Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:43]=[CH:42][C:19]([C:20]([NH:22][C:23]2[CH:28]=[C:27]([C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)[CH:26]=[CH:25][C:24]=2[NH:34]C(=O)OC(C)(C)C)=[O:21])=[CH:18][CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:43]=[CH:42][C:19]([C:20]([NH:22][C:23]2[CH:28]=[C:27]([C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)[CH:26]=[CH:25][C:24]=2[NH2:34])=[O:21])=[CH:18][CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [2-[(4-{1 [(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoyl)amino]-4-(3-thienyl)phenyl]carbamate (164 mg, 0.27 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 2 h. Concentration yielded a yellow residue that was dissolved in EtOAc, neutralized with sat. NaHCO3, washed with brine, dried (MgSO4), and evaporated. The resulting solid was dissolved in CH2Cl2 (15 mL) and MeOH (0.5 mL). Hexanes (5 mL) were added, and upon concentration to half-volume, the mixture was filtered to isolate 4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}-N-[2-amino-5-(3-thienyl)phenyl]benzamide as a white solid. 1H NMR (DMSO-d6) δ10.19 (s, 1H), 9.66 (s, 1H), 8.12 (t, J=5.7 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.58 (d, J=7.6 Hz, 2H), 7.54-7.52 (m, 2H), 7.49-7.47 (m, 3H), 7.38 (dd, J=4.7, 1.5 Hz, 1H), 7.33 (dd, J=8.2, 2.1 Hz, 1H), 7.26 (t, J=7.9 Hz, 2H), 7.01 (t, J=7.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.99 (s, 2H), 4.06 (dd, J=8.5, 6.2 Hz, 1H), 3.54 (ddd, J=13.3, 8.5, 5.0 Hz, 1H), 3.47 (dt, J=12.9, 6.2 Hz, 1H), 1.76 (s, 3H). MS (ESI) calcd [M+H]+ 499.1, found 499.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=4)=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:21][CH:22]=4)=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-c2ccc3oc(-c4ccc(Cl)cc4)nc3c2)cn1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2ccc3oc(-c4ccc(Cl)cc4)nc3c2)cn1
Temperature: 80 °C
Reaction time: 40 h
Yield: 41.2 %

Procedure:
To 5-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)pyridin-2-amine (96.5 mg, 0.30 mmol) in dry pyridine (3 mL) at room temperature was added acetyl chloride (26 μL, 0.36 mmol), and stirred at 80° C. for 40 h. After cooling, the mixture was poured into water to give a precipitate, which was filtered off. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 45 mg (41%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][N:3]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:17]3[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=3)=[N:9]2)=[CH:4][N:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc2cnc(Br)cc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3cnc(Br)cc3n2)cn1
Temperature: 60 °C
Yield: 54.8 %

Procedure:
7-Bromo-2-chloro-1,6-naphthyridine (Preparation 61, 44.5 mg 0.183 mmole) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (53.4 mg 0.256 mmole) were stirred in THF (1 mL) and 2M aqueous sodium carbonate solution (0.35 mL) was added. Palladium(dppf)dichloride.dichloromethane complex (4.0 mg, 0.0049 mmole) was added and the reaction heated at 60° C. for 4.5 hours under nitrogen. The reaction was diluted with ethyl acetate (15 mL) and the solution was washed with brine (7 mL). The brine was backwashed with ethyl acetate (7 mL) and the combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with EtOAc to afford the title compound (29 mg, 54%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:31])([F:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[NH:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CN(C=O)C.O>[Cl:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[NH:63][CH:64]1[CH2:69][CH2:68][N:67]([C:27](=[O:29])[CH2:26][NH:25][C:23]([C:20]2[CH:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([F:10])([F:31])[F:30])[NH:22][N:21]=2)=[O:24])[CH2:66][CH2:65]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Reaction time: 0.03 h
Yield: 44.1 %

Procedure:
DIPEA (137 mg, 1.06 mmol) was added to a stirred solution {[5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (95 mg, 0.3 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from (2′-trifluoromethyl)acetophenone) in DMF (2.0 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI.HCl (67 mg, 0.35 mmol). After 2 minutes of stirring, (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (75 mg, 0.3 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated under reduced pressure. The residue was purified washing with diethyl ether to afford 67 mg (43.5% Yield) of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 506.12, 97.9%, 1H NMR (300 MHz, DMSO-d6): δ13.2 (d, 1H), 8.2 (m, 1H), 7.5 (m, 5H), 7.2 (m, 2H), 6.85 (m, 1H), 6.5 (m, 2H), 4.8 (m, 1H), 4.3 (m, 1H), 4.1 (d, 2H), 4.0 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.7 (m, 1H), 1.9 (m, 2H), 1.3 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[O:33][N:32]=2)[CH:30]=1)[C:25](O)=[O:26])[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[O:33][N:32]=2)[CH:30]=1)[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26])[CH3:21]
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: CCc1cc(C(=O)O)cc(-c2noc(C(F)(F)F)n2)c1
Product: CCc1cc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)cc(-c2noc(C(F)(F)F)n2)c1
Yield: 45 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-ethyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (85 mg, yield 45%). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.05 (s, 1H), 7.89 (m, 2H), 7.80 (s, 1H), 7.52 (m, 2H), 7.37-7.29 (m, 3H), 4.00-3.94 (m, 2H), 3.89 (d, J=5.5 Hz, 2H), 3.78-3.72 (ddd, J=11.7 Hz, 7.8 Hz, 3.3 Hz, 2H), 2.69 (q, J=7.7 Hz, 2H), 2.36-2.30 (ddd, J=13.6 Hz, 6.5 Hz, 3.3 Hz, 2H), 2.08-2.02 (ddd, J=13.6 Hz, 7.7 Hz, 3.3 Hz, 2H), 1.23 (t, J=7.7 Hz, 3H). MS (ESI) m/z: Calculated for C27H25F3N4O3S: 542.16. found: 543.2 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1CCCCC1[O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][O:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=3)[CH2:33][CH2:32]2)=[N:29][CH:30]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:49][C:46]([F:47])([F:48])[O:45][C:42]1[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][N:29]=3)[CH2:36][CH2:35]2)=[CH:40][CH:41]=1
Reactant: FC(F)(F)Oc1ccc(OCC2CCN(c3ccc(OC4CCCCO4)cn3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc(N2CCC(COc3ccc(OC(F)(F)F)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Pyridinium p-toluenesulfonate (PPTS) (0.917 g) was added to an ethanol solution (20 ml) of 5′-(tetrahydropyran-2-yloxy)-4-(4-trifluoromethoxyphenoxymethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (1.65 g), and the mixture was stirred for 4 hours while heating under reflux. After cooling the reaction mixture to room temperature, a sodium hydrogen carbonate aqueous solution was added thereto, and ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off and the precipitated solid was collected by filtration. The solid was then washed with diisopropyl ether and dried to afford the title compound as a yellow powder (0.94 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH:20]=[CH:21][CH2:22]Br)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:27][CH3:28])[CH:25]=[CH2:26]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH:20]=[CH:21][CH2:22][N:27]([CH2:24][CH:25]=[CH2:26])[CH3:28])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OCC=CCBr)ccc21
Reactant: C=CCNC
Product: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C

Procedure:
In analogy to example 2.6, 6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and N-allyl-methylamine were converted to yield 6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless oil, MS: 373 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:14](=[O:16])[CH:13]([NH:12][C:10]([C:7]2[CH:6]=[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:24])([F:26])[F:25])[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][N:8]=2)=[O:11])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:31][CH2:30][CH2:29]1
Reactant: C1CNC1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)N2CCC2)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and azetidine (CAN 503-29-7) as starting materials and isolated (23 mg, 41%); MS (ESI, m/z): 428.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH:5]=[O:6])([CH3:4])[CH3:3].[Li][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1.CCCCCC>[CH3:1][C:2]([CH3:4])([CH:5]([OH:6])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:3]
Reactant: CC(C)(C)C=O
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(O)C(C)(C)C
Temperature: -65 °C
Reaction time: 1 h

Procedure:
20 g (0.232 mol) of pivaldehyde dissolved in 600 mL of THF was added to a 2 L 3-neck round bottom flask equipped with a magnetic stir bar, thermometer and rubber stopper. The vessel was maintained under N2. The reaction mixture was cooled to −65° C. in a dry ice/acetone bath. 112 mL (0.279 mol) of a 2.5 M BuLi solution in hexane was slowly added in 5 mL portions with a 20 mL glass syringe, maintaining the temperature below −55° C. The reaction was stirred at 60° C. for one hour, then allowed to warm to −5° C. over one hour. The reaction was cooled again to 60° C. and slowly quenched with NH4Cl/H2O solution, maintaining the temperature below −50° C. 100 mL of water were added and the reaction was allowed to warm to room temperature. The THF was removed on a rotary evaporator with a bath temperature of 25° C. until an oil was observed. The product was extracted with ethyl ether, and the ether was dried and evaporated carefully to yield 31.0 g of 2,2-dimethyl-heptan-3-ol that was used directly in a subsequent oxidation reaction. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.2 (m, 1H), 1.2-1.7 (m, 3H), 0.93 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23](OC)=[O:24].[Cl-].[NH4+]>O1CCCC1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:23](=[O:24])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(OC)c1
Reactant: Cc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Cc2ccncc2)c1
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
To a solution of 4-methyl-pyridine (1.04 mL, 10.74 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. a 1 M solution of sodium hexamethyldisilazide in tetrahydrofuran (21.5 mL, 21.5 mmol, 2 eq) was added dropwise and the reaction was stirred for 20 minutes. Neat methyl 3-methoxybenzoate (1.8 g, 10.74 mmol, 1 eq) was then added and the reaction was stirred at 0° C. for one hour. The reaction was poured into saturated ammonium chloride solution and, after basification with saturated aqueous NaHCO3, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was taken up with n-hexane and filtered to give 1.75 g (72%) of the desired product as beige solid (1.775 g, 50%).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH:20][C:23](=[O:25])[CH3:24])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:21][CH:22]=1)([OH:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Yield: 63 %

Procedure:
The procedure of Example 4 was repeated to react 2-(4-carboxybenzamido)-4-aminobenzoic acid with acetic anhydride, and the reaction product was treated as in Example 4 to yield 63% of 2-(4-carboxybenzamido)-4-acetamidobenzoic acid having a melting point in the range of from 302° to 304° C. (decompose).
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C1COCC1>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: C1CCOC1
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
Cis,trans-muconic acid (19 g, 133.8 mmol) is dissolved in THF (250 mL) at room temperature and a crystal of iodine (160 mg, 0.63 mmol, 0.5 mole percent) is added. The reaction is performed in the presence of ambient light in the laboratory. The reaction mixture is allowed to stir at room temperature for 5 hours and the precipitant is filtered washed with acetonitrile and dried under reduced pressure to yield 16 g of trans,trans-muconic acid, an 84 percent yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=1.[F:18][C:19]([F:29])([F:28])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CCOC(C)=O.O.CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][C:19]([F:29])([F:18])[F:28])[CH2:22][CH2:23]2)=[O:15])=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(-c2cc(F)ccc2F)nc1
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(-c2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL flask was added 6-(2,5-difluorophenyl)nicotinic acid (100 mg, 0.46 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (77.5 mg, 0.46 mmol), EDAC (89.7 mg, 0.468 mmol), HOBT (57.5 mg, 0.46 mmol), and DMA (2 mL) followed by NMM (0.117 mL, 1.06 mmol). The reaction was stirred for 1 hour at room temperature and then diluted with EtOAc (0.2 mL) followed by H2O (4 mL). The resulting solids were washed in H2O and collected by filtration. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.12 (1H, d, J=2.2 Hz), 8.55 (1H, d, J=7.5 Hz), 8.31 (1H, dd, J=8.3, 2.3 Hz), 7.95 (1 H, dd, J=8.2, 1.5 Hz), 7.73-7.84 (1H, m), 7.35-7.51 (2H, m), 3.73-3.90 (1H, m), 3.19 (2H, q, J=10.3 Hz), 2.95 (2H, d, J=11.9 Hz), 2.39-2.50 (2H, m), 1.82 (2H, dd, J=14.0, 3.2 Hz), 1.53-1.68 (2H, m). LC/MS (M+H)=400.36 expected, 400.0 observed.
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]=[S:25]>>[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]1[N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11][S:25]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]Cc1ccccc1
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1Cc1ccccc1

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:5]2.[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:5]2[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:21]=1[O:20][CH3:19]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CC(C)(C)C1Nc2cc(Br)ccc2-n2cccc21
Product: COc1ccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C(C)(C)C)c(OC)c1

Procedure:
7-Bromo-4-tert-butyl-5-(2,4-dimethoxybenzoyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 7-bromo-4-tert-butyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (see Example 114, Step 1) and 2,4-dimethoxybenzoyl chloride according to the procedure of Example 106, Step 2. The product was purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) and isolated as a white foam. MS (ESI) m/z 469/471 ([M+H]+); HRMS: calcd for C24H25BrN2O3, 468.1049; found (ESI+), 469.11175.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH3:15])[CH:5]=1)(=O)[CH3:2].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].[BH4-].[Na+]>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:17]([S@:20]([NH:22][C@@H:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH3:15])[CH:5]=1)[CH3:2])=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: Cc1cc([C@@H](C)N[S@](=O)C(C)(C)C)ccc1NS(C)(=O)=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 45.5 %

Procedure:
To a solution of titanium(IV) ethoxide (1.32 g, 5.8 mol) and N-(4-acetyl-2-methylphenyl) methanesulfonamide (800 mg, 3.5 mmol) in tetrahydrofuran (20 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (423 mg, 350 mmol) under a nitrogen atmosphere and the mixture was heated at 70° C. for 16 hours. It was quenched with water and the resulting white precipitate was filtered off. The filtrate was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with hexane/ethyl acetate (4:1). The yellow oil obtained was dissolved in tetrahydrofuran (10 mL) and the solution was added to sodium borohydride (242 mg, 6.4 mmol) in tetrahydrofuran (10 mL) at −70° C. The mixture was stirred at −70° C. for 5 hours and then quenched with methanol. It was stirred at room temperature for 1 hour and concentrated in vacuo to furnish 530 mg (45%) of the title compound. MS (ESI) m/z 333 (M+H)+, 331 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[N:29]=[CH:28]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]1[CH2:18][CH2:17][N:16]([S:32]([C:30]3[N:29]=[CH:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:15][CH2:14]1)=[N:8][CH2:7][CH2:6]2
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COc1ccc2c(c1)CCN=C2C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN=C2C1CCN(S(=O)(=O)c2cn(C)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a stirred solution of 6-methoxy-1-piperidin-4-yl-3,4-dihydro-isoquinoline (0.094 g, 0.385 mmol) and triethylamine (0.078 g, 0.77 mmol) in CH2Cl2 (3 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (0.070 g, 0.385 mmol). The reaction mixture was stirred at RT under an atmosphere of N2 overnight. The reaction mixture was diluted with CH2Cl2 (10 ml) and washed with water (2×5 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via radial chromatography (SiO2, 1 mm, CH2Cl2 to 5% MeOH/CH2Cl2) to give the product as an oil (0.084 g, 0.216 mmol, 56% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([CH3:54])=[C:36]([C:40]2[C:49](=[O:50])[C:48]3[C:43](=[CH:44][C:45]([N:51]([CH3:53])[CH3:52])=[CH:46][CH:47]=3)[NH:42][CH:41]=2)[CH:37]=[CH:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:53][N:51]([CH3:52])[C:45]1[CH:44]=[C:43]2[C:48]([C:49](=[O:50])[C:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[O:25])=[CH:20][N:19]=5)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=4)[C:35]=3[CH3:54])=[CH:41][NH:42]2)=[CH:47][CH:46]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: Cc1c(Br)cccc1-c1c[nH]c2cc(N(C)C)ccc2c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1-c1c[nH]c2cc(N(C)C)ccc2c1=O
Temperature: 100 °C
Yield: 38.7 %

Procedure:
To Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (27 mg, 0.062 mmol), 3-(3-Bromo-2-methyl-phenyl)-7-dimethylamino-1H-quinolin-4-one (22 mg, 0.062 mmol), potassium phosphate (26 mg, 0.12 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (1.7 mg, 0.0036 mmol), and bis(dibenzylidineacetone)palladium(0) (1.0 mg, 0.0018 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 1 hour. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 7-Dimethylamino-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one (14 mg, 0.024 mmol). MS (ESI) 591.1 (M+H)+.