Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][C@@:7]1([CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[N:13]=[C:12]2[S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][O:8]1.[N:29]1([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>C(OCC)(=O)C>[N+:16]([C:14]1[N:13]=[C:12]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[N:11]([CH2:10][C@:7]([OH:8])([CH3:6])[CH2:9][N:32]2[CH2:31][CH2:30][N:29]([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:43][CH:42]=3)=[O:36])[CH2:34][CH2:33]2)[CH:15]=1)([O-:18])=[O:17]
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Sc2ccc([N+](=O)[O-])cc2)CO1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1ccc([N+](=O)[O-])cc1
Yield: 89.4 %

Procedure:
N,N-Dimethylformamide (0.5 ml) solution of (R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole (100 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazine-1-carboxylate (103 mg) was stirred at 60° C. for 1 day. Water and ethyl acetate were added to the reaction mixture, and the organic layer was taken by separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a silica gel column chromatography (eluent: dichloromethane/methanol=50/1 to 30/1) and a basic silica gel column chromatography (eluent: dichlomethane), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-{3-[4-nitro-2-(4-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (173 mg, yield: 90%) as pale yellow amorphous product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Cl[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)ccc2ccccc12
Product: COc1c(-c2cnnc(Cn3ccnc3C)c2)ccc2ccccc12

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared from 2-(1-methoxy-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][NH:7][C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[N:5]1.[H-].[Na+].Cl[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25]>O1CCCC1>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][N:7]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[C:6]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)=[N:5]1
Reactant: O=C1CNC(c2cc(Cl)cc(Cl)c2)=NN1CC(F)(F)F
Reactant: C=CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC(=O)N(CC(F)(F)F)N=C1c1cc(Cl)cc(Cl)c1
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one (110 mg, 0.34 mmol) in 5 mL tetrahydrofuran at was added sodium hydride (30 mg, 0.67 mmol). After the reaction stirred 5 min, the allyl chloroformate (0.07 mL, 0.67 mmol) was added dropwise. After the reaction was heated at reflux for 6 h, it was quenched with water and diluted with ethyl acetate. The two layers were separated and the aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (100% hexanes-10% ethyl acetate/hexanes) afforded the acylated product 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4-allyloxycarbonyl-4,5-dihydro-1,2,4-triazin-6-one (130 mg, 93%) as a yellow oil in 100% purity by gas chromatography (GC).
Reaction SMILES: [CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][C@@H:46]([C:48]2[CH:59]=[CH:58][C:51]3[O:52][C:53]([CH3:57])([CH3:56])[O:54][CH2:55][C:50]=3[CH:49]=2)[O:45][C:44]1=[O:60])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C@@H:46]([C:48]4[CH:59]=[CH:58][C:51]5[O:52][C:53]([CH3:56])([CH3:57])[O:54][CH2:55][C:50]=5[CH:49]=4)[O:45][C:44]3=[O:60])[CH:12]=2)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN(C1CCCCC1)S(=O)(=O)c1cccc(CO)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(S(=O)(=O)N(COCC[Si](C)(C)C)C5CCCCC5)c4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A solution of N-cyclohexyl-3-(hydroxymethyl)-N-({2-(trimethylsilyl)ethoxy}-methyl)benzenesulfonamide (508 mg) in DMF (8 ml) under nitrogen at 20° was treated with sodium hydride (60% dispersion in mineral oil, 58 mg) and the mixture was stirred 15 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (400 mg) in DMF (2 ml) was added and the mixture was stirred at 20° for 72 h. Phosphate buffer solution (pH 6.5, 10 ml) and water (20 ml) were added and the mixture was extracted with EtOAc (30 ml). The extract was washed with water (2×30 ml), dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-PE (1:1) gave the title compound (530 mg). LCMS RT=4.47 min, ES+ve 793 (MH)+.
Reaction SMILES: Cl.C(OC(=O)NC[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:32])[NH:17][CH2:18][C:19]2[S:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[CH:22][CH:23]=2)=[CH:12][N:11]=1)(C)(C)C.[NH2:34][C:35]1C(C(O)=O)=NC=C(N)N=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)C>[F:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[O:24][C:21]1[S:20][C:19]([CH2:18][NH:17][C:16](=[O:32])[C:13]2[CH:14]=[CH:15][C:10]([NH:34][CH3:35])=[N:11][CH:12]=2)=[CH:23][CH:22]=1
Reactant: Nc1cnc(C(=O)O)c(N)n1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)cn1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 85.5 %

Procedure:
Ethanol (20 mL) and 5N hydrochloric acid (0.8 mL) were added to (5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)carbamoyl)pyridin-2-yl)methyl-carbamic acid tert-butyl ester described in Preparation Example A+-3 (87 mg, 0.19 mmol), and the solution was stirred for 25 minutes at 80° C. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (58 mg, 0.162 mmol, 85.5%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][CH2:36]Br.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.8 g, 1.81 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.109 g, 4.5 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,4-dibromobutane (0.432 g, 1.99 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. upon which saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate (400 mg) as a thick liquid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 80.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (500 mg, 0.93 mmol), 4-methylsulfonyl phenylboronic acid (560 mg, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (65 mg, 0.093 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 35% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine (390 mg, 81%) as a white solid: LC/MS m/e calcd for C28H28N2O4S2 [M+H]+ 521.67, observed 520.7.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)=[O:11])#[N:2].Cl.[CH3:25][N:26](C)[CH2:27]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC.Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:26]([CH3:27])[CH3:25])=[O:17])=[CH:14][CH:13]=1)=[O:11])#[N:2]
Reactant: N#Cc1cccc(OCCCC(=O)c2ccc(C(=O)O)cc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(C(=O)CCCOc2cccc(C#N)c2)cc1

Procedure:
240 mg (0.78 mmol) of 4-[4-(3-cyanophenoxy)butyryl]benzoic acid, 150 mg (0.78 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 121 mg (0.78 mmol) of 1-hydroxybenzotriazole (hydrous, 87%) and 100 mg of 50% aqueous dimethylamine solution were stirred together in 5 ml of dimethylformamide at room temperature overnight. 1 N hydrochloric acid was added to the resultant mixture. After the extraction with dichloromethane, the extract was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by the silica gel chromatography with ethyl acetate as the eluent to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.CN(C(ON1N=[N:37][C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC[C@H]1C#N.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:36]3[CH2:35][CH2:34][CH2:33][C@H:31]3[C:32]#[N:37])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#C[C@@H]1CCCN1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)N1CCC[C@H]1C#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol), HATU (15 mg, 0.039 mmol), (S)-pyrrolidine-2-carbonitrile hydrochloride (4 mg, 0.032 mmol), and N-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL). The reaction mixture was stirred under nitrogen at 40° C. for 10 min and then at room temperature for 30 min. The solution was concentrated and purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA) to afford the title compound as a yellow film (4 mg, 29%). 1H NMR (500 MHz, CD3OD) δ 0.94 (d, J=6.9 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 1.04-1.13 (m, 1H), 2.12-2.17 (m, 2H), 2.25-2.29 (m, 2H), 2.60-2.63 (m, 1H), 3.72-3.75 (m, 1H), 3.83-3.87 (m, 1H), 4.90 (d, J=13.7 Hz, 1H), 5.05 (d, J=12.7 Hz, 1H), 5.50 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 8.25 (s, 1H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C@H:3]([NH:8][C:9]([C:11]1[O:15][C:14]([C:16]2[N:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:10])[C:4](=[O:7])[NH:5][CH3:6].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][CH:2]([CH3:30])[C@H:3]([NH:8][C:9]([C:11]1[O:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:20][N:21]=2)=[CH:13][CH:12]=1)=[O:10])[C:4](=[O:7])[NH:5][CH3:6]
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cn2)o1)C(C)C
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(-c3ccccc3)cn2)o1)C(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A flask charged with trifluoromethanesulfonic acid 6-[5-((S)-2-methyl-1-methylcarbamoyl-propylcarbamoyl)-furan-2-yl]-pyridin-3-yl ester (50 mg, 0.11 mmol), phenylboronic acid (27 mg, 0.22 mmol), palladiumtetrakistriphenylphosphine (13 mg, 0.01 mmol), and potassium carbonate (61 mg, 0.44 mmol) is flushed with argon. Toluene (2 mL), ethanol (0.5 mL), and water (1 mL) are added and the reaction is stirred at 100° C. for 2 hours. The reaction is cooled to room temperature, ethyl acetate (10 mL), is added and the mixture washed with water (10 mL), brine (10 mL), and dried over MgSO4. The solution is filtered and evaporated in vacuo to give an oil that is purified by preparative HPLC. 5-(5-Phenyl-pyridin-2-yl)-furan-2-carboxylic acid ((S)-2-methyl-1-methylcarbamoyl-propyl)-amide is obtained as a white solid, 16 mg, 38%, LC/MS ESI m/z (M+H)+=377.43.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1[N:26]=[CH:27][N:28]([CH2:30][CH2:31][CH2:32][OH:33])[CH:29]=1.CC([O-])(C)C.[K+]>COCCOC.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:33][CH2:32][CH2:31][CH2:30][N:28]4[CH:27]=[N:26][N:25]=[CH:29]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: OCCCn1cnnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCn4cnnc4)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidin-1-carboxylic acid tert-butyl ester (31.6 mg, 95.5 μmol), as prepared in Example 12b, 3-[1,2,4]-triazol-4-yl-propan-1-ol (ChemPacific) (12.0 mg, 94.5 μmol), and KOtBu (11.7 mg, 104 μmol) in DME (100 μL) and DMSO (50 μL) was stirred at rt for 1 hr. The resulting homogeneous amber solution was partitioned with DCM (2 mL) and 0.5M sodium phosphate/pH 7 (2 mL). The organic layer was concentrated to provide the crude title compound. LC/MS (ESI): calcd mass 438.2, found 439.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 138.3 %

Procedure:
2.90 g (13.3 mmol) of 4-chlorobenzenesulfonylisocyanate and 2.21 g (14.1 mmol) of 2-amino-4-nitrobenzoic acid were treated in the same way as in Example 1 to obtain 7.02 g of the above-identified compound (yield 57.9%). Properties: colorless crystal, Melting point: 258°-260° C., PMR (δppm, DMSO-d6): 7.10 (1H,s), 7.77 (2H,d), 7.92 (1H,d), 8.10 (1H,d), 8.19 (2H,d).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:5]([F:8])([F:7])[F:6]>CO.[Pd]>[CH3:1][CH:2]([CH3:18])[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:5]([F:6])([F:7])[F:8]
Reactant: CC(C)C=C(c1ccccc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(C)C=C(c1ccccc1N)C(F)(F)F

Procedure:
A solution of 1.14 g (4.4 mmol) 1-(3-methyl-1-trifluoromethyl-but-1-enyl)-2-nitrobenzene in 20 ml methanol is hydrogenated over 10% Pd/C (230 mg) at room temperature for 20 minutes. Then the catalyst is filtered off and the solvent removed in a water-jet vacuum. The crude product is purified by column chromatography over silica gel (eluant:methylenechloride/hexane=2:1). Yield: 0.6 g ((sum E+Z isomer) 2-(3-methyl-1-trifluoromethyl-but-1-enyl)phenylamine in the form of a brown oil. After column chromatography both isomers are obtained in pure form (1H-NMR).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([C:23]([O-:25])=[O:24])[C:3]([O:5][C:6]1[C:7]([F:22])=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])=[C:10]([C:13]#[N:14])[C:11]=1[NH2:12])=O.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:13]([C:10]1[C:11]2[N:12]=[C:3]([C:2]([CH3:26])([CH3:1])[C:23]([O:25][CH2:38][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:24])[O:5][C:6]=2[C:7]([F:22])=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[CH3:15])#[N:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1c(C#N)c(N)c(OC(=O)C(C)(C)C(=O)[O-])c(F)c1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)C(=O)OCc3ccccc3)nc2c1C#N
Yield: 856.5 %

Procedure:
A mixture of 4-amino-5-cyano-2-fluoro-6-methylbiphenyl-3-yl 2,2-dimethylmalonate (I-63) (500 mg, 1.12 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.112 mmol) and toluene (20 ml) was heated under reflux for 2 hours. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried on anhydrous magnesium sulfate, then the solvent was evaporated away to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (411 mg, 86%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(Br)n1
Yield: 82.2 %

Procedure:
6-bromopicolinic acid (1.99 g) in DMF (10 mL) was treated with potassium carbonate (1.40 g) and then methyl iodide (4 mL) at room temperature for 20 h. The reaction mixture was diluted with dichloromethane (60 mL) and filtered. The filtrate was extracted with brine (twice), dried (MgSO4), and concentrated under vacuum to give methyl 6-bromopicolinate as a pale yellow solid (1.75 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:23])=[C:19]([CH3:33])[CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])=[C:19]([CH3:33])[CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1cc(Br)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 28 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 5-bromo-N-(4-fluorobenzyl)-3-methylthiophene-2-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 28% yield: mp 175-177° C.; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=7.8 Hz, 1H), 7.43-7.36 (m, 5H), 7.31 (dd, J=8.5, 5.6 Hz, 2H), 7.02 (dd, J=8.5, 8.5 Hz, 2H), 6.84 (s, 1H), 6.20 (t, J=5.4 Hz, 1H), 6.14 (dd, J=7.8, 2.4 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H), 5.03 (s, 2H), 4.54 (d, J=5.4 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 162.9, 162.2, 139.8, 139.7, 134.7, 134.4, 133.8 (JC-F=3.3 Hz), 129.5 (JC-F=8.1 Hz), 128.8, 127.8, 126.8, 121.9, 115.6 (JC-F=21.4 Hz), 103.4, 98.1, 70.6, 43.2, 15.9; MS (ES+) m/z 449.3 (M+1).