Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCCC.[Cu]>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: C1COCCN1
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: CSc1ccc(N2CCOCC2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
A mixture of 2-Chloro-5-(methylthio)-benzoic acid (1 g, 4.7 mmol), morpholine (620 ul, 7.1 mmol), potassium carbonate (1.05 g, 7.6 mmol) and Copper (24 mg, 0.38 mmol) in pentanol (6 ml) was stirred for 1 h at room temperature. The mixture was heated to 100° C and stirred for 40 minutes. The solvent was evaporated. The residue was taken up in water and acidified to pH 2. The aqueous layer was extracted twice with ethylacetate. The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over silicagel: eluent: heptane/ethylacetate 0-20% over 15 minutes to provide the title compound as a brown solid (120 mg, 10%), MS (m/e): 252.1 (M−H, 100%)
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:23]=[C:22]([Cl:24])[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[C:13]([O:29][CH3:30])[CH:12]=1)=[O:10])C1C=CC=CC=1.[H][H]>C1COCC1.[OH-].[Pd+2].[OH-]>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:23]=[C:22]([Cl:24])[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[C:13]([O:29][CH3:30])[CH:12]=1)([OH:10])=[O:8]
Reactant: [H][H]
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 g (2.284 mmol) 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine are dissolved in 50 ml THF and combined with 100 mg palladium hydroxide. The reaction mixture is stirred for 16 h at ambient temperature and 4 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][N:23]3[CH2:22][CH2:21][N:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:25][CH2:24]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nnn(-c2cccc(Cl)c2)n1
Reactant: CCOC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(Cc2nnn(-c3cccc(Cl)c3)n2)CC1
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (22.3 mg, 0.107 mmol) was dissolved in 1,2-dichloroethane under argon and ethyl-1-piperazine carboxylate (16.4 uL, 0.112 mmol) was added followed by sodium triacetoxy borohydride (31.8 mg, 0.150 mmol). The reaction was allowed to stir overnight. Ethyl acetate was added and the solution was washed with sodium bicarbonate (sat.), brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using 45% EtOAc/Hexanes and 100% EtOAc to yield the title compound as a white solid (17.4 mg, 46%). 1H NMR (CDCl3) δ (ppm): 8.190 (s, 1H); 8.070 (m, 1H); 7.469 (m, 2H); 4.139 (q, 2H); 3.983 (s, 2H); 3.541 (m, 4H); 2.604 (m, 4H); 1.263 (t, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2C=CC=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>ClCCl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH:48]([CH3:53])[CH3:49])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in dichloromethane (2 mL) were added HBTU (30 mg, 0.079 mmol) and isopropylamine (0.032 mL, 0.37 mmol). The mixture was stirred at r.t. overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (22 mg, 51%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C=O)C>[Si:13]([O:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C1CC(O)CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Temperature: 0 °C

Procedure:
4-Hydroxy-2-pyrrolidone (1.00 g, 9.89 mmol) was suspended in DMF (25 mL) and cooled to 0° C. Imidazole (1.01 g, 14.84 mmol) and TBS—Cl (1.57 g, 10.39 mmol) were added and the reaction was then warmed to room temperature. After 30 minutes the reaction was poured into water (˜50 mL) and the resulting white precipitate was collected by filtration, dried in an oven, and used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH2:13][C:14](Cl)=[O:15].[NH:17]1[CH:21]=[CH:20]N=N1.C([O-])([O-])=O.[K+].[K+].O>S1(CCCC1)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH2:13][C:14]1[O:15][CH:20]=[CH:21][N:17]=1
Reactant: c1c[nH]nn1
Reactant: O=C(Cl)Cc1cc(-c2ncco2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Brc1ccc(-c2ncco2)cc1Cc1ncco1
Temperature: 140 °C

Procedure:
A mixture of the title compound of Step (C), 1H-1,2,3-triazole (144 mg, 2.1 mmol) and K2CO3 (1.3 g, 9.5 mmol) in 3.8 ml sulfolane was heated at 140° C. for 3 hrs. After cooling, 30 ml H2O was added and the mixture was extracted with 1:1 EtOAc/hexane. The combined organic extracts were washed with H2O and brine, dried and concentrated. The residue was chromatographed on silica gel using 3:1 hexane/EtOAc to afford the title compound of this step (256 mg, 44% for three steps).
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH3:18]>C(O)C.CO>[NH2:18][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6]
Reactant: COC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Reactant: N
Solvent: CO
Solvent: CCO
Product: N#CC(C#N)=C(N)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
3-Methoxy-3-(4-nitrophenyl)-2-cyanoacrylonitrile (14.4 g, 0.063 mol) was suspended in ethanol (1 L) in a flask equipped with a magnetic stirrer. To the suspension was added 60 mL (ca. 0.20 mol) of a 10% (w/w) solution of ammonia in methanol. The mixture was stirred vigorously for 15 min, at which time HPLC analysis showed the absence of starting material. The now homogeneous mixture was concentrated in vacuo to ca. 80 mL. The solid that had formed was collected with the aid of a small amount of additional ethanol and was pressed well with rubber dam. The cake was washed with of ethanol (2×5 mL) and was left to dry in a hood draft. The dry solid weighed 8.8 g. The filtrate was concentrated and mixed with dichloromethane (10 mL). The resulting solid was collected, washed with dichloromethane (2×2 mL), dried, and combined with the 1st crop to yield 9.9 g (46% for 2 steps). HPLC analysis indicated a purity of 91%. NMR (60 MHz) (DMSO-d6) δ 8.8 (bs, 0.5H); 8.0 (AB, 4H); 3.2 (bs, 1H); 2.8 (bs, 0.5H). The IR spectrum showed nitrile stretches at 2221 and 2207 cm−1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C([C@@H:38]1COC(=O)[N:39]1C([C@@H](C(C)C)CS(N1CCN(C2N=CC(C3C=CC(C#N)=CC=3)=CN=2)CC1)(=O)=O)=O)C1C=CC=CC=1>>[C:38]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])(=[O:21])=[O:22])[CH2:16][CH2:15]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:39]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)O
Yield: 14 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4 fluorophenyl)pyrimidin-2-yl] piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(2-{4-[2-(R)-(4-(R)-benzyl-2-oxooxazolidine-3-carbonyl)-3-methylbutane-1-sulfonyl]piperazin-1-yl}pyrimidin-5-yl)benzonitrile (0.70 g), to give the title compound as a white solid (0.07 g, 14%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]3[CH2:19][CH2:20][CH2:21][C:14]=3[C:13]=2[CH:22]=1)(=O)=O.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:24][O:23][C:10]1[C:9]([O:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:22][C:13]2[C:14]3[CH2:21][CH2:20][CH2:19][C:15]=3[C:16](=[O:18])[O:17][C:12]=2[CH:11]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCOS(C)(=O)=O)CCC3
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCN1CCN(c2ccccc2)CC1)CCC3
Yield: 90 %

Procedure:
Method B (24 h at 80° C.); starting materials: 2,3-dihydro-8-[2-(methanesulfonyloxy)ethoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 81) and 1-phenylpiperazine; yield 90%; fusion point 155°-156° C. (from isopropanol). Fumarate: method E; yield 94%; fusion point 182°-185° C. (from acetone).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>CC(C)=O.C(OCC)(=O)C>[C:26]([O:29][CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 0 °C
Yield: 91.3 %

Procedure:
3.0 g of 21-bromo-17-hydroxy-1,4-pregnadiene-3,20-dione is stirred in 60 ml of acetone with 3.0 g of potassium acetate at 50° C. The reaction mixture is introduced into ice water after 2 hours, the thus-precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate, thus producing 2.6 g of 21-acetoxy-17-hydroxy-1,4-pregnadiene-3,20-dione, mp 214° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[CH2:23]([N:9]([C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: CCI
Reactant: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccccc1)c1cccc(C(=O)OC)c1F
Yield: 61.2 %

Procedure:
Methyl 3-benzamido-2-fluorobenzoate (3.10 g, 11.0 mmol) was dissolved in N,N-dimethylformamide (30 ml), and the solution was cooled. 60% Sodium hydride (0.53 g, 13.2 mmol) was added thereto, and the reaction mixture was agitated without heating or cooling. 10 minutes later, ethyl iodide (2.05 g, 13.0 mmol) was added to the mixture, and the mixture was agitated overnight at room temperature. Water was added dropwise to the reaction mixture, and the reaction mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and then the filtrate was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (developer solvent: ethyl acetate/n-hexane=1/5), as a result of which 2.03 g (yield: 61%) of the indicated compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[NH2:24][C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:24][C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
In 500 ml of a mixture of chloroform-tetrahydrofuran (2:1), were dissolved 29.9 g of N-(4-methoxybenzoyl)-phenylalanine, 23.2 g of methyl tyrosinate hydrochloride, 10.1 g of trethylamine and 11.6 g of H-hydroxysuccinimide and the mixture was cooled with ice. To the cold solution was added 20.6 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred for two hours and then allowed to sit at room temperature overnight. The precipitates were removed by filtration and the filtrate was concentrated. The residue was extracted with ethyl acetate. The extract was washed with 2% hydrochloric acid, 4% sodium bicarbonate and water, then dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 35 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate with a mp. 195°-197° C in a yield of 74%. Analysis, calculated for C27H28O6N2C 68.05, H 5.92, N 5.88, found C 67.84, H 5.92, N 5.57.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]([CH3:19])[CH2:21][CH2:22]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: CN1CCNc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 25.1 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1 mL) was added 1-methyl-1,2,3,4-tetrahydro-quinoxaline (26.7 mg, 0.18 mmol, 1.2 equiv; [CAS RN 36438-97-8]), N-ethyldiisopropylamine (97 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 15.6 mg (25%) of the title compound. MS (ISP): 413.9 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[CH3:21][S:22][CH3:23].C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[CH:11]=[C:10]([CH2:21][S:22][CH3:23])[C:8]([NH2:9])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC
Reactant: CC(C)(C)c1ccc(N)c(Cl)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1cc(C(C)(C)C)cc(Cl)c1N
Temperature: -5 °C
Reaction time: 1 h

Procedure:
4-t-Butyl-2-chloroaniline (30 g) was dissolved in dichloromethane (1.21) and the solution was cooled to -5° C. N-chlorosuccinimide (21.7 g) was added portionwise to the vigorously stirred solution and stirring was continued for 1 h. Dimethyl sulfide (35 ml) was added to the solution (-5° C.) and stirring was continued for a further 1 h. The solution was then cooled to -65° C. and triethylamine (27 ml) was added. This solution was allowed to warm to room temperature overnight. The solution was evaporated to half volume, washed with sodium hydroxide (1N), water and brine successively. The organic solution was dried and evaporated and the residue was purified on silica using hexane to 3% ether in hexane as eluant. This afforded the product (31.2 g) as a red oil. 1H NMR (CDCl3, 250 MHz) δ 1.27 (9H, s, (CH3)3), 1.99 (3H, s, SCH3 ), 3.69 (2H, s, CH2SCH3), 4.38 (2H, br s, NH2), 6.92 (1H, d, J=2.0 Hz, ArH), 7.21 (1H, d, J=2.0 Hz, ArH). MS (CI+) m/z 244 (M+ +1, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13]C(C#N)=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=1.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:21]([C:20]([OH:23])=[O:22])=[CH:9][C:8]=2[C:15]([F:18])([F:16])[F:17])[CH:6]=1
Reactant: Cc1cn(-c2ccc(C#N)cc2C(F)(F)F)cn1
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cn(-c2ccc(C(=O)O)cc2C(F)(F)F)cn1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzonitrile (1.01 g, 4 mmol), 6 mL of acetic acid and 3 mL of 12 M hydrochloric acid (37%) is shaken for 16 hours at 95° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The resulting residue is evaporated twice with toluene, dissolved in water and the pH is adjusted to ˜5-6 by dropwise addition of 1M sodium hydroxide solution. The aqueous phase is extracted twice with ethyl acetate. The organic phase is dried (Na2SO4) and evaporated to yield the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH:17]([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2].[I:20]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:8]=[C:7]([I:20])[C:6]=1[O:15][CH2:16][CH:17]([F:18])[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(F)F)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(I)c(OCC(F)F)c(C(C)(C)C)c1
Temperature: 38 °C
Yield: 100.1 %

Procedure:
2,4-Di-tert-butyl-1-(2,2-difluoro-ethoxy)-benzene (6.75 g, 25 mmol), N-iodosuccinimide (6.74 g, 30 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10 mmol) were combined in dichloromethane (75 mL) and heated at 38° C. for 7 h. TLC (hexanes) indicated a small amount of starting material still present and the reaction was treated with additional N-iodosuccinimde (0.33 g). After 4 h the reaction was washed with 10% Na2SO2O3 solution (50 mL). The aqueous was backwashed with dichloromethane (100 mL) and then the combined organic portions washed with water (75 mL) and the combined organic portions washed with water (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide an orange oil (9.92 g). The material was purified by flash chromatography using hexane to give 8.88 g (90%) of a light pink oil which solidified over time. 1H NMR (250 MHz, CDCl3): δ 7.66 (d, 1H, J=2.4), 7.36 (d, 1H, =2.4), 6.29 (tt, 1H, J=55.3, J=4.3), 4.24 (td, 2H, J=13.2, J=4.3), 1.40 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:3]=1.C(Cl)(=O)C>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[O:14][C:12](=[O:13])[CH2:11]2
Reactant: O=C(O)Cc1cc(Br)ccc1C(=O)O
Solvent: CC(=O)Cl
Solvent: CC(C)=O
Product: O=C1Cc2cc(Br)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 4-bromo-2-carboxymethyl-benzoic acid (product of step i)) (11.0 g) in acetone (200 mL) was treated with acetyl chloride (13.3 g) and the solution stirred at room temperature for 17 hours. The reaction mixture was evaporated then azeotroped with toluene to yield the sub-title compound (9.8 g).
Reaction SMILES: C=CCCCCCC.B1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:10]1[CH2:11][CH2:12][CH2:13]2.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH2:29][CH3:30])[O:25][C:24]([C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:33]([O:47][CH3:48])[CH:32]=1)=[C:23]([OH:49])[C:22]2=[O:50]>O1CCCC1.[OH-].[Na+]>[CH2:29]([C:28]1[CH:27]=[C:26]2[C:21]([C:22](=[O:50])[C:23]([OH:49])=[C:24]([C:31]3[CH:32]=[C:33]([O:47][CH3:48])[C:34]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[C:35]([O:37][CH3:38])[CH:36]=3)[O:25]2)=[CH:20][C:19]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:10])[CH3:30]
Reactant: B1C2CCCC1CCC2
Reactant: CCc1cc2oc(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)c(O)c(=O)c2cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C=CCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1cc2c(=O)c(O)c(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)oc2cc1CC
Reaction time: 7 h

Procedure:
To a stirring solution of 1-octene (0.032 g, 0.3 mmol, 1.4 eq) in tetrahydrofuran (1 ml) under argon at 0° C. was added 9-BBN in tetrahydrofuran (0.5M, 0.6 ml, 0.3 mmol, 1.5 eq). The reaction was stirred for 7 hours then 6-bromo-7-ethyl-3-hydroxy-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 57 (0.102 g, 0.2 mmol) in tetrahydrofuran (4 ml), 3M NaOH solution (0.2 ml) and dichloropalladium(dppf) (0.005 g, 0.006 mmol, 0.03 eq) were added and the reaction heated to reflux for 15 hours. The reaction was then quenched with water and diethyl ether and acidified (6 M HCl). The organic layer was collected and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give a red oil.