one (0.25 g), ethoxyamine hydrochloride (1.3 equiv) and sodium acetate trihydrate (1.3 equiv) were stirred in ethanol (30 ml) at room temperature for 4 hr. The mixture was then immediately extracted with ether. The dried (MgSO4) organic extract was evaporated to give 5-(1,4-dimethylnaphth-2-yl)-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 4, Example 10.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[O:10])=[N+]=[N-].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:24]1([P:17](=[N:1][C:4]2[CH:8]=[CH:7][S:6][C:5]=2[CH:9]=[O:10])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=Nc1ccsc1C=O
Solvent: C1CCOC1
Product: O=Cc1sccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 3-azido-2-thiophenecarbaldehyde (11-1, 1.00 g, 6.53 mmol, 1 equiv, prepared by the method of Gronowitz, S., Westerlund, C., and Hornfeldt, A.-B. Acta. Chem. Scand. B 1975, 29, 224-232) and triphenylphosphine (1.71 g, 6.53 mmol, 1.00 equiv) in THF (30 mL) was stirred at 23° C. for 6 h. The reaction mixture was concentrated to give 3-[(triphenylphosphoranylidene)amino]-2-thiophenecarbaldehyde (11-2). 1H NMR (400 MHz, CD3OD) δ 10.35 (s, 1H), 7.72 (m, 6H), 7.58 (m, 2H), 7.49 (m, 6H), 7.27 (dd, 1H, J=4.5, 0.8 Hz), 6.09 (d, 1H, J=4.5 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:17]=[C:16]([CH2:18]O)[O:15][N:14]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH2:18][C:16]1[O:15][N:14]=[C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(OCc2ccc3ccccc3n2)no1
Product: ClCc1cc(OCc2ccc3ccccc3n2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of 3-(2-quinolylmethoxy)-5-isoxazolylmethanol (1.54 g) and thionyl chloride (5 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 2-(5-chloromethyl-3-isoxazolyloxymethyl)quinoline (1.61 g, yield 98%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 126–127° C.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[PdH2]>[C:2]1([CH2:1][CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)C(=O)C=Cc1ccccc1
Agent: [PdH2]
Solvent: CCO
Product: O=C(O)C(=O)CCc1ccccc1
Reaction time: 2 h

Procedure:
Benzalpyruvic acid (2-oxo-4-phenyl-3-butenoic acid) prepared as in step B of Example 2 (26.4 g, 0.15 mol) was dissolved in 150 ml ethanol. The catalyst from Example 1 was then added to the unsaturated acid. The reactor was pressurized to 10 psi with hydrogen and aged with good agitation for two hours. The catalyst was then removed by filtration and the titled product isolated in quantitative yield following vacuum concentration. 1H NMR (CDCl3, DMSO-d6) δ: 3.9 (m, 4H), 7.3 (s, 5H), 10.9 (s, 1H). IR (KBr) cm-1 : 3500m, 3000m, 1725s, 1700s, 1600m, 1200s, 970m.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:25])[F:24])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1.[N:26]1[N:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]2=[C:28]([C:35](Cl)=[O:36])[CH:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:24])[F:25])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[N:11]=[CH:10][C:9]=2[NH:21][C:35]([C:28]2[CH:27]=[N:26][N:30]3[CH:31]=[CH:32][CH:33]=[N:34][C:29]=23)=[O:36])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc(N)c1-c1cc(Cl)ccc1OC(F)F
Reactant: O=C(Cl)c1cnn2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3cccnc23)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine (60.0 g, 154 mmol) in THF (100 mL) was added dropwise over 30 minutes to an ice/water cooled mixture of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (27.8 g, 153 mmol), and DIPEA (49.5 g, 383 mmol) in THF (300 mL). On complete addition the mixture was left to stir at room temperature for 1 hour. The solvent was evaporated and the residue diluted with 0.5 N aqueous HCl and extracted with ethyl acetate. The combined organic extract was passed through Celite® to remove the residual solid and the filtrate washed with 1M aqueous K2CO3, water and brine, dried (Na2SO4) and evaporated to give a red solid. The solid was triturated with 10% diethyl ether in cyclohexane. The solid was collected by filtration, washed with 1:1 diethyl ether in cyclohexane and left to air dry to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amide as an off-white solid (59.2 g, 73%). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.61 (s, 1H), 8.77-8.78 (m, 1H), 8.51 (dd, 1H), 8.36 (s, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 7.36 (d, 1H), 7.29 (s, 1H), 7.01 (dd, 1H), 6.42 (t, 1H), 5.39-5.41 (m, 2H), 3.60-3.64 (m, 2H), 0.87-0.89 (m, 2H), 0.09 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH:16]=[CH2:17])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl.P([O-])([O-])([O-])=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([CH2:15][CH:16]2[CH2:17][O:26]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A solution of 4-allyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 12.8 mmol, prepared according to J. Comb. Chem. 2002, 4, 125) in DCM and 0.3 M phosphate buffer (pH 8, 150 mL) was treated with mCPBA (3.5 g, 1.1 eq, 70%) and the mixture vigorously stirred at rt overnight. Further 3.5 g of mCPBA were added. After a total of 24 h, the phases were separated, the org. phase dried over MgSO4 and concentrated. CC (hex/EA 2:1 to 1:1 to EA) gave the desired intermediate as colourless oil (0.88 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]3=[CH:20][CH:21]=[N:22][N:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:23]N1C(=O)CCC1=O>ClCCl>[Br:23][C:20]1[CH:21]=[N:22][N:10]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCCC2=C1C(c1ccc(Cl)c(Cl)c1)n1nccc1N2
Solvent: ClCCl
Product: O=C1CCCC2=C1C(c1ccc(Cl)c(Cl)c1)n1ncc(Br)c1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
The product from Example 6 (0.52 g, 1.56 mmol) in dichloromethane was treated with N-bromosuccinimide (0.28 mg, 1.56 mmol) and allowed to stir at ambient temperature overnight. The mixture was filtered and the filter cake washed with CH2Cl2 to provide the title compound (0.54 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26](=[NH:34])[NH:27][O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:35]([O:37][C:38](OCC)(OCC)OCC)[CH3:36].C(O)(=O)C>O1CCOCC1>[CH2:35]([O:37][C:38]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26](=[NH:34])[NH:27][O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=2)[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=1)[CH3:36]
Reactant: CCOC(=O)ONC(=N)c1ccccc1-c1ccc(CNc2c(N)cccc2C(=O)OC)cc1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)ONC(=N)c1ccccc1-c1ccc(Cn2c(OCC)nc3cccc(C(=O)OC)c32)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The pale brown syrup (8.58 g) obtained in Example (57a) was dissolved in dioxane (20 ml). To the solution were added tetraethoxymethane (8.64 g) and acetic acid (1.56 g). The mixture was stirred for 2 hours at 100° C. The reaction mixture was concentrated to dryness. The residue was crystallized from ethyl acetate (50 ml). Resulting crystalline precipitates were collected by filtration to obtain the title compound.
Reaction SMILES: C=C1OC(=O)C1.[C:7]([O:13][CH2:14][CH2:15][C:16]#[N:17])(=[O:12])[CH2:8][C:9]([CH3:11])=O.[NH3:18]>C(C#N)CO.CN(C)C1C=CN=CC=1.O1CCCC1>[NH2:18]/[C:9](/[CH3:11])=[CH:8]\[C:7]([O:13][CH2:14][CH2:15][C:16]#[N:17])=[O:12]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: N
Agent: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: N#CCCO
Solvent: C1CCOC1
Product: C/C(N)=C/C(=O)OCCC#N
Reaction time: 1 h
Yield: 36 %

Procedure:
In 37.5 g of 95% ethylene cyanohydrin was dissolved 100 mg of 4-dimethylaminopyridine, and 38.6 ml of diketene was added thereto dropwise at 70° to 80° C. for one hour under stirring, following by stirring at 70° to 80° C. for 2 hours. Sixty two grams of the resulting crude 2-cyanoethyl acetoacetate was dissolved in 400 ml of tetrahydrofuran. To the solution was added 20 g of molecular sieves 4A, following by blowing an ammonia gas for 2 hours with stirring under ice-cooling. The resulting solution was stirred in a container closed with a rubber stopper at a room temperature for 18 hours. Molecular sieves 4A was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a yellow crystal. Recrystallization from ethyl acetate/n-hexane gave 22.2 g (yield: 36%) of 2-cyanoethyl 3-aminocrotonate as a pale yellow crystal.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.32 ml (0.0027 mol) of 4-fluoro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (3:1). 0.59 g (87%) of 1-benzyl-piperidin-4-yl 4-fluoro-benzoate was obtained as a greenish oil.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([N+]([O-])=O)[CH3:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].C([OH:20])C>>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:20])[CH3:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(C=C(C)[N+](=O)[O-])cc1
Reactant: CCO
Product: CCOC(=O)c1ccc(CC(C)=O)cc1

Procedure:
The title compound was prepared in an identical manner to that described in Description 2 using 1-(4-carboethoxyphenyl)-2-nitroprop-1-ene and replacing the solvent with ethanol. γ(CDCl3) 8.62 (3H, t, J=7 Hz), 7.87 (3H, s), 6.29 (2H, s), 5.64 (2H, q, J=7 Hz), 2.76 (2H, d, J=9 Hz), 2.0 (2H, d, J=9 Hz).