Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O[C@@H]1CCNC1>>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](O)C2)cc1
Agent: O[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@@H](O)C2)cc1
Yield: 91 %

Procedure:
Title compound II was obtained in 91% yield by following the procedure described above for the synthesis of compound 157 (scheme 5, step 1) but substituting (S)-hydroxypyrrolidine for (R)-3-hydroxypyrrolidine. 1H NMR (DMSO-d6) δ(ppm): 7.69 (d, J=8.8 Hz, 2H), 6.51 (d, J=8.8 Hz, 2H), 5.02 (d, J=2.4 Hz, 1H), 4.40 (bs, 1H), 3.43 (dd, J=10.6, 4.6 Hz, 1H), 3.37 (m, 1H), 3.32 (m, 1H), 3.14 (d, J=10.8, 1H), 2.03 (m, 1H), 1.91 (m, 1H), 1.50 (s, 9H). LRMS (ESI): (calc) 263.15 (found) 264.1 (MH).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]([C:32]2[CH:33]=[CH:34][C:29]([S:28][CH3:27])=[CH:30][CH:31]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(SC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), [4-(methylthio)phenyl]boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.24 g, 17%).
Reaction SMILES: [CH3:1][C:2](Br)([CH3:17])[C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:2]([CH3:17])([CH3:1])[C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: COC(=O)COc1ccc(C(=O)C(C)(C)Br)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)C(C)(C)N2CCN(c3ccncc3)CC2)cc1
Reaction time: 816 h

Procedure:
Methyl 4-(2,2-dimethylbromoacetyl)phenoxyacetate (1.58 g) was added to a stirred solution of 1-(4-pyridyl)piperazine (1.63 g) in acetonitrile (40 ml). After 34 days, the solid formed was removed by filtration and the filtrate evaporated to give an oil. Purification by flash chromatography on silica, eluting with 0.5 to 4.0% v/v methanol/dichloromethane gave the title compound, 240 mg, as a white foam: NMR (d6DMSO) δ 8.49 (2H, d), 8.12 (2H, d), 6.96 (2H, d), 6.77 (2H, d), 4.87 (2H, s), 3.69 (3H, s), 3.28 (4H, t), 2.58 (4H, t), 1.25 (6H, s); m/e 398 (M+H)+ ; calculated for C22H27N3O4.0.25H2O: C, 65.7; H, 6.8; N, 10.4. found: C, 65.3; H, 6.9; N, 10.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18](O)[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:10]=23)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH2:18][CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:10]=23)=[CH:4][CH:3]=1
Reactant: CC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of (+/−)-methyl [9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pytrolo[1,2-a]indol-1-yl]acetate (see Example 14, 85 mg) in CH2Cl2 were added trifluoroacetic acid (0.5 mL) and triethylsilane (0.2 mL). The mixture was stirred for 1 hour at r.t. and solvent was removed. The residue was purified by silica gel chromatography eluted with 30% EtOAc/hexane to give 70 mg of the title compound as a white foam which has hydrolyzed following the procedures described in Step 10 of Example 7.
Reaction SMILES: CC1C2C=COC=2C(Br)=CC=1F.C[C@H]1CNCCN1.[CH3:20][C:21]1[C:26]2[CH:27]=[C:28]([F:30])[O:29][C:25]=2[C:24]([N:31]2[CH2:36][CH2:35][NH:34][C@@H:33]([CH3:37])[CH2:32]2)=[CH:23][C:22]=1[F:38].[Cl-:39].[NH4+]>CO>[ClH:39].[CH3:20][C:21]1[C:26]2[CH:27]=[C:28]([F:30])[O:29][C:25]=2[C:24]([N:31]2[CH2:36][CH2:35][NH:34][C@@H:33]([CH3:37])[CH2:32]2)=[CH:23][C:22]=1[F:38]
Reactant: [Cl-]
Agent: C[C@H]1CNCCN1
Agent: Cc1c(F)cc(Br)c2occc12
Agent: Cc1c(F)cc(N2CCN[C@@H](C)C2)c2oc(F)cc12
Solvent: CO
Product: Cl

Procedure:
Beginning with 4-methyl-5-fluoro-7-bromobenzofuran and 2(S)-methylpiperazine, 1-(4-methyl-5-fluorofluorobenzofur-7-yl)-3(S)-methylpiperazine was prepared as described. A solution of this material in methanol was treated with a methanolic solution containing one equivalent of ammonium chloride. The mixture was slowly concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid collected by filtration to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].[NH2-].[Na+].C1C2C(=CC=CC=2)CCC1.C(O)C>O>[CH3:13][CH:12]([CH3:14])[CH2:11][CH2:10][C:9]1[NH:8][C:3]2[C:2]([CH:1]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Cc1ccccc1NC(=O)CCC(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccc2c(c1)CCCC2
Solvent: O
Solvent: CCO
Product: CC(C)CCc1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 70 %

Procedure:
The following procedure is cited in Bull. Soc. Chim. Fr. (37):190 (1925). N-(2-methylphenyl)-4-methylvaleramide (20.5 g), sodium amide (90%) (11.0 g), and tetralin (100 ml) were mixed in a 500 ml round bottom flask equipped with a magnetic stirrer and reflux condenser and heated at reflux for 2 hours. After cooling to room temperature, ethanol (10 ml) was added, followed by H2O (150 ml). The layers were separated, the organic layer was filtered through a pad of anhydrous magnesium sulfate, and the solution was placed in a 200 ml round bottom flask equipped with a 10-inch vacuum jacketed Vigreux column. Tetralin was distilled at 35-45° C./0.5 mm Hg. The residue was transferred to a 50 ml round bottom flask equipped with a 4-inch Vigreux column, and distillation at 118-129° C./0.5 mm Hg provided 2-(3-methyl-n-butyl)-indole 13.1 g (70%) as a slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:24])([F:23])[F:22])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)#[N:32].C(=O)([O-])O.[Na+]>O1CCCC1>[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)([C:21]([F:22])([F:24])[F:23])[O:13][N:12]=3)[CH:15]=2)=[O:38])=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)Nc2cccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 3-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenylamine (0.300 mg, 0.79 mmol) (Example I3) in tetrahydrofuran (4 ml) was added pyridine (0.128 ml, 1.59 mmol). 4-Cyano-benzoyl chloride (0.176 g, 1 mmol) was added under vigorous stirring at ambient temperature. The reaction mixture was stirred for 3 hours at ambient temperature. Aqueous sodium hydrogen carbonate (saturated) was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give Compound No. A4 of Table A (0.342 g, 85% yield). 1H-NMR (400 MHz, CDCl3): 8.68 (s, 1H), 8.10 (s, 1H), 8.0 (m, 2H), 7.75 (m, 3H), 7.49 (s, 2H), 7.42 (m, 3H), 4.12 (d, 1H), 3.72 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[O:15])[C:5]#[N:6].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@:24]([OH:39])([C@H:31]([S:33][CH:34]([CH2:37]O)[CH2:35][OH:36])[CH3:32])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C@H:14]2[O:36][CH2:35][C@H:34]([S:33][C@H:31]([CH3:32])[C@:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])([OH:39])[CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[CH2:37][O:15]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A mixture of 4.63 g (23.0 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile [produced as described in Step 1(II) above], 8.73 g (24.3 mmol of (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [produced as described in Japanese Patent Application (Kokai) Hei 8-333350)], 5.07 g (26.7 mmol) of p-toluenesulfonic acid monohydrate and 200 ml of anhydrous tetrahydrofuran was allowed to stand at ambient temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated using a rotary evaporator and dried in vacuo. The resulting residue was dissolved in 150 ml of anhydrous tetrahydrofuran and the resulting mixture was then evaporated to dryness in vacuo using a rotary evaporator. This procedure was repeated twice more. A solution of the resulting residue in 150 ml of anhydrous tetrahydrofuran was poured into a saturated aqueous sodium hydrogen carbonate solution with stirring. The product was then extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residual oil was purified by chromatocraphy on a silica gel (500 g) column using a 2:1 mixture of ethyl acetate and hexane as the eluant to give 9.35 g (yield 74%) of the title compound as a yellow amorphous solid.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].[NH3:25]>CO>[C:19]1([S:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][CH:6]=[C:5]3[C:3]([NH2:25])=[O:4])(=[O:17])=[O:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 50 %

Procedure:
In a similar fashion using route 53 general procedure 122, 8-benzenesulfonylamino-quinoline-4-carboxylic acid methyl ester 225 (25 mg, 0.073 mmol) and NH3 in MeOH (7M; 3 ml) gave the title compound (13 mg, 50%) after purification by recrystallisation from DCM.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][CH2:10][CH2:11]Br.[F:13][C:14]1[C:15]([O:28][CH3:29])=[C:16]([CH:24]=[CH:25][C:26]=1[F:27])[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[F:13][C:14]1[C:15]([O:28][CH3:29])=[C:16]([CH:24]=[CH:25][C:26]=1[F:27])[N:17]([CH2:11][CH2:10][F:9])[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20]
Reactant: COc1c(NC(=O)C(F)(F)F)ccc(F)c1F
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(N(CCF)C(=O)C(F)(F)F)ccc(F)c1F
Temperature: 65 °C
Reaction time: 5 h
Yield: 19.1 %

Procedure:
2.44 g (0.018 mole) of potassium carbonate, a catalytic amount of potassium iodide and 1.80 g (0.014 mole) of 2-fluoroethyl bromide were added to a solution of 3.00 g (0.012 mole) of 3,4-difluoro-2-methoxy-N-(trifluoroacetyl)aniline (XI) [prepared as described in Step (C1) above] dissolved in 50 ml of dimethylformamide. The mixture was then stirred at 65° C. for 5 hours. At the end of this time, the solvent was distilled off from the mixture under reduced pressure. The residue was extracted with ethyl acetate and purified by column chromatography through silica gel eluted with toluene, to give 0.69 g of 3,4-difluoro-N-(2-fluoroethyl)-2-methoxy-N-(trifluoroacetyl)aniline (XII, R9' =2-fluoroethyl) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2.[CH:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([CH:17]([CH3:18])[CH2:19][CH3:20])=[CH:22][CH:23]=2)=[O:16])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:12])(=[O:13])[N:6]=2
Reactant: CC1=CN2CCS(=O)(=O)N=C2C(C(=O)O)=C1
Reactant: CCC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)C2=CC(C)=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylic acid 2,2-dioxide (76 mg) in DMF (3 mL) were added 4-sec-butylaniline (0.069 mL), HOBt (67 mg), and EDCI HCl (84 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (10 mL), and the resulting precipitate was collected by filtration. The obtained solid was recrystallized from DMSO-ethanol to give the title compound (114 mg) as pale-yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([C:23]3[C:24]([CH3:30])=[N:25][C:26]([NH2:29])=[N:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[Cl:31])(=[O:16])=[O:15])[CH2:9][CH2:8]1>N1C=CC=CC=1>[NH2:29][C:26]1[N:25]=[C:24]([CH3:30])[C:23]([C:21]2[CH:20]=[CH:19][C:18]([Cl:31])=[C:17]([S:14]([NH:13][CH:10]3[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C:1](=[O:3])[CH3:2])[CH2:12][CH2:11]3)(=[O:16])=[O:15])[CH:22]=2)=[CH:28][N:27]=1
Reactant: Cc1nc(N)ncc1-c1ccc(Cl)c(S(=O)(=O)NC2CCC(CN)CC2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)NCC1CCC(NS(=O)(=O)c2cc(-c3cnc(N)nc3C)ccc2Cl)CC1

Procedure:
Acetyl chloride (0.045 ml, 0.066 mmol) is added to a stirred solution of N-(4-aminomethyl-cyclohexyl)-5-(2-amino-4-methyl-pyrimidin-5-yl)-2-chloro-benzenesulfonamide (Example 3-18) (0.090 g, 0.22 mmol) in dry pyridine (1 ml). After 30 min the reaction mixture is absorbed on silica and the product is purified by chromatography on silica, eluting with ethyl acetate to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: COc1ccccc1B(O)O
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3OC)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 18 mg, 17%; LC/MS tr 1.54 min; MS(ES+) m/z 366 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:20][CH2:19][O:18]1>CN(C=O)C>[OH:18][CH2:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1OCCO
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (1.10 g, 8.08 mmol) in anhydrous DMF (12 mL) was added K2CO3 (2.23 g, 16.16 mmol) and ethylene carbonate (1.42 g, 16.16 mmol) at room temperature. The resulting reddish-orange suspension was stirred at 110° C. for 6 hours under nitrogen. DMF was removed and the residue was diluted with water (50 mL) and dichloromethane (50 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (2×20 mL). The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 4-(2-hydroxy-ethoxy)-3-methylbenzaldehyde as a brown oil. Yield: 1.46 g (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:16][C@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[O:9])[C@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and rac-cis-N-((3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 459, [M+1]+.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.CCN(C(C)C)C(C)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[CH:37]=O)[N:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:32]3[N:33]=[C:29]([CH3:28])[S:30][CH:31]=3)[CH:35]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2csc(C)n2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of the chlorhydrate salt of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate (100 mg; 0.34 mmol; 1.0 equiv.) in anh. DCE (1.5 ml) was treated successively with DIPEA (0.12 ml; 0.69 mmol; 2.0 equiv.), 3-(2-methylthiazol-4-yl)benzaldehyde (70 mg; 0.34 mmol; 1.0 equiv.), and NaBH(OAc)3 (102 mg; 0.48 mmol; 1.4 equiv.). The resulting mixture was further stirred at rt, under nitrogen, for 72 h. DCM (50 ml) and a solution of aq. sat. NaHCO3 (35 ml) were then added. The organic layer was further washed with a solution of aq. sat. NaHCO3 (35 ml) and with brine (35 ml). The resulting organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded 5-(2,6-dimethoxyphenyl)-1-(3-(2-methylthiazol-4-yl)benzyl)pyrrolidin-2-one as a beige solid. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 409.15 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([C:17]([NH2:19])=O)[S:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([C:17]#[N:19])[S:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2csc(C(N)=O)n2)cc(Cl)c1OC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(-c2csc(C#N)n2)cc(Cl)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A solution of 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carboxamide (1.58 g) (Example 1c) in pyridine (9 ml) was cooled to 0° C. and treated with trifluoroacetic anhydride (4 ml) whilst maintaining the internal temperature below 10° C. The mixture was stirred at room temperature for 10 min, then cooled and treated dropwise with water (45 ml) whilst maintaining the internal temperature below 30° C. The precipitated solid was collected by filtration and dried under vacuum at 60° C. Recrystallisation from dichloromethane-ether afforded 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carbonitrile (1.25 g), m.p. 147°-149° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C(C)C)[Na]>CC(O)C.C(C1C=CC=CC=1)(=O)C>[CH:1]([OH:8])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CC(C)O[Na]
Solvent: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: OC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
1.82 g of benzophenone (10 mmol) and 98 ml of 2-propanol were added to a 100 ml flask under argon atmosphere and heated to reflux. A 0.1 M NaOiPr solution in 2-propanol (2 ml) and 400 μl of a 2-propanol solution containing the catalyst (7) (3 mg, 0.0039 mmol dissolved in 8 ml of 2-propanol) were added. The molar ratios of benzophenone/catalyst/NaOiPr were equal to 50000/1/1000. 1H NMR analysis of the mixture indicated that the reaction was complete after 2 hours. By evaporating the solvent, a colourless residue was obtained which was extracted with 30 ml of diethyl ether. This solution was then passed through a silica filled column to remove the catalyst and sodium alkoxide. The filtrate was treated with Na2SO4, filtered, and removal of the solvent led to benzhydrol which was dried under reduced pressure (10−2 mmHg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]O>C1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]([O:19][CH3:26])=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazole (0.2 g) was dissolved in a mixture of methanol and benzene (1:5, 10 ml), and trimethylsilyldiazomethane (0.6 ml, 2.0M hexane solution) was added dropwise thereto under ice-cooling, followed by stirring of the mixture at room temperature for 30 minutes. The reaction mixture was poured into an ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.17 g, 81%) as a colorless solid.