Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C@H:21]2[O:23][C@@H:22]2[C:24]([O:26]C2C=CC3C(=CC=CC=3)C=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:37]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C@H:21]2[O:23][C@@H:22]2[C:24]([NH2:37])=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(Oc1ccc2ccccc2c1)[C@H]1O[C@@H]1c1ccccc1CCCCCCCCc1ccccc1
Solvent: CO
Product: NC(=O)[C@H]1O[C@@H]1c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 5 h
Yield: 76 %

Procedure:
The ester of Example 6b, (2S-trans)-2-naphthalenyl 3-[2-(8-phenyloctyl)phenyl]oxiranecarboxylate (2.03 g, 4.2 mmol), in methanol (21 mL) was cooled to 5° C. and a solution of ammonia saturated methanol (20 mL) was added dropwise. After stirring for 5 h at 10°-15° C., the solution was evaporated. The residue was dissolved in toluene and evaporated to a solid. The solid was dissolved in toluene and washed with water, NaOH (10%), water, and finally brine. After drying (MgSO4) and evaporation, the residue was dissolved in boiling hexane CH2Cl2 (8:2), filtered and allowed to stand at 20° C. for 4 h. The solid was collected and dried (0.1 mm Hg, 25° C.) to yield the titled oxiranecarboxamide 1.11 g (76%): mp 80°-82° C.; [α]D -8.3° (c 1, CH2Cl2); HPLC RT 5.48 min (2S-enantiomer); 9.99 min (2R-enantiomer) (Bakerbond Chiracel OC; 25 cm×4.6 mm; hexane:isopropanol, 1:1; 1.0 mL/min; UV detection at 211 nm); HPLC showed the product at >99% e.e. Anal. Calcd for C23H29O2N: C, 78.59; H, 8.32; N, 3.99. Found: C, 78.35; H, 8.34; N, 3.90.
Reaction SMILES: [O:1]=[S:2]1(=[O:13])[CH:6]([CH3:7])[C:5]2[C:8]([Cl:12])=[CH:9][CH:10]=[CH:11][C:4]=2[NH:3]1.[N+:14]([O-])([O-:16])=[O:15].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[O:13]=[S:2]1(=[O:1])[CH:6]([CH3:7])[C:5]2[C:8]([Cl:12])=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:4]=2[NH:3]1
Reactant: CC1c2c(Cl)cccc2NS1(=O)=O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1c2c(Cl)ccc([N+](=O)[O-])c2NS1(=O)=O
Reaction time: 24 h
Yield: 20.7 %

Procedure:
1,3-dihydro-2,2-dioxo-4-chloro-3-methyl-2,1-benzisothiazole (200 mg, 0.92 mmol) was dissolved in methylene chloride (30 ml) followed by the addition of sodium nitrate (86 mg, 1.01 mmol). The addition of sulfuric acid (0.18 ml/3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture is allowed to stir. After about 24 hours, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (50% Ethyl acetate/Hexane) gave the desired product (50 mg, 21%). EI-MS m/z 263.5 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:17]1[CH2:16][CH2:15][N:14]([C@H:11]2[CH2:10][CH2:9][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: Fc1ccc([C@H]2CC[C@@H](N3CCNCC3)CC2)cc1
Reactant: ClCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc([C@H]2CC[C@@H](N3CCN(Cc4ccccc4Cl)CC3)CC2)cc1

Procedure:
The title compound was prepared by refluxing cis 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine (0.35 g, 1.3 mmole) and 2-chlorobenzyl chloride (0.21 g, 1.3 mmole) in acetonitrile with excess potassium carbonate for 18 hr. The solvent was removed in vacuo and the crude material recrystallized from 2-propyl acetate to give the product (85%, mp: 86°-87° C.). Calc'd for C23H28ClFN2.0.4H2O: C, 70.09%; H, 7.37%; N, 7.11%. Found: C, 70.12%; H, 7.52%; N, 7.07%.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23](#N)[CH3:24].O>>[C:5]1([CH2:4][CH2:3][CH2:2][CH2:1][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[C:19]([F:20])([F:21])[F:22])[CH:24]=[CH:23][CH:8]=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: O
Product: O=C(O)c1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Yield: 95 %

Procedure:
The title compound was prepared analogously to 4-(octyloxy)-3-(trifluoromethyl)benzoic acid (11a) in >95% yield. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) is 3.14 min with gradient 20-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1.[CH3:35][NH2:36]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=2[CH:11]=[C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.055 g, 70%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 232-235° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C:14]1([CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:16][O:15]1)=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([C:14]1([CH:17]([F:7])[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:16][O:15]1)=[O:13]
Reactant: COC(=O)C1(C(O)CCCCOc2ccc(Cl)cc2)CO1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(C(F)CCCCOc2ccc(Cl)cc2)CO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of 967 mg (6 mmol, 733 μl) of diethylaminosulfur trifluoride in 25 ml of methylene chloride cooled to -78° C. under a nitrogen atmosphere is added dropwise a solution of 945 mg (3 mmol) of 2-[5-(4-chlorophenoxy)-1-hydroxypentyl]-2-oxiranecarboxylic acid methyl ester (isomer A) in 25 ml of methylene chloride over 30 minutes. The mixture is stirred at -78° C. for 30 minutes and then is allowed to come to room temperature. The mixture is stirred at room temperature for 1.5 hours, is quenched with brine and is extracted with ethyl ether. The combined ethereal extracts are dried over magnesium sulfate, filtered and rotoevaporated to give a crude solid. Trituration with cyclohexane:isopropyl ether and subsequent high vacuum drying affords 597 mg of the title compound (isomer A) (Rf 0.45 in hexane:ethyl ether (1:1)): m.p. 76°-78° C.; IR (KBr) γ1740, 1497, 1257, 832 and 758 cm-1 ; NMR (CDCl3) δ1.54-2.02 (6H, m), 3.10 (1H, dd, J=3, 6 Hz), 3.18 (1H, d, J=6 Hz), 3.80 (3H, s), 3.96 (2H, t, J=7 Hz), 5.19 (1H, ddd, JHF = 48 Hz, 10, 3 Hz), 6.85 (2H, d, J=7 Hz) and 7.27 (2H, d, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>O>[C:25]([NH:1][C:2]1[O:3][CH:4]([CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1)(=[O:27])[CH3:26]
Reactant: CC(c1c[nH]c2ccccc12)C1OC(N)=NC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1=NC(=O)C(C(C)c2c[nH]c3ccccc23)O1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-amino-5-[1-(indol-3-yl)ethyl]-2-oxazolin-4-one (100 mg) was dissolved into pyridine (0.5 ml). Acetic anhydride (117 μl) was added. The mixture was stirred for 2 hours at 80° C. To the reaction mixture was added water. The mixture was made acidic using 4N hydrochloric acid. The whole was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentration of the solution gave a residue, which was subjected to the silica gel chromatography. The eluent with hexane-acetone (1:1) was collected and concentrated to provide the titled compound (16 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:6]1[C:7]2[C:3](=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc2cc(-c3cccc4[nH]ccc34)ccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
4-bromo-1H-indole (31.0 mg, 0.158 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (114.5 mg, 0.302 mmol), Fibercat palladium catalyst (Johnson-Matthey, 34.5 mg), and K2CO3 (2 M in water, 0.45 ml, 0.90 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (10 ml, 2×5 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA). The fractions with product were purified on silica gel (3:1->1:1 hexanes/EtOAc) to afford title compound (12.8 mg, 22%). MS (ESI pos. ion) m/z: 369 (M+H). Calc'd Exact Mass for C23H16N2OS: 368.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:14](=[O:15])[CH2:13][CH2:12][Cl:11])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCCl
Solvent: c1ccccc1
Product: O=C(CCCl)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Nitroaniline (0.3 moles), β-chloropropionyl chloride (0.35 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 4 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(3-nitrophenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)phenylboronic acid (2.2 g, 8.5 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.79 g, 10.2 mmol), Pd(PPh3)2Cl2(179 mg, 0.26 mmol), K2CO3 (2.35 g, 17 mmol), and Cu2O (37 mg, 0.26 mmol) in THF (6 mL) and H2O (3 mL) in a tube sealed under N2 was heated at 80° C. for 4 h, cooled to rt and partitioned between EA and water, extracted with EA (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE to afford 1,3-bis(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.5 g, yield 55%) as oil.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of EtSO2-D-Phe-Pro-OBn (28.5 g, 64 mmol) in ethyl acetate (500 mL) was added 10% Pd/C (5 g). The vessel was evacuated and placed under an atmosphere of hydrogen. After stirring for 16 h, the solution was filtered over diatomaceous earth, and the filter pad was then washed twice with methanol and filtered. The combined filtrates were concentrated in vacuo to give 22 g (97%) of off-white solid.
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17](Cl)=[N:16][C:15]([CH2:22][O:23][CH3:24])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)=[N:16][C:15]([CH2:22][O:23][CH3:24])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COCc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Yield: 54 %

Procedure:
Sodium iodide (720 mg, 4.8 mmol) and hydriodic acid (2.0 mL, 47% aqueous solution) were added to the solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidine as prepared for Example 5.B. and (1.2 g, 4.0 mmol) and 4-aminobenzotrifluoride (1.3 g, 8 mmol) in dioxane (20 mL) and the reaction solution was stirred at 100° C. overnight. Solvent was removed in vacuo and the residue was dissolved in water. Solid sodium carbonate was added to the solution to a pH>7 then extracted by ethyl acetate. Ethyl acetate phase was washed by brine, and dried over sodium sulfate. Solvent was removed and the residue was purified by column chromatography to yield the product as a beige solid (910 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19](O)=[O:20].[CH2:22]([N:24]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36])[CH2:25][CH3:26])[CH3:23]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:24]([CH2:22][CH3:23])[CH2:25][CH3:26])=[C:29]([C:35]([F:36])([F:37])[F:38])[CH:30]=1)=[O:20]
Reactant: O=C(O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Reactant: CCN(CC)Cc1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)Cc1ccc(NC(=O)Cc2c(Cl)cc(-n3cnc4cccnc43)cc2Cl)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 7 but using (2,6-dichloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 56.1) and 4-diethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 549.9/551.9 [M+H]+; tR=3.93 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:22][C:3]2[CH:4]=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]3=[O:21])[C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[N:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nccc(OCc2ccccc2)n1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nccc(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
2.6 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 1.7 g of 4-benzyloxy-2-chloropyrimidine were dissolved in 20 ml of N,N-dimethylformamide, to this solution was added 1.07 g of potassium carbonate, and the mixture was stirred for 2 hours at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 1.6 g of 4-benzyloxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[C:23]4[O:27][CH2:26][O:25][C:24]=4[CH:28]=[CH:29][C:21]=3[O:20][CH2:19][CH2:18][O:17][CH3:16])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COCCOc1ccc2c(c1B1OC(C)(C)C(C)(C)O1)OCO2
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3c(OCCOC)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-(2-methoxy-ethoxy)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A34) the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: Cc1nc2ccccc2s1
Reactant: O=Cc1ccccc1Cl
Solvent: CC(=O)OC(C)=O
Product: Clc1ccccc1C=Cc1nc2ccccc2s1

Procedure:
The synthetic sequence commences with the condensation of a 2-chloro-benzaldehyde with 2-methylbenzothiazole II in boiling acetic anhydride to give 2-(2'-chlorostyryl)benzothiazole III.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[CH3:11][S:12][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(C=O)cc1F
Yield: 73.4 %

Procedure:
A solution of 3,4-difluorobenzaldehyde (2.8 g, 20 mmol) and sodium thiomethoxide (1.5 g, 20 mmol) in dimethylformamide (20 ml) was heated at 80° C. under an argon atmosphere for 2 hours. The reaction was cooled, poured into water (125 ml) and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and evaporated. The residue was distilled (bp 110-111° C., 0.5 mm Hg) to give 2.5 g (75%) of the desired aldehyde: Anal. Calc'd. for C8H7FSO (MW 170.21): C, 56.45; H, 4.15; S, 18.84. Found: C, 56.40; H, 4.00; S, 18.90.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]CC4C=CC=CC=4)=[C:18]([O:30]CC4C=CC=CC=4)[CH:17]=3)[CH2:10][N:9]([CH3:38])[C:8](=[O:39])[C:7]=2[CH:40]=1.[H][H]>[Pd].CO>[ClH:2].[OH:30][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[OH:22])[CH2:15][CH2:14][NH:13][C:11]1[CH2:10][N:9]([CH3:38])[C:8](=[O:39])[C:7]2[CH:40]=[CH:3][CH:4]=[CH:5][C:6]=2[N:12]=1
Reactant: CN1CC(NCCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)=Nc2ccc(Cl)cc2C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CC(NCCc2ccc(O)c(O)c2)=Nc2ccccc2C1=O

Procedure:
A mixture of 11.34 g (0.0197 m) of 7-chloro-2-(3,4-dibenzyloxyphenethylamino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one hydrochloride and 10% palladium on charcoal catalyst in 250 ml of absolute methanol is hydrogenated until no more hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is concentrated to dryness in vacuo to give crude 3,4-dihydro-2-(3,4-dihydroxyphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one hydrochloride hemi methanolate. Several recrystallizations from ethanol/ether give the pure product, m.p. 179° - 180° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(F)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(F)cc2)cc1
Yield: 53 %

Procedure:
To a mixture of 4-fluoro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Step 1) (4.5 g. 15.4 mmol) and sodium bicarbonate (2.59 g, 30.8 mmol) in isopropanol (200 mL), 3-bromo-1,1,1-trifluoroacetone (3.2 mL) was added. After heating the reaction mixture at 75–80° C. for 22 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.2 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 1/1) to give 2-(4-fluorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (3.28 g, 53%) as a white solid: mp (DSC) 203° C. Anal. Calc'd for C17H14N2F4SO3: C, 50.75; H, 3.51; N, 6.96. Found: C, 51.16; H, 3.69; N, 6.54.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=[CH:16][NH:17][CH2:18][CH3:19])[C:5](=[O:15])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[C:5](=[O:15])[CH2:6][CH:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:17]([CH2:18][CH3:19])[CH:16]=1
Reactant: CCNC=C(C(=O)C=Cc1ccc(Cl)cc1)C(=O)OC
Solvent: CN(C)C=O
Product: CCN1C=C(C(=O)OC)C(=O)CC1c1ccc(Cl)cc1

Procedure:
5.2 g. of 2-(ethylaminomethylene)-5-(4-chlorophenyl)-3-oxo-4-pentenoic acid methyl ester in 50 ml. of dimethylformamide were held at 140°-150° C. for 3 hours. After removal of the solvent, there was obtained 1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid methyl ester in the form of a uniform oily residue.