Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[C:13]([Br:17])[C:14]([Br:16])=[CH:15][C:10]=2[NH:9][C:8](=[O:18])[C:7]2[CH:19]=[CH:20][CH:21]=[N:22][C:6]1=2)=[O:4].[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[Br:16][C:14]1[C:13]([Br:17])=[CH:12][C:11]2[N:5]([C:3](=[O:4])[CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]3)[C:6]3[N:22]=[CH:21][CH:20]=[CH:19][C:7]=3[C:8](=[O:18])[NH:9][C:10]=2[CH:15]=1
Reactant: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CCl)c2ncccc21
Reactant: OCCN1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CN2CCN(CCO)CC2)c2ncccc21

Procedure:
11-Chloroacetyl-8,9-dibromo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (0.05 mole) and 0.13 mole 4-(2-hydroxyethyl)piperazine, dissolved in 800 ml. ethanol are heated to reflux for a period of 20 hours. The hot solution is then filtered, the filtrate evaporated in vacuo and the remaining residue recrystallized from 2-propanol to give 8,9-dibromo-6,11-dihydro-11-[[4-(2- hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:30]=[CH:29][C:13]([C:14]([NH:16][C@H:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[CH3:18])=[O:15])=[CH:12][C:11]=1[Cl:31])=[O:9].[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33].C(N(CC)CC)C>O1CCCC1>[Cl:31][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:10]=1[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH2:2][NH:1][C:35]([NH:34][CH2:32][CH3:33])=[O:36])=[O:9])[C:14]([NH:16][C@H:17]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=2[N:20]=1)[CH3:18])=[O:15]
Reactant: CCN=C=O
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)NC[C@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
200 mg (0.3 mmol) of 4-[(2R)-2-aminomethylpyrrolidin-1-ylcarbonyl]-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide, 26 mg (0.36 mmol) of ethyl isocyanate, and 0.2 mL (1.2 mmol) of triethylamine are stirred for 16 hours at ambient temperature in 20 mL of tetrahydrofuran. Then the solvent is distilled off and the residue is chromatographed on silica gel, eluting with dichloromethane/ethanol (9:1). Yield: 140 mg (86%); Rf value: 0.38 (silica gel; dichloromethane/ethanol=9:1); C25H28Cl2N6O3 (531.44); mass spectrum: (M+H)+=531/533 (chlorine isotope) and (M−H)−=529/531 (chlorine isotope).
Reaction SMILES: C1C=C([N+]([O-])=O)C2C(=NON=2)C=1N[C@H:14]([C@@H:17]([OH:24])[C@H:18]([OH:23])[C@H:19]([OH:22])[CH2:20][OH:21])[CH:15]=[O:16].[OH2:25]>>[O:21]=[CH:20][C@@H:19]([C@H:18]([C@@H:17]([C@@H:14]([CH2:15][OH:16])[OH:25])[OH:24])[OH:23])[OH:22]
Reactant: O
Reactant: O=C[C@H](Nc1ccc([N+](=O)[O-])c2nonc12)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 3 h

Procedure:
At 72 hpf, larvae were placed into a 96-well plate (6 eggs/well in 200 μL E3 water supplemented with 0.2 mM 2-phenylthiourea; Sigma). Drug of interest was added for h. The solution was then replaced with E3 water supplemented with 600 μM 2-NBDG and incubated for 3 h. The larva were washed with E3 water and anesthetized with 0.02% tricaine-supplemented E3 water. One larva was then placed on a chamber slide, containing 3% methylcellulose in E3 water, for fluorescent microscopy (Leica DM2500 microscope equipped with a DFC425 C digital camera). Images were captured at 50× magnification. The remaining 5 larvae where lysed with 120 μL of CelLytic M solution (Sigma-Aldrich) and sonication (4° C., 10″/5″ pulse, 10 min). Lysed larvae were centrifuged at 10000 rpm for 10 min. 100 μL of the supernatant was transferred to a 96-well plate and fluorescence was measured with a fluorescent microplate reader (SpectraMAX Gemini XS, Molecular Devices; λex=466 nm λex=540 nm).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:28][C:29]1[CH:30]=[C:31]([OH:37])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>CN(C=O)C>[F:28][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[O:37][C:8]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11]
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Reactant: COc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cc(C(F)(F)F)ccc2C(=O)Nc2cc[nH]c(=O)c2)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Cs2CO3 (651.6 mg, 2.0 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (60.0 mg, 0.2 mmol) and 3-fluoro-4-methoxyphenol (284.3 mg, 2.0 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (81) (45.6 mg, 54%). ESI-MS m/z calc. 422.09. found 423.3 (M+1)+; Retention time: 1.65 minutes (3 minutes run).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.O.[Sn](Cl)Cl>C(O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Yield: 91 %

Procedure:
To a slurry of 3-bromo-6-nitro-1-(phenylsulfonyl)-1H-indole (2.80 g, 7.35 mmol) in ethanol (73.5 mL) was added a solution of tin (II) chloride monohydrate (6.63 g, 29.4 mmol) in water (11.0 mL) at 30° C. Once the addition was complete, the reaction was heated to reflux for 3.5 h, then quenched with 2.0 N sodium hydroxide to a pH of 8. The remaining slurry was diluted with ethyl acetate (100 mL), and the aqueous layer was removed and filtered. The organic phase was washed with 2.0 N sodium hydroxide (2×100 mL), and the combined aqueous layers were extracted with ethyl acetate (3×200 mL). The combined organic phases were concentrated to give a tacky, orange solid for 3-bromo-1-(phenylsulfonyl)-1H-indol-6-amine (2.35 g, 6.69 mmol, 91%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: CC(=O)O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
Bromine (0.715 ml) was added dropwise to tert-butyl 4-(3-methoxyphenyl)piperazine-1-carboxylate (3.4 g) dissolved in cold acetic acid (25 ml) under argon. The resulting solution was stirred at room temperature for 90 minutes. The reaction mixture was concentrated to dryness and diluted with ethyl acetate, dichloromethane and a saturated aqueous solution of sodium bicarbonate. The phases were stirred, separated and the organic phase was dried over magnesium sulfate and concentrated in the presence of silica gel. The crude product was purified by flash chromatography on silica gel eluting with 10 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromo-3-methoxy-phenyl)piperazine-1-carboxylate (1.770 g, 41.0%). NMR Spectrum: (CDCl3) 1.48 (s, 9H), 3.08-3.17 (m, 4H), 3.54-3.62 (m, 4H), 3.88 (s, 3H), 6.40 (dd, 1H), 6.47 (d, 1H), 7.37 (d, 1H)
Reaction SMILES: I[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([NH2:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]1([N:6]2[C:2]([C:26]3[CH:27]=[CH:22][CH:23]=[C:24]([CH2:28][O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[CH:25]=3)=[CH:3][C:4]([NH2:13])=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC1(C)OB(c2cccc(COCC(F)(F)F)c2)OC1(C)C
Reactant: Nc1cc(I)n(-c2ccccc2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: Nc1cc(-c2cccc(COCC(F)(F)F)c2)n(-c2ccccc2)n1
Yield: 95.8 %

Procedure:
To a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (221 mg) prepared according to the same procedures as Preparation 2 in 1,2-dimethoxyethane (2.2 ml) were sequentially added 4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,3,2]dioxaborolane (269 mg) prepared in Preparation 28, a 2M aqueous solution of sodium carbonate (1.1 ml), tricyclohexylphosphine (43.4 mg) and palladium (II) acetate (17.4 mg) at room temperature, and the mixture was stirred at 100° C. for 12 hours. To this reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate at room temperature, and then the mixture was filtered through Celite, and subjected to elution with ethyl acetate. The filtrate was extracted with ethyl acetate, the resulting organic layer was washed with was a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (258 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[CH:9][NH:8][CH:7]=1)([OH:3])=[O:2].CO.[CH3:14]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+]>C(OCC)C.C(O)C.O>[CH3:14][O:2][C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[CH:9][NH:8][CH:7]=1)=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: Cc1c[nH]cc1CCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)CCc1c[nH]cc1C
Temperature: 70 °C
Yield: 80.4 %

Procedure:
3-(2-Carboxyethyl)-4-methylpyrrole (123 g) was mixed with 1500 mL of ethyl ether and 250 mL of methanol in a magnetically stirred receiver flask. A separate 3 L, 3 neck round bottom flask was equipped with magnetic stirring, a distillation head and condenser leading to the inlet of the receiver flask, and heated in a water bath. Into the 3 L flask was placed 240 g of Diazald, dissolved in 1800 mL of ethyl ether, and a solution of 73 g of potassium hydroxide, dissolved in 360 mL of 95% ethanol and 112 mL of water. The 3 L flask was stirred and heated to 65-75° C. in a water bath, and the diazomethane-ether mixture was distilled into the stirred receiver flask over about 2.5 hrs. Ethyl ether (200 mL) was added to the 3 L flask, and the distillation continued until complete. The receiver flask was stirred for another 30 minutes, and then 10 mL of acetic acid was added. The mixture was extracted twice with 500 mL of water each time, and then twice with 200 mL of saturated sodium bicarbonate each time. The ether layer was dried over anhydrous sodium sulfate, and distilled to leave a dark fluid residue. The residue was distilled twice through a 4 inch Vigreux column and once through a 10 inch vacuum-jacketed Vigreux column to give 108 g (80.6% yield) of 3-(2-methoxycarbonylethyl)-4-methylpyrrole. BP 108-113 C at 0.5 mm.
Reaction SMILES: C1(CC2NC(=O)C(C(C)C)CC2O)CCCCC1.[CH2:19]([C@H:26]1[CH2:31][C@H:30]([OH:32])[C@H:29]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:28][C:27]1=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:28][C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:30]1[O:32][C:27](=[O:40])[C@@H:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:31]1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H]1Cc1ccccc1
Agent: CC(C)C1CC(O)C(CC2CCCCC2)NC1=O
Product: N[C@@H](Cc1ccccc1)[C@@H]1C[C@H](Cc2ccccc2)C(=O)O1

Procedure:
Following the procedure described in Example 7 and replacing the product of Example 6 with the product of Example 9 provides the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>CN1C(=O)CCC1>[N+:22]([C:21]1[C:16]([N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10]2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ncccc2[N+](=O)[O-])CC1
Yield: 83.8 %

Procedure:
Anhydrous TEA (0.76 ml, 5.49 mmol) was added to piperidin-4-yl-carbamic acid tert-butyl ester (1 g, 5 mmol) and 2-chloro-3-nitro-pyridine (0.791 g, 5 mmol) in anhydrous NMP (3 ml). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 10 minutes. The brown solution was partitioned between EtOAc and water and the organic phase was washed several times with water, dried over sodium sulphate and concentrated in vacuo to give the title compound as a yellow solid (1.35 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1C=CC=CC=1.[CH:40](OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)(C)C.C1OC2C=C(/C=C/C(C3C=CC(F)=CC=3Cl)=O)C=CC=2O1.C(OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C=C.C(OC1C=C(CC(NC(C2C=C(OC)C=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C>>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:25]=[C:26]([CH3:40])[CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OC(C)C)c1)c1ccccc1N1CCCCC1
Agent: C=CCOc1cc(CC(=O)NC(CCC)c2ccccc2N2CCCCC2)ccc1C(=O)O
Agent: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1cc(OC)ccc1N1CCCCC1
Agent: O=C(/C=C/c1ccc2c(c1)OCO2)c1ccc(F)cc1Cl
Product: CCOC(=O)c1ccc(CC(=O)NC(C=C(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
The mixing ratio of 75/25 is obtained from the corresponding ratio of intensities of the particularly characteristics signals in the 400 MHz-1H-NMR spectrum (CDCl3). The position of the signals is: 3-methyl-2-buten-1-yl compound: olefinic H: 5.25 (d), CH3: 1.64 (s) and 1.77 (s), benzylic <CH—6.00 (t), benzylic CH2—; 3.52 ppm (s) 3-methyl-1-butyl compound: CH3: 0.90 (d), benzylic <CH—5.35 (m), benzylic —CH2—; 3.54 ppm (s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@@H:15]([C:17]3[O:21][NH:20][C:19](=[O:22])[CH:18]=3)[CH2:14][CH2:13][N:12]2C(OC)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@@H:15]([C:17]3[O:21][NH:20][C:19](=[O:22])[CH:18]=3)[CH2:14][CH2:13][NH:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(S(C)(=O)=O)cc1
Agent: Br
Product: CS(=O)(=O)c1ccc([C@H]2C[C@@H](c3cc(=O)[nH]o3)CCN2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
(2R,4S)-Methyl 2-(4-(methylsulfonyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (536 mg, 1.41 mmol) was dissolved in hydrogen bromide (33% in AcOH, 5 mL, 71.37 mmol) and stirred at room temperature for 20 h. The reaction mixture was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-(methylsulfonyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (309 mg, 68%), 1H NMR (600 MHz, dmso) δ 1.39 (q, 1H), 1.49 (dq, 1H), 1.87-1.93 (m, 1H), 2.01 (d, 1H), 2.76 (t, 1H), 2.87-2.94 (m, 1H), 3.11-3.19 (m, 1H), 3.17 (s, 3H), 3.80 (d, 1H), 5.74 (s, 1H), 7.64 (d, 2H), 7.85 (d, 2H). HRMS Calcd for [C15H18N2O4S+H]+: 323.1065. Found: 323.1042.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N:19]([C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CN1Cc2cccnc2C(N2CCNCC2)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CN1Cc2cccnc2C(N2CCN(C(=O)Cc3ccncc3)CC2)c2ccc(Cl)cc21
Reaction time: 0.02 h

Procedure:
(8-Chloro-6,11-dihydro-6-methyl-5H-pyrido[3,2-c][1]benzazepin-11-yl)-piperazine (100 mg, 0.305 mmol), 4-pyridine-acetic acid (83.6 mg, 0.61 mmol), EDCl (0.116 g, 0.61 mmol) and HOBT (82.4 mg, 0.61 mmol) were dissolved in DMF (2 ml) and stirred for 1 minute, and then NMM (1 ml) was added. The reaction mixture was stirred at 20° C. for 21 hours and then diluted with water (50 ml), and the aqueous phase was then extracted with EtOAc (about 8 times) until no product was visible in the aqueous layer. The EtOAc phase was then washed with aqueous Na2CO3 and evaporated to a residue (152 mg). This was chromatographed on silica gel to afford partially purified title compound (123 mg), which was rechromatographed on silica gel; two fractions, 51.3 and 50.8 mg, were isolated. The latter gave m.p. 83-87° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[C:11]([O:14][CH2:15][CH2:16][O:17]C)(=O)C.Cl>C1C=CC=CC=1.O>[CH3:11][O:14][CH2:15][C:16]([CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:17]
Reactant: COCCOC(C)=O
Reactant: CC1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COCC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
2.5 g of 60% sodium hydride was suspended in 50 ml of benzene and a mixture of 5.6 g of 4methylcyclohexanone and 5.4 g of methoxyethyl acetate was added dropwise thereto under cooling. After stirring at room temperature for two hours, 20 ml of water was added and the pH value of the reaction mixture was adjusted to 3 with concentrated hydrochloric acid. After removing the benzene phase the aqueous phase was extracted with ether. The benzene solution and the ether solution were combined, washed with water, dried and concentrated to give 7.4 g of crude 2-methoxyacetyl4-methylcyclohexanone. This crude product was subjected to the subsequent step.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=O)=[N:4][N:3]=1.[NH4+:12].[OH-]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:12])=[O:9])=[N:4][N:3]=1
Reactant: CCOC(=O)c1nnc(Br)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1nnc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (13.5 g, 56.9 mmol) in THF (50 mL) at room temperature was added NH4OH (28 wt. %, 39.6 mL, 164 mmol). The mixture was stirred at room temperature overnight and a precipitate appeared in the aqueous layer. Volatile materials were removed in vacuo. The mixture was diluted with water and the precipitate was collected, washed with water and dried under vacuum to give the title compound. 1H NMR (400 MHz, acetone-d6): δ7.99 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C@H:17]([NH:19][C:20]([C:22]1([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:23]1)=[O:21])[CH3:18].Br[C:33]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:34]=1[NH2:35].C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:35][C:34]1[C:36]([F:40])=[CH:37][CH:38]=[CH:39][C:33]=1[C:6]1[CH:5]=[CH:4][C:3]([C@H:17]([NH:19][C:20]([C:22]2([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:23]2)=[O:21])[CH3:18])=[C:2]([F:1])[CH:7]=1
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Nc1c(F)cccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2N)cc1F

Procedure:
N-{(1R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide (1.50 g, 3.377 mmol), 2-bromo-6-flouroaniline (401 ul, 3.545 mmol), tris(dibenzylideneacetone)dipalladium (309 mg, 0.338 mmol), cesium carbonate (1.10 g, 3.377 mmol) and 1.65M tri-t-butylphosphine in dioxane (491 ul, 0.810 mmol) were suspended in dioxane (15 ml), degassed with Argon purge and heated to 90 C for 15 minutes. After this time, the mixture was filtered through a Gelman Acrodisc and the filter was washed with EtOAc (10 ml) and methanol (20 ml). The combined filtrates were concentrated in vacuo and the residue purified by column chromatography eluting with a 0-100% EtAOc/CH2Cl2 gradient to give N-[(1R)-1-(2′-amino-3,3′-difluoro-1,1′-biphenyl-4-yl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide. Low resolution mass spectrometry: (M+H+)=428.2. 1H NMR (400 MHz, (CD3)2SO) δ 9.79 (s, 1H), 8.28 (d, 1H, J=7.6 Hz), 7.48 (t, 1H, J=8.2 Hz), 7.19-7.26 (m, 2H), 7.02-7.09 (m, 1H), 6.89 (d, 1H, J=7.6 Hz), 6.61-6.68 (m, 1H), 5.22-5.29 (m, 1H), 1.45-1.57 (m, 2H), 1.42 (d, 3H, J=7.1 Hz) and 0.93-1.08 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:10][C:9](=[O:11])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]([CH3:25])[C:9](=[O:11])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)NC(=O)CC1c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CC(=O)N1C
Temperature: 25 °C

Procedure:
A solution of 100 g (0.33 mole) of (±) 5,5-diethoxycarbonyl-4-phenylpyrrolidin-2-one in 500 ml of absolute dimethylformamide was added dropwise to a suspension of 9.64 g (0.36 mole) of sodium hydride in 200 ml of absolute dimethylformamide at room temperature under an N2 atmosphere. The mixture was subsequently stirred at room temperature until the evolution of gas had ended, a solution of 93.7 g (0.66 mole) of methyl iodide in 50 ml of absolute dimethylformamide was then added and the mixture was stirred at room temperature until all the starting material had reacted (about 1 hour, thin layer chromatography check). The reaction mixture was poured into 2 l of buffer solution, pH=7, and extracted five times with 600 ml of diethyl ether each time.