Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH2:6][C:5]1=[O:17])(=[O:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:15])([F:14])[F:16])[CH:11]=2)[C:6](=[C:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccc(C(F)(F)F)cc21
Reactant: O=C(O)c1ccccc1
Product: CC(=O)N1C(=O)C(=C(O)c2ccccc2)c2ccc(C(F)(F)F)cc21

Procedure:
Prepared from 1-acetyl-6-trifluoromethyl-2-indolinone and benzoic acid
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:41]=[CH:40][CH:39]=[CH:38][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH:24]=2)[N:10]=1.O[Li].O>C1COCC1.O.C(Cl)Cl>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][CH:25]([N:23]2[CH:24]=[C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:38]=[CH:39][CH:40]=[CH:41][C:5]=4[CH2:4][C:3]([OH:42])=[O:2])[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][N:12]=3)[CH:21]=[N:22]2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cn2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A135) (300 mg, 0.510 mmol) and LiOH.H2O (855 mg, 20.4 mmol) in THF (20 mL) and H2O (1 mL) was stirred at 40° C. overnight. The mixture was diluted with DCM (50 mL) and water (50 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined washings were dried (Na2SO4) and the volatiles were removed in vacuo to yield the title compound (A136) as a yellow oil (270 mg, 92%). LCMS-A: rt 6.679 min; m/z 575.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]([C:14]([O:16][CH3:17])=[O:15])[NH:5]1.Br[CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH:19]([N:5]1[CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:3])[CH3:24]
Reactant: COC(=O)C(C)Br
Reactant: COC(=O)[C@H]1Cc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)N1C(=O)c2ccccc2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Sodium hydride (60% oil dispersion, 0.51 g, 12.4 mmol) was added to a stirring solution of (R)-methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1.3 g, 6.2 mmol) in DMF (13 ml). After stirring for 30 min at ambient temperature, methyl 2-bromopropionate (1.1 ml, 9.3 mmol) was added. After stirring at 40° C. for 2 h, the reaction was removed from the heat and quenched with water. The reaction mixture was transferred to a separatory funnel with EtOAc/water. Extraction with EtOAc (2×) and washing the combined organic layers with saturated NaHCO3, water, and brine and drying over MgSO4 afforded 2.0 g of crude product after evaporation of the solvent. Flash chromatography (SiO2, hexanes to 80% EtOAc in hexanes) afforded Isomer A (0.53 g, 29% yield), Isomer B (0.28 g, 15% yield) and a mixture of the two isomers (0.28 g, 15% yield). All have MS (ESI) 292 (M+H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.C(O)(=O)C.[CH3:9][C:10]1([CH3:22])[O:14][C:13]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:12]=2[O:11]1>O>[CH3:9][C:10]1([CH3:22])[O:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([N+:1]([O-:4])=[O:3])=[CH:15][C:13]=2[O:14]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2O1
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2O1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A solution of 90% (fuming) nitric acid (22 ml) and glacial acetic acid (11 ml) cooled at 12° C. was treated in portions with solid compound from Example 3B (5.4 g, 27.7 mmoles) so as to maintain the temperature of <17° C. After the addition, stirring was continued for 15 minutes, when the internal temperature began to fall. The mixture was diluted to 100 ml with water, the yellow solid filtered, washed with water, taken up in CH2Cl2, dried (Na2SO4) and evaporated to give 5.43 g (82%) of pure title compound.
Reaction SMILES: [C:1]([N:11]([CH3:17])[C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]2[N:37]([C:40](=[O:46])[CH:41]([NH2:45])[CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:39][CH:26]12)=[O:24])([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)C.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH:28]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]2[N:37]([C:40](=[O:46])[CH:41]([NH:45][C:14](=[O:16])[CH:12]([N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH3:17])[CH3:13])[CH:42]([CH3:43])[CH3:44])[CH2:38][CH2:39][CH:26]12)=[O:24])([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)C(N)C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution containing Cbz-N(Me)Ala-OH (196 mg, 0.83 mmol) and crude 15 (307 mg, 0.76 mmol) in anhydrous NMP (3 mL) was cooled to 0° C. HATU (315 mg, 0.83 mmol) and DIPEA (118 mg, 0.91 mmol) were added and the reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and EtOAc (1:4) and washed successively with 1M HCl, aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 420 mg (88%) of crude 16 which was used without further purification. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.37-7.25 (m, 9H), 6.96 (m, 1H), 6.69 (br s, 1H), 5.19 (m, 2H), 4.91 (m, 1H), 4.81 (m, 1H), 4.58-4.46 (m, 2H), 4.04 (m, 2H), 3.97 (app d, J=12.6 Hz, 0.5H), 3.84 (app d, J=12.6 Hz, 0.5H), 3.40-3.25 (m, 2H), 2.88 (s, 3H), 2.48 (dd, J=5.7, 13.5 Hz, 0.5H), 2.33 (dd, J=5.4, 12.9 Hz, 0.5H), 2.06-1.82 (m, 2H), 1.51 (s, 4.5H), 1.49 (s, 4.5H), 1.36 (d, J=6.9 Hz, 3H), 0.91 (dd, J=2.7, 6.6 Hz, 3H), 0.83 (dd, J=1.8, 6.9 Hz, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:21][O:20][C:5]1[C:6]2[N:7]=[C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])[S:9][C:10]=2[C:2]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(Br)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(-c2cccnc2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 8 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid (4-methoxy-7-pyridin-3-yl-benzothiazol-2-yl)-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (7-bromo-4-methoxy-benzothiazol-2-yl)-amide (192 mg, 0.50 mmol) and 4-pyridylboronic acid (123 mg, 1.0 mmol) using the general procedure A as a white solid in 8% yield. MS: m/e=381 (M+).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:10]=1[CH3:21])C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][C:17]([F:20])([F:18])[F:19])[C:10]=1[CH3:21]
Reactant: Cc1c(OCc2ccccc2)c(=O)ccn1CC(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Cc1c(O)c(=O)ccn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 88.1 %

Procedure:
3-(Benzyloxy)-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (820 mg, 2.8 mmol) was mixed with 10% palladium on charcoal (wet, 84 mg) in methanol (20 mL). The mixture was stirred at room temperature under hydrogen at 30 psi in a Parr apparatus for 35 minutes. The mixture was filtered through Celite™ and the filtrate was concentrated. The residue was triturated with ether to give 3-hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (511 mg) as off-white solid. Yield=89%; 1H NMR (DMSO-D6, 90 MHz) δ (ppm): 7.60 (d, J=7.4 Hz, 1H), 6.20 (d, J=7.4 Hz, 1H), 4.99 (q, J=8.8 Hz, 2H) and 2.29 (s, 3H).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.Cl.[CH3:16][NH:17][CH3:18].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[CH3:16][N:17]([CH3:18])[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(CCC=O)cc1
Reactant: CNC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CC(=O)Nc1ccc(CCCN(C)C)cc1
Yield: 127.1 %

Procedure:
To a suspension of N-[4-(3-Oxo-propyl)-phenyl]-acetamide (96 mg, 0.50 mmol), dimethylamine hydrochloride (82 mg, 1.0 mmol), and sodium acetate (66 mg, 0.80 mmol) in methanol (0.5 mL) is added sodium cyanoborohydride (47 mg, 0.75 mmol). Upon completion of the reaction, the solvent is evaporated under reduced pressure and the residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate. The combined extracts were concentrated to give N-[4-(3-dimethylamino-propyl)-phenyl]-acetamide (0.14 g, >100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Temperature: 80 °C
Yield: 83 %

Procedure:
To methyl 3-chloro-4-hydroxy-benzoate (3.0 g, 16.1 mmol) in DMF (19 mL) was added potassium carbonate (8.9 g, 64.3 mmol) followed by 2-iodopropane (5.5 g, 3.2 mL, 32.2 mmol). The reaction mixture was heated at 60° C. for 1.5 hours. The reaction mixture was cooled, filtered and diluted with EtOAc and the solvent was concentrated in vacuo. The material was dissolved in EtOAc and washed with water (3×10 mL) and brine (1×10 mL). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo to give methyl 3-chloro-4-isopropoxybenzoate. To the ester was added dioxane (47 mL) and sodium hydroxide (42.7 mL of 1 M, 42.7 mmol) and the reaction was heated at 80° C. for 15 minutes. The reaction was cooled and solvent was removed in vacuo. The resulting residue was dissolved in water and washed with EtOAc (3×10 mL) and the layers were separated. The aqueous layer was acidified to pH 1 and was extracted with EtOAc (3×10 mL). The organic layer was separated and dried over Na2SO4, filtered and the solvent was removed in vacuo to yield 3-chloro-4-isopropoxy-benzoic acid (2.86 g, 83%) as a white solid. ESI-MS m/z calc. 213.6. found 215.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400.0 MHz, CDCl3) δ 8.05 (d, J=2.2 Hz, 1H), 7.90-7.87 (dd, J=8.8, 2.2; H, 1H), 7.06 (d, J=8.8 Hz, 1H) and 3.90 (s, 3H) ppm.
Reaction SMILES: II.Cl[CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[CH3:11][CH:12]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16](=[O:22])[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[CH2:13]1.[Cl-].[NH4+]>C(Br)CBr.O1CCCC1>[CH3:11][CH:12]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16]([CH:4]2[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)([OH:22])[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[CH2:13]1
Reactant: CC1Cc2ccccc2C(=O)c2ccsc21
Reactant: CN1CCC(Cl)CC1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC1Cc2ccccc2C(O)(C2CCN(C)CC2)c2ccsc21
Reaction time: 2 h

Procedure:
4.8 g of iodine-activated magnesium are covered with a layer of 60 cc of anhydrous tetrahydrofuran and cauterized with a few drops of ethylene bromide. A solution of 25.0 g of 4-chloro-1-methylpiperidine in 160 cc of anhydrous tetrahydrofuran is then added dropwise at such a rate that the solvent boils continually, and stirring is subsequently effected at the boil for 2 hours. The reaction mixture is cooled to 10°, and a solution of 20.0 g of 9,10-dihydro-10-methyl-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-one in 100 cc of anhydrous tetrahydrofuran is added dropwise at this temperature. After stirring at room temperature for 11/2 hours and at the boil for 30 minutes, the reaction mixture is cooled, poured on 300 cc of a 20% ammonium chloride solution, and the organic phase is separated. The aqueous solution is extracted with methylene chloride, the combined organic solutions are washed with water, dried over sodium sulphate and concentrated by evaporation. The 9,10-dihydro-10-methyl-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-ol, obtained as residue, is recrystallized twice from isopropanol. M.P. 177°-178°.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=O)=O.[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24].O.C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH2:22]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH2:23][CH3:24]
Reactant: CCCNCCC
Reactant: COC(=O)c1ccc(OCCCCCOS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCN(CCC)CCCCCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A solution of the compound 25 (3.70 g) and dipropylamine (3.00 mL) in isopropyl alcohol (40 mL) was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and saturated sodium bicarbonate water (40 mL) was added. The aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:90→0:100) to obtain the title compound (1.94 g) having the following physical properties.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33]1)(=[O:31])[CH3:30]>>[C:29]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH2:41][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:33]1)(=[O:31])[CH3:30]
Reactant: CC(=O)n1cc(C=O)c2ccccc21
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CC(=O)n1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c2ccccc21

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 1-acetyl-1H-indole-3-carbaldehyde according to the procedure of Example 66. MS (ES) m/z 550.0.
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:3][N:2]=[C:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12
Reactant: NO
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=O)=C21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=NO)=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 5.8 g of hydroxylamine hydrochloride are added to the mixture of 15 g of 1-(2-oxopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]-azepin-2-one, 6.2 g of powdered potassium carbonate, 120 ml of methanol and 10 ml of water. It is refluxed for three hours and stirred at room temperature overnight. The suspension is evaporated, the residue is suspended in 200 ml of chloroform-water (3:1) and filtered off, to yield the 1-(2-hydroxyiminopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 216°-218°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O.CCOC(C)=O.CCCCCC>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:20][C:6]2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:17][CH:16]=1
Reactant: OCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc(Cl)cc(OCc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
The product from Example 193a (0.75 g, 3.7 mmol), 4-bromobenzyl alcohol (0.77 g, 4.1 mmol) and K2CO3 (0.64 g, 4.6 mmol) in DMF (15 ml) was heated at 110° C. for 23 hours. The reaction mixture was cooled to room temperature, diluted with H2O, acidified to pH 2 with 10% HCl, and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound. The residue was treated with 50 mL of a mixture of n-hexane and EtOAc (3:1) and silica gel. After being stirred at room temperature for 30 minutes, the mixture was filtered through celite. The filtrate was evaporated and the resulting solid washed with i-Pr2O to give the title compound as a pale yellow crystals (0.70 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[C:15]=2[F:22])=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O-])([O-])=O.[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH:34]([F:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=O)=O>C(C(C)=O)C>[CH2:1]([C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:33][CH:34]([F:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:16]([F:21])[C:15]=2[F:22])=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCc1cnc(-c2ccc(O)c(F)c2F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCc1cnc(-c2ccc(OCC(F)CCCCCC)c(F)c2F)nc1

Procedure:
0.08 mol of 5-heptyl-2-(2,3-difluoro-4-hydroxyphenyl)pyrimidine, together with 11.6 g of K2CO3 and 25.6 g of optically active 2-fluoro-1-octyl tosylate in 70 ml of methyl ethyl ketone, are refluxed for 12 hours under a protective gas atmosphere. The reaction mixture is then hydolysed [sic], and the product is then worked up in a customary manner and purified by chromatography, to give optically active 5-n-heptyl-2-[2,3-difluoro-4-(2-fluorooctyloxy)phenyl]pyrimidine of melting point 56° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9]C2N=C(N3C4C=CC(C(O)=O)=CC=4N=C3)C=CN=2)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([C@@H:34]([NH:36][C:37]2[N:42]=[C:41]([N:43]3[C:47]4[CH:48]=[C:49]([C:52]([OH:54])=O)[CH:50]=[CH:51][C:46]=4[N:45]=[CH:44]3)[CH:40]=[CH:39][N:38]=2)[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N)C1C=CC=CC=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:28]1([C@@H:34]([NH:36][C:37]2[N:42]=[C:41]([N:43]3[C:47]4[CH:48]=[C:49]([C:52]([NH:9][CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[O:54])[CH:50]=[CH:51][C:46]=4[N:45]=[CH:44]3)[CH:40]=[CH:39][N:38]=2)[CH3:35])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(C(=O)O)ccc32)n1)c1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(C(=O)O)cc32)n1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: NCc1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(C(=O)NCc4ccccc4)cc32)n1)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of a mixture 10 mg (0.028 mmol) of 2-[(S)-1-phenylethylamino]-4-[5-carboxy-benzimidazol-1-yl]pyrimidine and 2-[(S)-1-phenylethylamino]-4-[6-carboxy-benzimidazol-1-yl]pyrimidine (EXAMPLE 106 Step C) and benzylamine (0.003 mL, 0.028 mmol) in 0.6 mL CH2Cl2 was added N-methylmopholine (0.004 mL) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10 mg). The solution was stirred for 4 hours then quenched with water. The organic fraction was concentrated and the product purified by chromatography to afford the title compounds. Partial 1H NMR (500 MHz CD3OD): δ 8.73 (brs, 1H); 8.57 (brs, 1H); 8.33 (brs, 1H); 7.82 (d J=10 Hz, 1H); 7.70 (d J=10 Hz, 1H); 6.82 (brs, 1H); 6.63 (brs, 1H); 5.23 (br, 1H); 4.70 (d J=5.5 Hz, 2H); 1.63 (d J=6.5 Hz, 3H). Partial 1H NMR (500 MHz CD3OD): δ 8.47 (br, 1H); 8.36 (br, 1H); 8.20 (s, 1H); 6.79 (d J=5.5 Hz, 1H); 6.60 (br, 1H); 5.18 (br, 1H); 4.72 (d J=5.5 Hz, 2H); 1.62 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](O)=O>>[Br:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(Br)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-bromo-4-chlorobenzoic acid: MS (ESI): m/z 481 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21]>CC(N(C)C)=O>[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][O:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=C1CCc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C1CCc2cc(OCC(F)(F)C(F)(F)F)ccc21
Temperature: 97.5 °C
Reaction time: 10 h

Procedure:
6.5 g of 5-fluoro-1-indanone are dissolved in 50 ml of dry dimethylacetamide and, after addition of 36.5 g of anhydrous ground potassium carbonate and 12.9 g of 2,2,3,3,3-pentafluoropropanol, stirred at 95-100° C. for 10 h. The solvent is then removed by distillation in vacuo; 300 ml of water are added to the residue, and the aqueous phase is extracted with ethyl acetate several times. The organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo. Purification on silica gel affords 5-(2,2,3,3,3-pentafluoropropoxy)-1-indanone as a brown oil which crystallizes after some time; melting point 52-54° C.