Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([NH:12][C:13]([C:15]2[O:19][N:18]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=2)=O)[CH:6]=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[N:4]=1>CC(O)=O.[Fe]>[C:20]([C:17]1[CH:16]=[C:15]([C:13]2[NH:9][C:8]3[C:3]([O:2][CH3:1])=[N:4][C:5]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])=[CH:6][C:7]=3[N:12]=2)[O:19][N:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1nc(-c2ccccc2C(F)(F)F)cc(NC(=O)c2cc(C(C)(C)C)no2)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1nc(-c2ccccc2C(F)(F)F)cc2nc(-c3cc(C(C)(C)C)no3)[nH]c12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide (110 mg, 0.237 mmol, prepared as described in STEP C above) in AcOH (5 mL) was treated with iron powder (66.1 mg, 1.18 mmol), and the mixture was heated to 100° C. for 3 h. The AcOH was removed in vacuo. The residue was taken up in saturated aqueous NaHCO3 (50 mL) and extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min). The chromatography was repeated as above to yield 2-(3-tert-butyl-isoxazol-5-yl)-4-methoxy-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]-pyridine as a white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C21H19N4O2F3: 417.1 (M+H). Measured: 417.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>C1COCC1>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]([OH:19])=[O:18])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 1-bromo-4-(trimethylsilyl)-benzene (Aldrich) (6.42 g, 28.04 mmol) in a clean, dry 250 mL round-bottom flask was added THF (100 mL) and the mixture was cooled to −78° C. with stirring for 10 minutes under nitrogen. Then, a 2.5M solution of n-butyllithium in hexanes (13.46 mL, 1.2 eq) was added slowly over about seven minutes. The resulting mixture was stirred at −78° C. for 1.5 hours (solution turned light yellow). Then, at −78° C. an excess of dry ice (4 large pieces) were added to the reaction mixture (solution turned color, then became clear) and the dry ice bath was removed and stirred for 15 minutes. TLC confirmed that the reaction was complete, and after stirring an additional 10 minutes at −78° C., the reaction was quenched with water (100 mL). Ethyl acetate (500 mL) was then added and with stirring 4N HCl was added to pH=2. The layers were separated and then washed the ethyl acetate layer with brine (1×250 mL) and finally the organic layer was dried over magnesium sulfate, filtered, concentrated and pumped to give 4-Trimethylsilanyl-benzoic acid as a white solid (5.49 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C:13]([S:16][C:17](=O)[CH3:18])([CH3:15])[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].BrC[CH:22]1[CH2:26][CH2:25]C[O:23]1.[O-]CC.[Na+]>C(O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[C:13]([CH3:15])([S:16][CH2:17][CH:18]2[CH2:25][CH2:26][CH2:22][O:23]2)[CH3:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: BrCC1CCCO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(SCC1CCCO1)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 50 °C
Yield: 71.8 %

Procedure:
To a solution of 100 mg (0.35 mmol) of thioacetic acid S-[1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-1-methyl-ethyl]ester in ethanol (2 mL) were added 70 mg (0.42 mmol) of 2-(bromomethyl)tetrahydrofuran and 340 μL (1.05 mmol) of sodium ethoxide solution (21% in ethanol) at room temperature. The reaction was heated to 50° C. for 18 h. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography (silica, eluent: heptanes, 0-20% ethyl acetate) to afford 82 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-furan-2-ylmethylsulfanyl)-propionamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>C(Cl)Cl.CO>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
96 mg (0.56 mmol) of 4-chlorophenylacetic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.39, FD-MS: M+ =580.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C@H:4]1[OH:16].[NH2:17][C:18]1[C:30]([Cl:31])=[CH:29][C:21]([C:22](N2C=CN=C2)=[O:23])=[C:20]([O:32][CH3:33])[C:19]=1[O:34][CH3:35]>C(#N)C>[NH2:17][C:18]1[C:30]([Cl:31])=[CH:29][C:21]([C:22]([NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][C@H:4]2[OH:16])=[O:23])=[C:20]([O:32][CH3:33])[C:19]=1[O:34][CH3:35]
Reactant: COc1c(C(=O)n2ccnc2)cc(Cl)c(N)c1OC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1
Solvent: CC#N
Product: COc1c(C(=O)NC[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc(Cl)c(N)c1OC
Yield: 78.5 %

Procedure:
A mixture of intermediate (1-e) (0.087 mol) and intermediate (3-a) (0.087 mol) in acetonitrile (600 ml) was stirred and refluxed for 90 min. The reaction mixture was cooled, and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE with a drop of ACN, filtered off and dried (vacuum, 40° C.), yielding 30.3 g (80%) of (±)-1,1-dimethylethyl trans-4-[[(4-amino-5-chloro-2,3-dimethoxybenzoyl)amino]methyl]-3-hydroxy-1-piperidinecarboxylate (interm. 4).
Reaction SMILES: C[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17]>CN(C)C=O>[F:8][C:7]1[CH:2]=[C:3]([C:10]([O:12][CH3:13])=[O:11])[NH:4][C:5](=[O:17])[CH:6]=1
Reactant: COC(=O)c1c(C)c(F)cc[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (3, 1 g, 5.84 mmol) in dimethylformamide (25 mL) is added trifluoroacetic anhydride (1.62 mL, 11.68 mmol). The reaction is stirred at 50° C. for 3 h. The resulting mixture is concentrated and purified via flash chromatography to afford methyl 4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (4).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([NH:17]C(OC(C)(C)C)=O)[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O)[CH3:2]>Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:5]1[CH2:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[NH:17]1)=[O:25])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Cl)cc2)N1
Temperature: -50 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (120 mL) was added to (R)-2-t-butoxycarbonylamino-5-(4-chlorophenyl)-5-oxovaleric acid ethyl ester (17.4 g). Stirring was continued for 3 hours at room temperature. The solvent was removed under a vacuum, and ethyl acetate and saturated sodium bicarbonate solution was added, and the organic layer was partitioned. The organic layer was washed with brine and was dried with magnesium sulfate. The solvent was removed under a vacuum, and methanol (200 mL) and acetic acid (50 mL) were added to the residue. The reaction solution was cooled to −50° C., and sodium borohydride (1.07 g) was added over 20 minutes. After stirring for 4 hours at −50° C. to room temperature, the resultant was stirred overnight at room temperature. Disodium hydrogenphosphate solution was added to the reaction solution, and the solvent was removed under a vacuum, Water and ethyl acetate were added, and the organic layer was partitioned. Saturated sodium bicarbonate solution was added to the organic layer, and stirring was continued for 1 hour at room temperature, and the organic layer was partitioned. The organic layer was washed with brine and was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate), and the title compound (4.71 g) was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:24])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[C:5]([Cl:3])(=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Temperature: 40 °C
Reaction time: 0.83 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 9.35 ml (128 mmol) of thionyl chloride, and a water condenser, is placed 24.90 ml (80 mmol) of linoleic acid. Addition of the thionyl chloride is completed with heating to about 40° C. over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 50 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, (9Z,12Z)-octadeca-9,12-dienoyl chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:17]=[C:16]([CH3:26])[CH:15]=3)=[O:12])=[C:4]2[N:3]=1.[OH-].[NH4+:28]>>[NH2:28][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:17]=[C:16]([CH3:26])[CH:15]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(NC(=O)c2cnn3ccc(Cl)nc23)n(-c2cccc(Cl)c2)n1
Agent: [OH-]
Product: Cc1cc(NC(=O)c2cnn3ccc(N)nc23)n(-c2cccc(Cl)c2)n1
Temperature: 105 °C
Yield: 48 %

Procedure:
A mixture of 74% pure 5-chloro-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (55 mg, 0.14 mM, 1.0 equiv) and 3 mL of concentrated ammonium hydroxide was sealed and heated in a microwave reactor at 105° C. for 30 minutes. The reaction mixture was cooled and the precipitated product collected by filtration to give 25 mg (48%) of 5-amino-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was purified by reverse phase chromatography on C-18 with acetonitrile/water (0 to 60 gradient, 0.1% TFA) and lyophilized. LCMS (ESI) m+H=368.3 (one chlorine isotope pattern), 1H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 8.66 (d, 1H), 8.20 (s, 1H) 7.67 (s, 1H), 7.57 (d, 1H), 7.49 (dd, 1H), 7.44 (d, 1H), 6.89 (br s, 1H), 6.40 (overlapping d and s, 2H), 2.26 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(OCC)C>CS(C)=O.Cl>[Cl:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:3]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN1CCN(c2cc(Cl)cc(C#N)c2)CC1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
5-Fluoro-3-chloro-benzonitrile (Ig, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition OfK2CO3 (1.3 g, 9.6 mmol) and 1-methyl piperazine (1.4 ml, 12.8 mmol). The reaction mixture was heated at 80° C. for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with IN HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl-ρiρerazin-1-yl)-benzonitrile (1.4 g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M+H]+ 236, acidic method).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].[N+:11]([CH3:14])([O-:13])=[O:12].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][CH2:14][N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: CCc1ccccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCc1ccccc1CC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dissolve 2-ethyl benzaldehyde (7 mL, 53.2 mmol), nitromethane (8.5 mL, 158 mmol), and ammonium acetate (1.6 g, 20.8 mmol) in acetic acid (40 mL) and heat to reflux under a nitrogen atmosphere for 17 hours. Cool to room temperature and concentrate. Dissolve in isopropyl alcohol (150 mL) and chloroform (750 mL) and add silica gel (108 g). To the resulting slurry, slowly add sodium borohydride (7.8 g, 206 mmol). Stir the mixture for 17 hours, filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes), to give the desired compound as an orange oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[NH:9][C:8](=O)[CH:7]=2)=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[N:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: COc1ccc2c(-c3ccoc3)cc(=O)[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(-c3ccoc3)ccnc2c1
Temperature: 0 °C

Procedure:
To a solution of 4-(3-furyl)-7-methoxy-2-quinolinone (4.1 g) from Step 1 in THF (250 mL) at reflux was added LiAlH4 (1M in THF; 68 mL). The mixture was refluxed for 50 hr., cooled to 0° C., and then treated successively with H2O (2.6 mL), 15% aq. NaOH (2.6 mL), and H2O (7.8 mL). The precipitate that formed was removed by filtration, washing with THF, and the tiltrate was concentrated and redissolved in MeCN (100 mL). To this solution at r.t. was added a solution of Ce(NH4)2 (NO3)6 (8.7 g) in H2O (30 mL). After the addition was complete, H2O (500 mL) was added and the resulting mixture extracted with EtOAc (3x). The combined organics were washed with H2O (2x) and brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (silica gel; EtOAc/hexane (3:1)) provided 4-(3-furyl)-7-methoxyquinoline as a solid. A portion of this material (1.0 g) and pyridine hydrochloride (4 g) were heated at 175°-180° C. for 5 hr. While still hot, H2O (50 mL) and ice was added, causing the formation of a precipitate. Filtration and drying of this material provided the title compound as a solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[P:12](Cl)([Cl:14])[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][P:12]([Cl:14])[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1
Reactant: ClP(Cl)Cl
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(P(Cl)Cl)cc1

Procedure:
To a suspension of 53.3 g (0.4 mol) of aluminium chloride in 40 ml (0.39 mol) of chlorobenzene, 104.8 ml (1.2 mol) of phosphorus trichloride are added dropwise at ambient temperature. The reaction mixture is refluxed for three hours. Then within 30 minutes 37.2 ml (0.4 mol) of phosphorus oxychloride are added dropwise at 83° C. After 12 hours at ambient temperature the residue is stirred with petroleum ether and decanted off. The combined organic extracts are distilled under high vacuum at 57-61° C. and 0.048-0.035 mbar.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33]([N:39]1[CH2:44][C@H:43]([CH3:45])[NH:42][C@H:41]([CH3:46])[CH2:40]1)=[N:34]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[C@H:43]([CH3:45])[CH2:44][N:39]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[CH:38][C:29]=4[Cl:28])[N:34]=3)[CH2:40][C@@H:41]2[CH3:46])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-chloro-2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH2:34][CH2:35][O:36][CH3:37])=[N:19][C:20]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:22]=3[CH3:23])[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:37][O:36][CH2:35][CH2:34][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:38])=[O:3])=[CH:10][CH:11]=2)=[C:22]([CH3:23])[N:21]=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=2)[N:19]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3c(C)nc(-c4ccc(C(F)(F)F)cc4)nc3CCOC)cc21
Agent: [Li+]
Agent: [OH-]
Product: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 5g], {6-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([Br:16])[C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([Br:16])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C(Br)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
Bromo-(4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (2.08 gm, 6.38 mmol) was taken in DCM (63 ml) under argon atmosphere and cooled to 0-5° C., piperidine (0.56 ml, 5.74 mmol) was added dropwise to the mixture at 0-5° C. Reaction mixture was then stirred at room temperature for 30 min. Reaction mixture was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography over silica gel using 30-50% ethyl acetate in hexane as eluent to give bromo-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.2 gm).
Reaction SMILES: C(O[C:4](=[O:24])[CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])C.[CH2:25]([CH2:27][NH2:28])[OH:26]>C(O)C>[OH:26][CH2:25][CH2:27][NH:28][C:4](=[O:24])[CH:5]([OH:23])[CH:6]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: NCCO
Reactant: CCOC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Solvent: CCO
Product: O=C(NCCO)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Yield: 58 %

Procedure:
3 g of ethyl-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)-propionate was refluxed with 5.4 ml of ethanolamine in 50 ml of anhydrous ethanol for 20 hours. The solvent was removed under reduced pressure, the residue was taken up with water and the solid collected by filtration. After crystallization from ethyl acetate, 1.8 g of N-(2-hydroxyethyl)-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)-propionamide was obtained, m.p. 166°-188° C. Yield 58%.
Reaction SMILES: [Cl:1][C:2]1[CH:51]=[CH:50][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38]4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]4)[C:10]=3[N:9]=2)=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCCCC4CCCNC4)cccc3n2CCCC2CCCNC2)cc1

Procedure:
The title compound is prepared from (R) 2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole by standard deprotection techniques using trifluoroacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]4[CH2:22][CH2:23][CH2:24][CH:18]4[CH2:17]3)=[O:15])[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1[N:34]=[CH:33][C:32]([C@H:35]([NH2:37])[CH3:36])=[CH:31][N:30]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]4[CH2:22][CH2:23][CH2:24][CH:18]4[CH2:17]3)=[O:15])[CH:11]=[C:10]([C:25]([NH:37][C@@H:35]([C:32]3[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=3)[CH3:36])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCN4CCCC4C3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(C(=O)N3CCN4CCCC4C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1.0 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (35 mg, 0.25 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:18]([O:17][C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCNCC1
Yield: 90.7 %

Procedure:
A solution of 1-benzyl-4-tertbutyloxycarbonylaminopiperidine 5 (7.95 g; 27.4 mmol) in 120 ml of MeOH is poured into a hydrogenation reactor. 10% Pd/c-based catalyst is added (1.46 g; 1.38 mmol) and the mixture is subjected to a hydrogen pressure of 3.5 bars (50 psi) for 24 hours in a Parr type shaker. After filtration on celite and washing with methanol, the medium is concentrated in order to produce 4.98 g (Yield=91%) of product in the form of white crystals.