Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([NH:11][C:12](=[O:28])[CH:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH2:14][S:15]C(=O)C)[CH:10]=1)=[O:5])C>C(OCC)(=O)C>[C:4]([C:6]1[NH:7][CH:8]=[C:9]([NH:11][C:12](=[O:28])[CH:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH2:14][SH:15])[CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(NC(=O)C(CSC(C)=O)Cc2cccc(OC)c2)c[nH]1
Solvent: CCOC(C)=O
Product: COc1cccc(CC(CS)C(=O)Nc2c[nH]c(C(=O)O)c2)c1
Yield: 64.3 %

Procedure:
By working in a way similar to that described in example 17 and by using N-(2-ethoxycarbonyl-4-pyrrolyl)-3-acetylthio-2-(3-methoxybenzyl)-propanamide (0.98 g; 2.42 mmoles), prepared as described in example 24, a crude was obtained which, chromatographed on silica gel (eluent CH2Cl2 :CH3OH:CH3COOH=90:10:1) and collected with ligroin:ethyl acetate=1:1 afforded N-(2-carboxy-4-pyrrolyl)-3-mercapto-2-(3-methoxybenzyl)-propanamide (0.520 g; 64.2% yield) as white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][NH2:15]>C(Cl)(Cl)Cl>[CH3:14][NH:15][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CN
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccccc1C(F)(F)F

Procedure:
2-(Trifluoromethyl)benzoyl chloride and methylamine (2M, THF solution) were reacted in chloroform at room temperature to obtain N-methyl-2-(trifluoromethyl)benzamide.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[C:34]([N:2]=[N:3][CH2:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])=[O:21])=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(CN=NC(=O)c3ccncc3)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 5.0 g (9.2 mmol) of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamide monohydrochloride in 10 ml of methylene chloride is added 3.3 g (18.4 mmol) of isonicotinoyl chloride hydrochloride and 5.0 ml of triethylamine. The mixture is stirred at room temperature for 24 hours and purified by chromatography on silica gel with 80% ethyl acetate/hexane as the eluent to obtain 4-[5-[4-[(isonicotinoylimino)aminomethyl]phenoxy]pentyloxy]-N,N-bis(1 -methylethyl)benzamide:
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[CH:9]([CH3:12])[CH2:10][O:11][C:7]=2[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:14][O:13][C:6]1[C:7]2[O:11][CH2:10][CH:9]([CH3:12])[C:8]=2[C:3]([CH2:2][NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(CO)c2c1OCC2C
Reactant: Nc1ccncc1
Product: COc1ccc(CNc2ccncc2)c2c1OCC2C
Yield: 26.5 %

Procedure:
Substantially the same procedure as in Step B of Example 48 was repeated using Compound 59a obtained in Step A of Example 59 and using 4-aminopyridine instead of 4-mercaptopyridine to give Compound 61 (26.5%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CS(C)=O>[N:1]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccccn1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cn2ccccc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
2-aminopyridine (500 mg, 5.31 mmol) and ethyl chloroacetoacetate (870 mg, 5.31 mmol) were dissolved in DMSO and heated to 100° C. for 1 h under inert atmosphere. After 1 h, water added to reaction mixture followed by Work-up (H2O/AcOEt) and purification on 60-120 mesh silicagel using AcOEt and petroleum ether (30:70) gave the title compound (110 mg) as a brown liquid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.06 (d, J 6.7, 1H), 7.59 (s, 1H), 7.55 (d, J 9.4, 1H), 7.14 (t, J 7.9, 1H), 6.75 (t, J 6.7, 1H), 4.12 (q, J 7.1, 2H), 3.87 (s, 2H), 1.3 (t, J 7.1, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:19]([NH:21][C:22]([C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26](O)=[O:27])=[O:23])[CH3:20])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl>CCO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:19]([N:21]3[C:22](=[O:23])[C:24]4[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:26]3=[O:27])[CH3:20])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)c1ccccc1C(=O)O)c1cc2ccc(F)cc2nc1-c1cccc(F)c1
Agent: Cl
Solvent: CCO
Product: C[C@@H](c1cc2ccc(F)cc2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 49 %

Procedure:
To a solution of (S)-2-(1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (150 mg, 423 μmol), 3-fluorophenylboronic acid (65 mg, 465 μmol) and sodium carbonate (90 mg, 846 μmol) in MeCN (8 mL) and water (2 mL) was purged with N2 followed by the addition of Pd(PPh3)4 (24 mg, 21 μmol) and the resulting mixture was stirred at 90° C. overnight. The reaction mixture was diluted with EtOAc washed with water, brine and dried over Na2SO4. Purification using preparatory TLC eluted with 100% EtOAc afforded 2-(((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)carbamoyl)benzoic acid (120 mg, 66%). Mass Spectrum (ESI) m/e=433 (M+1). 2-(((S)-1-(7-Fluoro-2-(3-fluorophenyl)-quinolin-3-yl)ethyl)carbamoyl)benzoic acid was dissolved in EtOH (2 mL) and cond HCl (0.1 mL) was added. The resulting solution was heated to 80° C. for 4 h. Solvent was removed and satd NaHCO3 was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified via preparatory TLC using 3% MeOH/DCM saturated with NH3 gas to afford a white solid of 2-((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (85 mg, 49%). Mass Spectrum (ESI) m/e=415 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37][C:38]1[C:39]([O:56][CH3:57])=[CH:40][CH:41]=[C:42]2[C:47]=1[O:46][C:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[C:44](I)[C:43]2=[O:55]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:44]3[C:43](=[O:55])[C:42]4[C:47](=[C:38]([Br:37])[C:39]([O:56][CH3:57])=[CH:40][CH:41]=4)[O:46][C:45]=3[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1Br
Yield: 40 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-bromo-3-iodo-7-methoxy-2-phenyl-chromen-4-one (198 mg, 0.434 mmol) was reacted to give the title compound (100 mg, 40%). 1H NMR (400 MHz, CDCl3): δ 8.27-8.22 (d, 1H), 7.53-7.19 (m, 9H), 7.08-7.03 (d, 1H), 5.06 (s, 1H), 4.06 (s, 3H), 2.58-1.76 (m, 6H), 1.46-1.18 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:19](=[O:21])[CH3:20]>C1COCC1>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:19](=[O:21])[CH3:20])[CH:10]=2)[CH:6]=[N:7]1
Reactant: CON(C)C(C)=O
Reactant: Brc1ccc2cn[nH]c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cn[nH]c2c1
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of 6-bromo-1H-indazole (5.0 g, 25.4 mmol) in 40 mL THF was added dropwise n-BuLi (2.5M, 30 mL, 76.2 mmol) at −65° C., and the mixture was stirred for 2 h. Then, N-methoxy-N-methylacetamide (2.9 g, 27.9 mmol) was added. The reaction mixture was stirred for another 2 h at −65° C., then quenched with 40 mL H2O. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 100 mL brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EA=40/1) to give the title compound 24-a (370 mg, 9%) as a yellow solid. [M+H] Calc'd for C9H8N2O, 161; Found, 161.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:22])[C:10]([C:13]2[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]([Cl:21])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH:3]=1.C(Cl)Cl>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:22])[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([Cl:21])[CH:14]=2)([CH3:11])[CH3:12])=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH:3]=1
Reactant: COc1cc(Cl)cc(C(C)(C)C(=O)N(C)c2cnc(Cl)cc2-c2ccccc2Cl)c1
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)C(C)(C)c1cc(O)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reaction time: 6 h
Yield: 65.7 %

Procedure:
To a solution of 1.10 g (2.37 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramide in 20 ml CH2Cl2 4.74 ml (4.74 mmol) BBr3 (1 M in CH2Cl2) was added at 0° C. The reaction mixture was allowed to reach ambient temperature and stirred for 6 h After addition of 50 ml water the mixture was extracted three times with 60 ml CH2Cl2. The combined organic solvents were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) to give 0.70 g (65%) of the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>>[Br:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: OCc1cc(Br)c2cn[nH]c2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Product: O=Cc1cc(Br)c2cn[nH]c2c1
Yield: 53 %

Procedure:
According to the method of A52B, (4-bromo-1H-indazol-6-yl)methanol was oxidized with PDC to give the title compound as a beige solid (413 mg, 53%). MS ESI [M+H]+, calcd for [C8H5BrN2O+H]+ 225.0, 227.0; found m/z 224.9, 226.9.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[CH3:49][C@@H:50]1[CH2:55][O:54][CH2:53][CH2:52][NH:51]1>>[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][C@H:50]2[CH3:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: C[C@@H]1COCCN1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H]1COCCN1C(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and (R)-3-methylmorpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19IN4O4S, 538.0; m/z found, 537 [M−H]−. HPLC (reverse phase): RT=8.71 min. 1H NMR (400 MHz, CDCl3, rotameric broadening): 9.05 (d, J=1.8 Hz, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.94 (br s, 1H), 8.54 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.92 (dd, J=8.4, 7.4 Hz, 1H), 7.90-7.89 (m, 1H), 7.37 (dd, J=8.0, 1.6 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.5-4.0 (br m, 1H), 3.90-3.82 (m, 1H), 3.66-3.64 (m, 1H), 3.47 (dd, J=11.5, 2.7 Hz, 1H), 3.35-3.25 (m, 3H), 1.31-1.21 (br m, 3H).
Reaction SMILES: [C:1]([O:9][C@@:10]12[O:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>[N+](C)([O-])=O>[C:1]([O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@]12CCCC[C@H]1O2)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C[N+](=O)[O-]
Product: O=C(O[C@@H]1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a solution of (1R,2R)-2-benzoyloxy-1,2-epoxycyclohexane (0.030 g, 0.137 mmol, 93% ee) in anhydrous nitromethane (0.4 mL) was added p-TsOH (0.0024 g, 0.0137 mmol). Upon stirring at room temperature for 10 min, the reaction mixture was quenched with saturated NaHCO3 solution, extracted with ether, dried over anhydrous Na2SO4, filtered, concentrated, and purified on buffered silica gel (0.5-1% Et3N) by flash column chromatography [EtOAc-CH2Cl2-hexane (3:7:40)] to afford (R)-2-benzoyloxy cyclohexanone (0.0267 g, 89% yield, 90% ee).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].C(Cl)CCl.[Cl:28][C:29]1[CH:30]=[N+:31]([O-:54])[CH:32]=[C:33]([Cl:53])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:47])[F:46])=[C:40]([O:48][CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)O>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[N+:31]([O-:54])[CH:32]=[C:33]([Cl:53])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:47])[F:46])=[C:40]([O:48][CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)[O:21][C:20]([C:18]1[S:19][C:15]([S:12](=[O:14])(=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[N:2]([CH3:23])[CH3:1])=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: CN(C)C(=O)c1ccc(NS(=O)(=O)c2ccc(C(=O)O)s2)cc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccc(NS(=O)(=O)c2ccc(C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
5-(N-(4-(dimethylcarbamoyl)phenyl)sulfamoyl)thiophene-2-carboxylic acid (Int. 76) (54 mg, 0.152 mmol), DMAP (6.20 mg, 0.051 mmol), and EDC (38.9 mg, 0.203 mmol) were dissolved in DMF. (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (42.7 mg, 0.102 mmol) was added. The reaction was stirred at RT for 4 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was dried over Na2SO4 and concentrated under vacuum to give a crude product which was purified by preparative HPLC-Method 2 to give 10 mg of the desired product (Compound 77).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([C:19]2[N:24]=[CH:23][C:22]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][N:20]=2)(C(OCC2C=CC=CC=2)=O)[C:3]1=[O:33].[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH:4]([C:19]2[N:20]=[CH:21][C:22]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][N:24]=2)[C:3]1=[O:33]
Reactant: CN1C(=O)C(C(=O)OCc2ccccc2)(c2ncc(C#Cc3ccccc3)cn2)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)C(c2ncc(C#Cc3ccccc3)cn2)CC1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65493.5 %

Procedure:
To a solution of (RS)-benzyl 1,5,5-trimethyl-2-oxo-3-(5-(phenylethynyl)pyrimidin-2-yl)pyrrolidine-3-carboxylate (Example 5, step 2) (205 mg, 0.47 μmol) in 3 ml of ethanol was added 1N sodium hydroxide solution (933 μl, 0.94 mmol). After stirring for 1.5 h at room temperature, the pH was neutralized by addition of 1N HCl, and the solvent was evaporated in vaccuo. The residue (165 mg, yellow oil) was loaded onto a 20 g prepacked flash chromatography column. After elution with a 15% to 100% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 94 mg (66%) of the title compound as a light yellow crystalline solid, MS: m/e=306.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[C:14]=2[CH3:20])=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[C:14]([CH3:20])=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2C)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3)c2C)ccc1CCC(=O)O
Yield: 9 %

Procedure:
3-[4-(3-bromo-2-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester is reacted with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.031 g (9%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H25O5Cl 488, found 489 and 491 (M+1 and M+3, 100%).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])=[CH:26][C:19]=1[O:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O-:17])=[O:16].CCCCCC.C(OCC)(=O)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([NH:7][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])[CH:28]=[CH:29][C:18]=1[N+:15]([O-:17])=[O:16])[CH3:25])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: NCc1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCc1ccco1
Temperature: 25 °C

Procedure:
Furfurylamine (1 gram; 0.01 mole), methylene chloride (50 ml) and triethylamine were charged into a glass reaction vessel equipped with a thermometer, mechanical stirrer and addition funnel. The reaction mixture was cooled to a temperature of -10° C. and 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (4.3 grams; 0.01 mole) dissolved in methylene chloride (50 ml) was added dropwise with stirring and continued cooling. After the addition was completed the reaction mixture was allowed to warm to room temperature with continued stirring over a period of one hour. After this time the reaction mixture was transferred into a separatory funnel and was washed with water (100 ml), with dilute aqueous sodium bicarbonate (100 ml; 5% conc.) and again with water (100 ml). The washed solution was dried by passing it through phase separation paper and was then stripped of solvent leaving a dark red-brown oil. This oil was subjected to chromatography using a 150 cc clay column and hexane/ethyl acetate mixtures with increasing concentrations of ethyl acetate as the eluant. Fractions 9 and 10 were combined and stripped of solvent to yield the desired product N-furfuryl-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as an orange solid melting at 128° to 130° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][CH2:5][C:6]([OH:8])=O)[CH3:2].CN(P(N(C)C)(N(C)C)=O)C.S(Cl)(Cl)=O.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:32]([S:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])=[CH:31][C:29]=1[NH2:30]>C(OCC)C>[CH2:9]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]([NH:30][C:29]1[CH:31]=[C:32]([S:35]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)(=[O:36])=[O:37])[CH:33]=[CH:34][C:28]=1[O:27][CH3:26])=[O:8])[CH3:10]
Reactant: CCN(CC)CCC(=O)O
Reactant: COc1ccc(S(=O)(=O)N2CCOCC2)cc1N
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O=S(Cl)Cl
Product: CCN(CC)CCC(=O)Nc1cc(S(=O)(=O)N2CCOCC2)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a three-neck flask they are introduced 7.2g 3-diethylaminopropionic acid (hydrochloride) and 180 ml hexamethylphosphorotriamide. The suspension is cooled with an ice-bath and then 2,90 ml thionylchloride are added while maintaining the inner temperature between +5° - +10° C. The reaction mixture progressively gives a yellow solution. After 2 hours stirring 10.9 g of 2-methoxy 5-morpholinylsulphonyl aniline are added portionwise and the whole mixture is kept under stirring for 4 hours at room temperature and then let to stand for a night. The dark solution is thereafter diluted with 1 l ethyl ether and it appears a precipitate. After 1 hour standing the precipitate is collected, suction-filtered and washed with acetone. After thoroughly drying the raw product weighing 11.3g is recovered and further recrystallised from acetone.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=2)[N:22]=[C:21]1[CH3:32].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40]>O1CCCC1>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=2)[N:22]=[C:21]1[CH:32]=[C:39]([OH:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: CCOC(=O)c1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=c1c2cc(F)ccc2nc(C=C(O)c2ccccn2)n1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of diisopropylamine (0.061 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.134 mL, 0.34 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 20 min and then a solution 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.10 g, 0.35 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 min. In a separate vessel a solution of ethyl picolinate (0.491 mL, 3.6 mmol) in tetrahydrofuran (2 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold ethyl picolinate solution via canula over a two minute period. The resulting mixture was stirred 30 minutes at -78° C. and then was allowed to warm to ambient temperature. The reaction was quenched with water. The mixture was repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was triturated with ether/hexane and the yellow solid which formed was collected and dried to yield 0.054 g (40%) of 3-(2-chloro-phenyl)-6-fluoro-2-(2-hydroxy-2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one which had: mp>250° C. 1H NMR (DMSOd) δ8.45 (d, J=5 Hz, 1 H), 7.97 (d, J=7 Hz, 1 H), 7.90 (dt, J=1, 8 Hz, 1 H), 7.88-7.58 (m, 7 H), 7.35 (sym m, 1 H), 5.80 (s, 1 H). Analysis calculated for C21H13ClFN3O2 : C, 64.05; H, 3.33; N, 10.67. Found: C, 64.16; H, 3.71; N, 10.72.