Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.[CH:21](OC)(OC)OC>CN(C=O)C.Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:21][N:9]([CH:10]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]3)[C:3]=2[CH:4]=1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(Br)ccc2N)C1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2cnc3ccc(Br)cc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-((2-amino-5-bromophenyl)amino)azetidine-1-carboxylate (320 mg, 0.938 mmol), HC(OCH3)3 (5 mL) in DMF (10 mL) was added concentrated HCl (two drops). The reaction mixture was stirred at room temperature for 16 h then concentrated and diluted with DCM (50 mL) and washed with saturated NaHCO3 solution (25 mL). The organic layer was washed with water (50 mL) and dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to yield a crude desired product (250 mg, Yield 80%) which was used in the next step without further purification. LCMS (m/z): 352.1 (M+1).
Reaction SMILES: [C:1]([N:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6](=[O:10])[C:7](=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.[H][H]>C(O)C.[Pt]=O>[C:1]([N:5]1[CH2:11][CH2:12][CH2:13][NH:14][CH:7]([CH3:8])[C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(=O)N(CCC#N)C(C)(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC1NCCCN(C(C)(C)C)C1=O

Procedure:
N-(tert-butyl)-N-(2-cyanoethyl)-2-oxopropanamide obtained in Step A (440 mg) and platinum oxide (60 mg) were suspended in ethyl alcohol (40 mL) containing chloroform (0.3 mL) and mixed on a Parr shaker over an atmosphere of hydrogen at 40 psi for 16 h. The mixture was filtered, the catalyst was washed with methanol/dichloromethane (10:90) and the combined filtrate was evaporated and purified by Biotage® flash chromatography (silica gel, 5–10% methanol/dichloromethane) to yield the desired product.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49]C(=O)OC(C)(C)C)[CH2:44]2)=[C:34]2[CH2:40][CH2:39][CH:38]([C:41]#[N:42])[C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH2:49])[CH2:44]2)=[C:34]2[CH2:40][CH2:39][CH:38]([C:41]#[N:42])[C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1N)c2N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 112.1 %

Procedure:
TFA (0.02 mL, 0.3 mmol) was added to a solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (5.0 mg, 0.0072 mmol) in DCM (0.009 mL). The reaction mixture was stirred at room temperature for 15 min., then evaporated under reduced pressure. The resulting mixture was diluted with MeOH and neutralized with small amount of NH4OH. After filtration, the crude product was purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the title compound (4 mg) as a mixture of two diastereoisomers, which was further purified by chiral preparative LC (Phenomenex Lux® Cellulose-1 column, 21.2×250 mm, 5 μm particle, flow rate 18 mL/min., isocratic eluting with 45% EtOH in hexanes) to give the title compound as two separated diastereoisomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:19][CH2:18]2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Yield: 70.3 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.068 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.099 mmol) to afford the desired product (24.3 mg, 71%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.79 (s, 1H), 8.24 (d, J=1.7 Hz, 1H), 8.06-7.96 (m, 2H), 7.53-7.49 (m, 1H), 7.42 (dd, J=11.7, 2.2 Hz, 1H), 3.53 (d, J=12.8 Hz, 2H), 3.28-3.15 (m, 6H), 3.09 (d, J=7.0 Hz, 2H), 2.62-2.54 (m, 1H), 2.14-2.02 (m, 5H), 1.99 (d, J=12.5 Hz, 2H), 1.77-1.63 (m, 2H), 1.36-1.28 (m, 2H), 1.28-1.17 (m, 2H); ESI MS m/z 508 [C29H31ClFN3O2+H]+; HPLC 98.1% (AUC), tR=10.69 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
A mixture of compound 2,4,6-trichloro-pyrimidine (1 g, 5.63 mmol), 4-trifluromethoxy aniline (1.99 g, 11.24 mmol) and K2CO3 (0.7 g, 6.60 mmol) in 20 mL of ethanol was stirred at room temperature for 15 hours under nitrogen atmosphere. Ethanol was then removed under reduced pressure and water was added. The solid obtained was filtered and dried under vacuum to afford the compound (2,6-dichloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (1.7 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[NH4+].[Cl-]>CO.O.[Zn]>[NH2:14][C:9]1[CH:10]=[N:11][N:12]([CH3:13])[C:8]=1[N:6]1[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CN(c2c([N+](=O)[O-])cnn2C)CCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC1CN(c2c(N)cnn2C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.9 %

Procedure:
To a solution of tert-butyl (±)-2-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazine-1-carboxylate (500 mg, 1.54 mmol) in MeOH (20 mL) and H2O (5 mL) was added zinc (845 mg, 13 mmol) and NH4Cl (1.4 g, 26 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and filtered through Celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography PE/EtOAc (10/1˜1/10) as eluting solvents to give tert-butyl (±)-4-(4-amino-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (650 mg, ˜100%) as red solid. 1H NMR (500 MHz, CD3OD) δ (ppm): 7.22 (s, 1H), 4.35-4.33 (m, 1H), 4.12-4.11 (m, 1H), 3.94 (s, 3H), 3.43-3.46 (m, 1H), 3.25-3.30 (m, 2H), 3.01-3.00 (m, 1H), 2.89-2.87 (d, J=12 Hz, 1H), 1.49 (s, 9H), 1.34-1.36 (d, J=5.6 Hz, 3H); MS (ESI) m/z=296 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[CH2:22]([N:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[CH:12]1)[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Reactant: CC(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-nitrophenyl)-1H-imidazole (0.500 g, 2.64 mmol) in N,N-dimethylformamide (10 ml) was added cesium carbonate (1.292 g, 3.96 mmol) followed by 1-bromo-2,2-dimethylpropane (0.366 ml, 2.91 mmol). After heating at 85° overnight, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14])[CH3:2].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl>>[CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[C:10]([N:12]=[C:16]=[O:15])[C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14])[CH3:2]
Reactant: CCON=Cc1cc(N)c(Cl)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCON=Cc1cc(N=C=O)c(Cl)cc1Cl

Procedure:
65.3 g (0.28 mol) of 5-amino-2,4-dichlorobenzaldehyde (O-ethyl)-oxime (obtainable by the process given for precursors 28.1-28.3) and 60.9 g (0.31 mol) of diphosgene were reacted in the manner described for precursor 3.1. Yield: 72.9 g.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>O1CCOCC1.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>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:20]=[CH2:21])[C:3]1=[O:19]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(Br)c1=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
132 g (408 mmol) of the compound from Example 59A (alternative synthesis) are dissolved in 1.27 l of anhydrous dioxane, 136 g (428 mmol) of tributylvinyltin and 9.44 g (8.17 mmol) of tetrakis(triphenylphosphine)palladium are added and the mixture is stirred at 100° C. for 4 h. The mixture is allowed to cool and filtered through kieselguhr. The mixture is concentrated to dryness under reduced pressure. The residue is dissolved in dichloromethane and purified by chromatography on silica gel (petroleum ether/ethyl acetate 9:1, then 8:2, then 7:3). The product-containing fractions are combined, the solvents are removed and the residue is triturated with petroleum ether/diethyl ether (10:1). This gives 83 g (75% of theory) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:21])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]=O)[C:12]=2[O:11]1>C(O)(=O)C>[CH3:9][C:10]1([CH3:21])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH2:19][NH:1][C:2]3[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=3)[C:12]=2[O:11]1
Reactant: Nc1cccnc1Cl
Reactant: CC1(C)Cc2cccc(C=O)c2O1
Solvent: CC(=O)O
Product: CC1(C)Cc2cccc(CNc3cccnc3Cl)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
5 g of 3-amino-2-chloropyridine was dissolved in 80 ml of acetic acid, and 7.1 g of 2,2-dimethyl-7-formyl-2,3-dihydrobenzofuran was added. Then, the mixture was stirred at room temperature for about 30 minutes, and 16.5 g of triacetoxy sodium borohydride was added gradually under ice-cooling. After stirring the obtained reaction mixture at room temperature for about four hours, the solvent was concentrated. After adding ice-water to the residue and alkalizing it with an aqueous sodium hydroxide solution, it was extracted twice with ethyl acetate. After washing the organic layer with water and drying, it was concentrated and purified with a short column (dichloromethane/methanol=10:1) using silica gel to obtain 12.2 g of oily 3-[(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-chloropyridine.
Reaction SMILES: ClC[C:3]([O:5][CH2:6]C)=[O:4].C(=O)([O-])[O-].[K+].[K+].[O:14]=[C:15]([N:36]1[CH2:41][CH2:40][N:39]2[C:42]([C:46]([F:49])([F:48])[F:47])=[N:43][C:44](Br)=[C:38]2[CH2:37]1)[CH2:16][C@H:17]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[F:27]>[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co].[Co+2].CO>[C:31]([O:30][C:29]([NH:28][C@H:17]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[F:27])[CH2:16][C:15]([N:36]1[CH2:41][CH2:40][N:39]2[C:42]([C:46]([F:49])([F:48])[F:47])=[N:43][C:44]([C:3]([O:5][CH3:6])=[O:4])=[C:38]2[CH2:37]1)=[O:14])=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1)Cc1cc(F)c(F)cc1F
Agent: [Co+2]
Agent: [Co]
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
Refer to Journal of Organometallic Chemistry, 1985, 285(1-3), 293-303. Octacarbonyldicobalt (4.02 g, 11.76 mmol), ethyl chloroacetate (0.71 g, 5.88 mmol), potassium carbonate (1.62 g, 11.76 mmol) and 50 mL of methanol were added into the reaction flask. After stirring for 5 minutes, tert-butyl (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-prop yl]-carbamate 1n (2.3 g, 3.92 mmol) was added. The reaction mixture was stirred at 60° C. for 2 hours and then concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography with system B as eluant to obtain the title compound methyl (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-formate 1p (1.1 g, yield 50%) as a white solid. MS m/z (ESI): 565.0 [M+1].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[N:12]=[C:11]([Cl:13])[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]=12>>[Cl:13][C:11]1[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]2=[C:7]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=1
Reactant: COCCN
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: COCCNc1nc(Cl)nc2c1cnn2C

Procedure:
Reaction of 2-methoxyethylamine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-methoxy-ethyl)-amine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[N:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:5]3[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[N:45]=[C:44]([NH:43][C:33]4[CH:34]=[CH:35][C:36]([N:37]5[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]5)=[C:31]([O:30][CH3:29])[CH:32]=4)[N:46]=3)=[CH:8][CH:9]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2nc(-c3ccc(-n4ccnc4)cc3)cc(C(F)(F)F)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 4,4,4-trifluoro-1-(4-imidazol-1-yl-phenyl)-butane-1,3-dione (137 mg, 0.49 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (180 mg, 0.49 mmol) using in analogous manner the procedure described in example 29). Obtained as a pale-yellow solid (19 mg, 8%). Mp 248-250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[CH2:17][O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:10][C:9]=2[CH2:17][O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc(COCC(F)(F)F)c(-c2ccc(F)cc2)o1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: Fc1ccc(-c2oc(N3CCNCC3)nc2COCC(F)(F)F)cc1
Reaction time: 16 h
Yield: 85.1 %

Procedure:
A solution of 5-(4-Fluoro-phenyl)-2-methanesulfonyl-4-(2,2,2-trifluoro-ethoxymethyl)-oxazole (0.30 g; 0.85 mmol) in dry dioxane (6 ml) is treated with piperazine (0.37 g; 4.25 mmol) and heated in a pressure tube at 170 C. for 16 hours. The reaction mixture is partitioned between ethyl acetate (50 ml) and water (20 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol-ethyl acetate gradient (5%-20%) afforded the product as a light yellow solid (0.26 g; 86%). HNMR (CDCl3): 7.55 (m, 2H), 7.14 (t, 2H, J=8.8 Hz), 4.65 (s, 2H), 4.03 (qt, 2H, J=9.0 Hz), 3.57 (t, 4H, J=4.9 Hz), 3.01 (t, 4H, J=4.9 Hz). Mass spectrum: m/e calculated (MH+)=360; observed (MH+)=360.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[C:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:12])[CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2([CH3:12])[C:8]3[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[O:11][CH2:10]2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1(Cc2ccc(Cl)cc2)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-(4-Chloro-benzyl)-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (100 mg, 0.32 mmol), sodium hydroxide (100 mg, 2.5 mmol), ethanol (3 ml) and water (0.5 ml) in tetrahydrofuran (4 ml), was stirred for 12 h at room temperature. The reaction medium was acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product was obtained as a white solid. (M: 89 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.OS(O)(=O)=O>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1
Reactant: OC(CCCCl)(Cc1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Fc1ccc(CC(CCCCl)c2ccc(F)cc2)cc1

Procedure:
165 g (0.53 mol) of 4,5-bis(4-fluorophenyl)-4-hydroxypentyl chloride were hydrogenated in 1,650 ml of glacial acetic acid, with the addition of 16.5 g of palladium-on-charcoal (10%) and 80 ml of concentrated H2SO4, at room temperature for 5 hours. The catalyst was filtered off with suction, the filtrate was concentrated to about one quarter of the volume, methylene chloride and water were added, the pH was brought to 6 with concentrated NaOH and the organic phase was separated off, washed with NaHCO3 solution and water, dried and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[CH2:11][C:12]([O:14][CH3:15])=[O:13].O.O.O.C([O-])(=O)C.[Na+].CO>O>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(N)c1
Reactant: COC(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CNc1cccc(OC)c1

Procedure:
A mixture of 3-methoxyaniline (61.6 g), methyl chloroacetate (44 ml), sodium acetate trihydrate (114 g) and methanol (70 ml) was heated under reflux for 18 h. The mixture was poured into water (500 ml) and extracted with dichloromethane (3×250 ml). The combined, dried organic extracts were evaporated and the residue was treated with 10% concentrated sulphuric acid in methanol (250 ml). After 3 h the solution was poured carefully into 8% sodium bicarbonate (1200 ml) and partitioned with ether (4×500 ml). The combined organic extracts were washed successively with 0.5M citric acid solution (5×200 ml) and brine (500 ml), dried and evaporated to give an oil. Purification by FCC eluting initially with ether:petroleum ether 60°-80° (2:3) and then with ether:petroleum ether 60°-80° (1:1) gave the title compound (52 g) as an oil, t.l.c. (System A, 1:1) Rf 0.31.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([OH:33])[CH:23]1[CH2:22][CH2:21][N:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24]1
Reactant: Brc1ccccn1
Reactant: O=C(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccn1)C1CCN(Cc2ccccc2)CC1
Temperature: -65 °C
Reaction time: 8 h

Procedure:
2.1 ml (2.2 10-2 mole) of 2-bromopyridine in solution in 10 ml of tetrahydrofuran (THF) are added dropwise to a solution, cooled to -65° C., of 15.6 ml (2.5 10-2 mole) of n-BuLi and of 20 ml of THF. The mixture is stirred for 1/4 h at -65° C. and then 5.6 g (2 10-2 mole) of 1-benzyl-4-benzoylpiperidine in 20 ml of THF are added dropwise while the temperature is maintained at -65° C. The mixture is allowed to warm up very slowly and is then left overnight. It is heated to the reflux temperature for 2 h and then evaporated to dryness, and the residue is taken up with a mixture of water and ether. The ether phase is washed with water, dried, filtered and evaporated down. Chromatography on silica is carried out (eluent 95/5 CH2Cl2 /MeOH). A product which crystallizes from petroleum ether is collected. M.p.= 142°-143° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH:22]([OH:24])[CH3:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([C:22](=[O:24])[CH3:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-[6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]ethanol (0.20 g, 0.57 mmol) was dissolved in methylene chloride (5.00 mL) and cooled to 0° C. To this mixture, Dess-Martin periodinane (0.292 g, 0.689 mmol) was added. The mixture was stirred at 0° C. for 2 hours and then allowed to warm to 25° C. LCMS analysis indicated the reaction was complete. The mixture was extracted with EtOAc and the EtOAc extract was then washed with NaHCO3, sat. NaCl, dried and then the solvent was removed in vacuo to give the product, which was used in the next reaction. MS: 369 (M+Na+). 1H NMR (500 MHz, CDCl3): δ 7.35 (s, 1H); 5.33 (m, 1H, OCH); 3.95 (s, 411, OCH2); 2.63 (s, 3H, CH3); 1.99 (m, 4H); 1.82 (m, 2H); 1.63 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 198 (s, O═C); 171 (s, OC); 161 (s, NC); 157 (q, N2C); 119 (q, CF3); 108 (s, CH and O2C); 74 (s, OCH); 65 (s, OCH2); 32 (s, CH2); 28 (s, CH2); 26 (s, CH3).