Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:13][C:14]1[CH:19]=[C:18]([CH3:20])[O:17][C:16](=[O:21])[CH:15]=1.C1CCC(N=C=NC2CCCCC2)CC1.[Na].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C.C(O)C>[C:1]([C:4]1[O:8][C:7]([CH2:9][C:10]([C:15]2[C:16](=[O:21])[O:17][C:18]([CH3:20])=[CH:19][C:14]=2[OH:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(CC(=O)O)o1
Reactant: Cc1cc(O)cc(=O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(CC(=O)c2c(O)cc(C)oc2=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2.49 g (14.8 mmol) of 5-acetyl-2-furanacetic acid, 1.87 g (14.8 mmol) of 4-hydroxy-6-methyl-2-pyrone and 3.37 g (16.3 mmol) of DCC were suspended in 25 ml of chloroform, then 183 mg (1.50 mmol) of DMAP added and stirring carried out overnight at 60° C. The reaction liquid was cooled to room temperature and the insoluble material filtered off. The mother liquor was concentrated and the residue purified by column chromatography. The solid obtained was recrystallized from ethanol and Compound 13 (496 mg, 1.79 mmol, 12%) obtained. This was converted to the sodium salt with an equivalent quantity of sodium hydrogen carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.B(Br)(Br)Br.CCCCCCC.C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: COc1ccc(Cl)c(Oc2ccc(F)cc2)c1
Agent: BrB(Br)Br
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc(Cl)c(Oc2ccc(F)cc2)c1
Temperature: -78 °C
Yield: 86.4 %

Procedure:
Elution with 10:90 ethyl acetate:heptane with a gradient to 30:70 ethyl acetate:heptane afforded 1-chloro-2-(4-fluorophenoxy)-4-methoxybenzene (112 mg, 0.44 mmol, 49%). 1-Chloro-2-(4-fluorophenoxy)-4-methoxybenzene (110 mg, 0.44 mmol) prepared above, was dissolved in DCM (5.00 mL) and stirred under argon at −78° C. Boron tribromide (1.0M in DCM, 2.20 mL) was then added and the reaction stirred at −78° C. for 1 h. The reaction was allowed to warm to ambient temperature overnight, quenched with saturated Na2CO3 (aq) and then the aqueous and organic layers were separated. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel. Elution with 2:98 ethyl acetate:heptane with a gradient to 20:80 ethyl acetate:heptane afforded 4-chloro-3-(4-fluorophenoxy)phenol (92 mg, 0.38 mmol, 87%). M.S. (ESI) (m/z): 237, 239 [M−H]−
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=3[CH:20]=2)O1.Br[C:23]1[CH:28]=[CH:27][N:26]([CH3:29])[C:25](=[O:30])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:29][N:26]1[CH:27]=[CH:28][C:23]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=3[CH:20]=2)=[CH:24][C:25]1=[O:30]
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)NCCO3)OC1(C)C
Reactant: Cn1ccc(Br)cc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ccc3c(c2)C(=O)NCCO3)cc1=O
Temperature: 85 °C

Procedure:
A mixture of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (200 mg, 0.69 mmol), 4-bromo-1-methylpyridin-2(1H)-one (156 mg, 0.83 mmol), cesium carbonate (674 mg, 2.07 mmol), 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (49 mg, 0.069 mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5 mL). The mixture was heated in microwave at 85° C. for 40 min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dried over sodium sulfate and loaded onto silica gel. A flash column (5% MeOH in EtOAc) and reverse phase chromatography gave 7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.
Reaction SMILES: C1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])C=CC=CC=1.S(Cl)(Cl)=O.[NH3:39]>>[C:12]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH2:39])=[O:33])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N
Reactant: O=C(O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1

Procedure:
8-(1,4,5-Triphenylimidazol-2-yloxy)octanoic acid was treated with thionyl chloride followed by ammonia to give the title compound, m.p. 152.5°-153.5° C., Found: C, 76.6; H, 7.0; N, 9.1%: C29H31N3O2 requires: C, 76.8; H, 6.9; N, 9.3%
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]([CH:19]([C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:33]=3[F:40])[C:20](=[O:31])NCC(OC(OC)=O)(C)C)[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.CC(C)([O-])C.[K+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:19]([C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:33]=4[F:40])[C:20](=[O:31])[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CC(=O)N(c1ccc2[nH]cnc2c1)C(C(=O)NCC(C)(C)OC(=O)OC)c1cc(F)cc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C1C(=O)C(c2cc(F)cc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from ethyl 2-[(1H-benzo[d]imidazol-5-yl)[2,3,5-trifluorophenyl({2-[(methoxycarbonyl)oxy]-2-methylpropyl}carbamoyl)methyl]-carbamoyl]acetate (which may be prepared in accordance with the procedure described for Intermediate 3; 0.153 g, 0.271 mmol) and potassium tert.-butoxide solution (1M, 0.542 ml, 0.542 mmol) according to the method described in step 2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1>[Rh]>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Rh]
Product: COC(=O)C1CCC(O)CC1

Procedure:
The epoxides used as the starting materials in the general process described above can be obtained from available starting materials using an appropriate series of reactions. Thus, methyl 4-hydroxybenzoate is hydrogenated using 5% rhodium on alumina as catalyst to give methyl 4-hydroxycyclohexanecarboxylate. This is then oxidized with pyridinium chlorochromate resulting in methyl 4-oxocyclohexanecarboxylate. The 2-carbon homologation of methyl 4-oxocyclohexanecarboxylate to give methyl 4-(oxoethylidene)cyclohexanecarboxylate is carried out using the method developed by A. I. Meyers. Acetaldehyde t-butylimine is metalated with lithium diisopropylamide and then treated with diethyl chlorophosphate to provide the lithioeneaminephosphonate. Addition of methyl 4-oxocyclohexanecarboxylate and subsequent acid hydrolysis gives methyl 4-(oxoethylidene)cyclohexanecarboxylate. The reduction of this oxoethylidene compound with sodium borohydride gives methyl 4-(2-hydroxyethylidene)cyclohexanecarboxylate.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:26]=[CH:25][C:23](=[O:24])[NH:22][C:20]1=[O:21])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[F:32][C:33](I)([F:35])[F:34].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].CS(C)=O>[F:32][C:33]([F:35])([F:34])[C:25]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[N:19]([CH:26]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
0.37 g (1.0 mmol) of 2′,3′,5′-tri-O-acetyluridine and 0.058 g (0.3 mmol) of ferrocene were weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 2.1 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 60 to 70° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyl-2′,3′,5′-tri-O-acetyluridine (19F-NMR yield: 45%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5-Trifluoromethyl-2′,3′,5′-tri-O-acetyluridine was obtained as a white solid (0.17 g, yield: 40%) by column chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([OH:25])[C:23]#[CH:24].C(N(CC)CC)C>CC#N.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.[Cu]I>[F:19][CH:18]([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][CH2:22][OH:25])[CH:3]=2)=[O:21])=[CH:12][CH:13]=1
Reactant: O=C(C(=O)c1cccc(Br)c1)c1ccc(OC(F)F)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(C(=O)c1cccc(C#CCO)c1)c1ccc(OC(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of 1-(3-bromophenyl)-2-(4-(difluoromethoxy)phenyl)ethane-1,2-dione (0.500 g, 1.41 mmol), prop-2-yn-1-ol (0.395 g, 7.04 mmol), bis(triphenylphosphine)palladium(II) chloride (0.099 g, 0.14 mmol), copper(I) iodide (0.021 g, 0.11 mmol) and triethylamine (0.62 g, 6.11 mmol) in CH3CN (3 mL) was stirred at 60° C. overnight. The solvent is removed and the material is absorbed onto celite and purified by flash chromatography (silica, 25:75 ethyl acetate/hexanes) to afford 1-(4-(difluoromethoxy)phenyl)-2-(3-(3-hydroxyprop-1-ynyl)phenyl)ethane-1,2-dione (0.326 g, 70%) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-])=O.O.O.[Sn](Cl)Cl>CO.Cl>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([NH2:10])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1cc(F)c(Br)cc1F

Procedure:
To a solution of 2,5-difluoro-4-bromo-nitrobenzene (10 g, 42 mmol) in MeOH (200 mL) and conc. HCl (11 mL) was added tin(II)chloride dihydrate (38 g, 168 mmol) at room temperature. When complete the MeOH was distilled off under vacuum then water and celite were added. The mixture was neutralized with NaOH (50%) and filtered to remove the tin residue. The mixture was extracted with CH2Cl2 and the title compound 468A crystallized from CH2Cl2/hexane.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:32]=[C:33]1[NH:42][C:41]2[N:40]=[CH:39][C:38](/[CH:43]=[CH:44]/[C:45](O)=[O:46])=[CH:37][C:36]=2[CH2:35][CH2:34]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1)[C:45](=[O:46])/[CH:44]=[CH:43]/[C:38]1[CH:39]=[N:40][C:41]2[NH:42][C:33](=[O:32])[CH2:34][CH2:35][C:36]=2[CH:37]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1ccc(C)c2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c2ccccc12
Yield: 76 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(4-methyl-naphthalen-1ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.410 g, 76%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.67-10.62 (m, 1H), 8.38-8.29 (m, 1H), 8.15-7.94 (m, 3H), 7.60-7.55 (m, 3H), 7.36-7.02 (m, 3H), 5.30-5.06 (m, 2H), 3.04-2.73 (m, 5H), 2.65-2.45 (m, 5H); MS (ESI) m/e 386 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>C(Cl)Cl.CCOCC>[CH2:21]([NH:20][C:18]([NH:17][C:15]1[S:16][C:12]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:10][C:9]([OH:8])=[CH:23][C:13]=2[N:14]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3ccccn3)c2s1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of 1-[5-benzyloxy-7-(2-pyridyl)-1,3-benzothiazol-2-yl]-3-ethyl-urea (76 g, 0.187 mol) in DCM (1.7 L) was added methane sulfonic acid (270 mL, 4.17 mol) dropwise over 30 min. The reaction mixture was then stirred at rt for 3 h. After the completion of reaction (by TLC), the reaction mass was concentrated under reduced pressure. EtOAc (1 L) was added to the residue and the solution poured carefully onto crushed ice. The pH of the solution was maintained to 8-9 by addition of saturated NaHCO3 solution followed by extraction with EtOAc (3×5 L). The combined organics were washed with water, brine, dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was stirred in Et2O (1.0 L) for 1 h at rt then filtered to obtain the desired product (57.0 g, 97%). 1H-NMR (DMSO-d6): δ 1.08 (t, J=7.20 Hz, 3H), 3.20 (m, 2H), 6.86 (br s, 1H), 7.0 (s, 1H), 7.46 (s, 2H), 7.96 (m, 1H), 8.10 (m, 1H), 8.76 (m, 1H), 9.59 (br s, 1H) and 10.41 (br s, 1H). LCMS: 315.06 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl.C(#N)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:17])=[CH:15][CH:14]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(Br)ccc1F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: Fc1ccc(Br)cc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
To a solution of the above (5-bromo-2-fluorophenyl)-(4-chlorophenyl)-methanol (15.0 g, 48 mmol) and triethylsilane (18.5 mL, 116 mmol) in dichloromethane (40 mL) and acetonitrile (20 mL) at 0° C. under nitrogen, was slowly added boron trifluoride diethyl etherate (22.7 mL, 181 mmol). The resulting solution was stirred for 18 hours, while slowly warming to room temperature. The reaction was cooled in an ice-water bath, quenched by slow addition of 7 M aqueous potassium hydroxide solution (30 mL) and extracted with methyl tert-butyl ether (200 mL×2). The combined organic solution was washed with water (25 mL×2), brine (25 mL×2), dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography over silica gel eluting with a gradient of ethyl acetate in heptane gave 2-(4-chlorobenzyl)-4-bromo-1-fluorobenzene (5.0 g, 35% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) delta ppm 7.33-7.22 (m, 4H), 7.13 (d, J=8.4 Hz, 2H), 6.93 (dd, J=9.2, 9.2 Hz, 1H), 3.92 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[C:13]2[C:8](=[CH:9][C:10]([O:34][CH3:35])=[C:11]([O:32][CH3:33])[CH:12]=2)[N:7]1[C:36]([O:38][CH:39]([CH2:41][CH3:42])[CH3:40])=[O:37])=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:50]([O:52][CH3:53])=[O:51]>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([N:16]([CH2:17][C:18]2[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=2)[C:50]([O:52][CH3:53])=[O:51])[C:13]2[C:8](=[CH:9][C:10]([O:34][CH3:35])=[C:11]([O:32][CH3:33])[CH:12]=2)[N:7]1[C:36]([O:38][CH:39]([CH2:41][CH3:42])[CH3:40])=[O:37])=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 4) (approximately 500 mg, 0.83 mmol) and pyridine (195 mg, 2.5 mmol) were dissolved in anhydrous dichloromethane (100 mL) and cooled to 0° C. Methyl chloroformate (195 mg, 2.1 mmol) was added slowly. The reaction was stirred at 0° C. for 1 h, then at room temperature for 18 h. The reaction mixture was then diluted with chloroform, and washed with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 15% ethyl acetate/hexanes as eluent afforded the title product (400 mg). MS m/z 664.2 (M+); 1H NMR (CDCl3) δ 0.9 (t, 3H), 1.3 (t, 3H), 1.5 (m, 2H), 3.85 (s, 3H), 4.0 (t, 2H) 6.3 (s, 1 H), 7.8 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CS(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O.O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:10]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
(3R,4R)-1-Benzylpyrrolidine-3,4-diol (Diverchim S. A.; 150 mg, 0.776 mmol) was dissolved in dimethylsulfoxide (4 mL). After adding potassium hydroxide (348 mg, 6.21 mmol), the solution was stirred at 100° C. for 15 minutes. The reaction solution was further stirred at 100° C. for 4 hours after adding a dimethylsulfoxide (4 mL) solution of tetradecyl methanesulfonate (Nu-Chek Prep., Inc.; 568 mg, 1.94 mmol). The mixture was cooled to room temperature, and, after adding water, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform 100%) to give compound VI-5 (449 mg, 98.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccsc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccsc1
Yield: 71.9 %

Procedure:
15.0 g of N-(4-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine, 3.1 g of 50% sodium hydride and 10 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 14.1 g of ethyl 3-(4-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate are thereby obtained. Yield: 71.4%
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCOC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([C:11]([F:14])=[CH:12][CH:13]=1)[CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O.C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([C:11]([F:14])=[CH:12][CH:13]=1)[CH2:5][C:6]1[NH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCc1c(Cl)ccc(F)c1CC1=NCCN1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1c(Cl)ccc(F)c1Cc1ncc[nH]1

Procedure:
2-(3-Chloro-2-ethyl-6-fluoro-benzyl)-1H-imidazole was prepared from 2-(3-chloro-2-ethyl-6-fluoro-benzyl)-4,5-dihydro-1H-imidazole (Example 198), TCCA and DBU in analogy to Example 194e): light yellow crystals; MS (ISP): 241.2 ([M+H]+, 58%), 239.2 ([M+H]+, 100%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:3]=1.C([Li])(C)(C)C.C[O:23][B:24](OC)[O:25]C.CO>C1COCC1.O>[CH:8]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:4]1[CH:5]=[CH:6][C:2]([B:24]([OH:25])[OH:23])=[CH:3]1)([CH3:10])[CH3:9]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-bromo-1-(triisopropylsilyl)-1H-pyrrole (0.691 g, 2.28 mmol) in THF (10 mL) at −78° C. was added t-butyllithium (2.83 mL, 4.80 mmol of 1.7M solution in heptane). The solution was stirred at −78° C. for 45 min, then trimethylborate (2.38 g, 22.8 mmol) was added and stirred at −78° C. for 20 min. The reaction mixture was allowed to warm to rt and then cooled again to −78° C. before methanol:water (V:V=1:1, 0.9 mL) was added and the solution allowed warm to rt. The reaction mixture was quenched with brine (10 mL) and extracted with EtOAc (3×25 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid which was used without further purification.