Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C@@H:7]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[O:10])[NH2:8])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C.[NH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:33][C:32]=1[Cl:42]>C(Cl)Cl>[NH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([S:38]([NH:8][CH:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([NH2:1])=[C:3]([N+:20]([O-:22])=[O:21])[CH:4]=2)[C:9]([N:11]2[CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH2:16]2)=[O:10])(=[O:40])=[O:39])=[CH:33][C:32]=1[Cl:42]
Reactant: CC1CCN(C(=O)[C@@H](N)Cc2ccc(N)c([N+](=O)[O-])c2)CC1
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reaction time: 2 h

Procedure:
3.06 g (10 mMol) of 4-amino-3-nitro-phenylalanyl-(4-methyl-piperidine) are dissolved in 100 ml of methylene chloride and combined with 2.8 ml (20 mMol) of triethylamine. Then at ambient temperature 3.1 g (12 mMol) of 4-amino-3,5-dichloro-benzenesulphonic acid chloride in 20 ml of methylene chloride is slowly added dropwise. After 2 hours the precipitate is suction filtered, washed with methylene chloride and dried at 70° C. For further purification the precipitate is suspended in 100 ml of ethanol, decocted and after cooling suction filtered again.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[O:17]=[C:18]1[C:23]([CH:24]=O)=[CH:22][CH:21]=[CH:20][NH:19]1.C(Cl)Cl>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[CH:24][C:23]3[C:18](=[O:17])[NH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc[nH]c1=O
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]cccc1C=C1c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of 2-nitrofluorene (326 mg, 1.54 mmol) and 2-oxo-1,2-dihydro-pyridine-3-carbaldehyde (19 mg, 1.54 mmol) in 10 mL of methanol was added KF—Al2O3 (224 mg, 1.38 mmol). The resulting mixture was stirred at 85° C. After 24 hrs, TLC indicated that a new product was produced and lots of starting material was still remained. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was purified by silica gel column; eluting with 60% EtOAc in hexane afforded 26 mg of CYD-1-93 as a yellow solid. 1H-NMR (600 MHz, d6-DMSO) δ 12.18 (br s, 2H), 8.77 (d, 1H, J=1.8 Hz), 8.52 (d, 1H, J=1.8 Hz), 8.28 (m, 2H), 8.15 (m, 2H), 8.10 (d, 1H, J=7.8 Hz), 8.06 (m, 2H), 7.97 (m, 2H), 7.86 (m, 2H), 7.80 (s, 1H), 7.63 (m, 1H), 7.59 (m, 1H), 7.49 (m, 3H), 7.37 (m, 1H), 6.40 (m, 2H). 13C-NMR (150 MHz, CDCl3) δ 161.2, 161.1, 146.9, 146.2, 146.1, 143.6, 142.1, 141.7, 140.5, 139.6, 138.3, 137.3, 136.1, 136.0, 133.6, 133.4, 129.3, 129.1, 129.0, 128.8, 127.9, 127.4, 126.1, 125.9, 124.0, 123.9, 123.5, 121.9, 121.5, 121.1, 120.7, 120.5, 119.0, 105.1, 105.0.
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].[Na+]>CN(C=O)C>[N:18]1([C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1c2ccccc2c(-n2ccnc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 10-chloro-9-anthraldehyde (Aldrich, 15 g, 0.062 mol), imidazole (Aldrich, 10.2 g, 0.15 mmol) and DMF (300 mL) was warmed to 55° and treated with KotBu (MCB, 7.0 g, 0.07 mol) and stirred for 30 min. The reaction mixture was poured into 0.1N NaOH (1.5 L). The precipitate was filtered and then chromatographed on a plug of SiO2 (500 g) using CH2Cl2 (3 L) as the initial eluting solvent to remove starting material and byproducts. The yellow product band was then eluted with EtOAc (2 L) to yield, after removal of solvent and drying, 12.29 g (73%) of 10-(1H-imidazol-1-yl)-9-anthracenecarbaldehyde mp 194°-196°, (C, H, N), (EtOAc).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)([CH3:5])([CH3:4])[CH3:3].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:16][C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:17])=[CH:13][CH:12]=2)[CH3:15])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vial containing tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride from Step 1 was added N,N-dimethylaminopyridine (3.91 mg, 0.032 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (0.059 g, 0.24 mmol), N,N-dimethylformamide (2 mL), and triethylamine (0.18 mL, 1.28 mmol). The mixture was stirred at rt for 16 h, after which the solvent was fully evaporated. To the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give (R)-tert-butyl 4-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)benzoate as a brown solid. LC-MS: (FA) ES+ 430.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1([NH:9]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1)(=[O:4])=[O:3].[ClH:17]>C(Cl)Cl.O1CCOCC1>[CH3:1][S:2]([CH2:5][C:6]1([NH2:9])[CH2:8][CH2:7]1)(=[O:4])=[O:3].[ClH:17]
Reactant: CC(C)(C)OC(=O)NC1(CS(C)(=O)=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)CC1(N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 1-(methylsulfonylmethyl)cyclopropylcarbamate (crude, 1.05 g) in DCM (7 ml) was added 4M HCl in 1,4-dioxane (16 ml) at r.t. It was stirred further at room temperature for 1 h, at which time LC/MS analysis confirmed full consumption of starting material. Solvent was removed in vacuo and the solid was washed with ether to get the desired 1-(methylsulfonylmethyl)cyclopropanamine as an HCl salt.
Reaction SMILES: O[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[CH3:24]>OS(C(F)(F)F)(=O)=O>[Br:14][C:15]1[C:16]([CH3:24])=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][C:20]=1[CH2:2][N:3]1[C:7](=[O:8])[C:6]2[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:13]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])cc(CN2C(=O)c3ccccc3C2=O)c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
N-(Hydroxymethyl)phtalimide (2.36 g, 13.3 mmol) was dissolved in 20 mL of triflic acid at 0° C. The mixture was stirred for 20 minutes and then 2-bromo-5-nitrotoluene (2.88 g, 1 eq) was added. This solution was allowed to warm to room temperature and was stirred for 18 h. The mixture was poured slowly into 300 mL of ice-cold water. The aqueous layer was extracted with DCM. The combined organic layers were washed with 100 mL of water, dried over Na2SO4, filtered and evaporated to yield expected compound as a white solid (4.71 g, 94% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]=[CH2:6])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCCNC
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCN(C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere, a solution of N-methyl-3-buten-1-amine (6.86 g, 80.6 mmol) in dichloromethane (100 mL) was cooled to 0° C., and triethylamine (17.93 g, 177.2 mmol) and 4-(N,N-dimethylamino)pyridine (207 mg) were added. A solution of benzoyl chloride (11.89 g, 84.6 mmol) in dichloromethane (60 mL) was added dropwise via addition funnel over 1 h at 0-5° C. The resulting turbid mixture was stirred 3 h at 0° C. The mixture was then washed in succession with 1 M HCl solution (3×75 mL), 5% NaHCO3 solution (3×100 mL), and water (100 mL). The organic phase was dried (Na2SO4), filtered, and concentrated on a rotary evaporator to a yellow oil (12.66 g). Vacuum distillation using a 6 in. Vigreaux column and a short path distillation apparatus afforded 8.58 g (56.3%) of a colorless oil, bp 100-103° C. at 0.1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)C.N1C=CC=CC=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1ccc(N)c(C(=O)O)c1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(NS(=O)(=O)c2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Example 1C (0.033 g, 0.200 mmol) in dichloromethane (1 mL) was treated with 1M chlorotrimethylsilane in dichloromethane (440 μL, 0.044 mmol) and pyridine (56.6 μL, 0.70 mmol), shaken for 4 hours at ambient temperature, treated with a solution of benzenesulfonyl chloride (0.042 g, 0.24 mmol) in dichloromethane (1 mL), and shaken for 16 hours at ambient temperature. The mixture was concentrated, the residue was acidified to pH 1.0 with 5% aqueous HCl, and the solution was extracted with dichloromethane. The extracts were washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by C18 reverse-phase HPLC with acetonitrile/water/0.5 mM ammonium acetate to provide the desired product. MS (ESI(+)) m/e 306 (M+H)+, 323 (M+NH4)+, 328 (M+Na)+; (ESI(−)) m/e 304 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.96 (br s, 1H), 7.78 (d, 2H), 7.73 (d, 1H), 7.64 (m, 1H), 7.55 (m, 2H), 7.42 (m, 2H), 2.54 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>O.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C@@H:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][C@H:10]2[OH:13])=[CH:17][CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: O
Solvent: CCOCC
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccc(Cl)cc1

Procedure:
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine, 18.0 g. of p-chlorophenol and 3 drops of water was heated at 120° C. under nitrogen gas for 20 hr. The mixture was cooled and dissolved in 100 ml. diethyl ether. The ethereal solution was extracted with 2×50 ml. 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulfate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallizations from cyclohexane gave 4.7 g. (29%) of analytically pure product which melted at 101°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:32]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C2CCOCC2)cc1NC(=O)c1ncc[nH]1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCOCC2)cc1NC(=S)c1ncc[nH]1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
0.41 g of 1H-Imidazole-2-carboxylic acid [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-amide (1.36 mmol) were taken up in toluene (25.0 ml) and treated with 1.65 g of Lawesson reagent (4.08 mmol). The reaction mixture was heated to reflux for 16 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with methylene chloride. The combined organic phases were dried on sodium carbonate, evaporated and the residue was dried under high vacuum to yield 0.179 g of 1H-imidazole-2-carbothioic acid [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-amide (41%) as a yellow solid; M.p.: 189–190° C.
Reaction SMILES: [CH2:1]([O:6][C:7](=O)[CH:8]([NH:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:9]([C:8]1[N:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[C:4]2[CH2:3][CH2:2][CH2:1][O:6][C:7]=12)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCCCOC(=O)C(Cc1ccccc1)NC(=O)C(=O)OCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(c(Cc3ccccc3)n1)OCCC2
Temperature: 15 °C

Procedure:
Pent-4-en-1-yl2-(2-ethoxy-2-oxoacetamido)-3-phenylpropanoate (0.80 g, 1 eq) and DCM (15 mL) were added to a vessel with stirring. Pyridine (0.23 g, 1.2 eq) was then added and the mixture was cooled to 15° C. Tf2O (1.0 g, 1.5 eq) was added to the mixture over 15 min and the mixture was warmed to ambient temperature. The solution was stirred for 3.5 h after which time the reaction was quenched by DCM and 20 wt % aqueous NaOAc to form a biphasic mixture. The layers were separated and the organic layer was extracted with 6N HCl (3×10 mL). The combined acid layers were washed with DCM and the pH was adjusted to ˜9 with solid K2CO3. The basic aqueous layer was extracted with DCM. The organic layer was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.74 (s, 1H), 7.10-7.35 (m, 5H), 4.43 (q, J=7.12 Hz, 2H), 4.22-4.29 (m, 2H), 4.21 (s, 2H), 2.78 (t, J=6.41 Hz, 2H), 1.93-2.06 (m, 2H), 1.41 (t, J=7.12 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 165.08, 152.25, 149.62, 138.86, 138.06, 129.62, 128.61, 127.80, 125.61, 125.23, 66.70, 60.97, 38.55, 23.93, 20.92, 14.10; HRMS (M+H) m/z, calcd for C18H20NO3, 298.1443; found 298.1450.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][F:78])([CH2:75][F:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[F:78][CH2:77][C:74]1([CH2:75][F:76])[O:73][B:72]([OH:79])[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH:68]=[CH:69][C:70]1=2
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2c(c1)B(O)OC2(CF)CF)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (116 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by prep-TLC to provide the title product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Cl:12][C:13]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C(Cl)=CC=CC=1C=O.CNC>>[Cl:12][C:13]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: C[N+](C)=Cc1cccc(Cl)c1Cl
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: O=Cc1cccc(Cl)c1Cl
Agent: [Cl-]
Product: CN(C)C(c1cccc(Cl)c1Cl)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (2,3-dichloro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2,3-dichloro-benzaldehyde and dimethylamine.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CCN(C(C)C)C(C)C.[Si]([N:40]=[C:41]=[O:42])(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:41]([NH2:40])=[O:42])[CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1cc(OC2CCNCC2)c2nc(-c3nnc4ccccn34)ccc2c1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)N1CCC(Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-yloxy)quinoline (prepared as described in Example 9, 46 mg, 0.133 mmol) in CH2Cl2 (5 mL) were added DIEA (116 μL, 0.67 mmol), DMAP (2 mg, 0.01 mmol), and TMS-isocyanate (104 μL, 0.67 mmol). The reaction mixture was stirred at ambient temperature for 16 hours then partitioned between saturated NaHCO3 and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography with gradient elution (CH2Cl2 to 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2) to afford desired product (33 mg, 64%) as a colorless glass. MS ESI (+) m/z 411.2 (M+Na+) detected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)c1
Yield: 57.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (7.7 g) described in Preparation Example 8 and oxazolidin-2-one (1.6 g), the title compound (4 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: COC(OC)N(C)C
Product: COc1ccc(C(=O)C=CN(C)C)cc1

Procedure:
A mixture of 25 g. of p-methoxyacetophenone and 25 ml. of dimethylformamide dimethylacetal is refluxed for 9 hours. Evaporation gives an oil which crystallized on the addition of hexane. Recrystallization from methylene chloride and hexane gives the desired compound, m.p. 92°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([CH3:17])[CH3:16])C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:13][C:14](=[O:19])[C:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:17])[CH3:16]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 110 °C

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (7 g, 45 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (10.4 g, 58 mmol), K2CO3 (18.6 g, 135 mmol) and KI (0.97 g, 5.8 mmol) in DMF (20 mL) was heated at 110° C. for 3 h. Then the mixture was filtered and the filtrate was concentrated. The residue was used into next step reaction without further purification (7 g).
Reaction SMILES: [NH2:1][C:2](=[O:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([OH:8])=[O:7].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2](=[O:11])[CH2:3][C:4]([CH3:9])([CH3:10])[CH2:5][C:6]([O:8][CH3:12])=[O:7]
Reactant: CC(C)(CC(N)=O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(C)CC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-3,3-dimethyl-5-oxopentanoic acid (10.9 g; 68.6 mmoles) was dissolved in DMF (50 mL). Potassium carbonate (14.2 g; 103 mmoles) and methyl iodide (8.5 mL; 137.2 mmoles) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, washing the filter cake with DMF. The DMF was removed under vacuum and the residue was suspended in ethyl acetate. The solids were removed by filtration and the ethyl acetate was removed under vacuum to give the product, methyl 5-amino-3,3-dimethyl-5-oxopentanoate, as a yellow oil (11.5 g; 97%). 1H NMR (400 MHz) DMSO-d6 δ 7.22 (1H, s, br), 6.73 (1H, s, br), 3.58 (3H, s), 2.39 (2H, s), 2.09 (2H, s), 1.02 (6H, s).
Reaction SMILES: CN(C)[C:3]1[CH:8]=CC=C[CH:4]=1.C([O:13][C:14]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]2[C:15]=1[CH:16]=[C:17]([CH3:26])[C:18](=[O:25])[NH:19]2)C=C>CCCCCC>[CH2:8]([C:23]1[C:14]([OH:13])=[C:15]2[C:20](=[C:21]([CH3:24])[CH:22]=1)[NH:19][C:18](=[O:25])[C:17]([CH3:26])=[CH:16]2)[CH:3]=[CH2:4]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C)c2[nH]c(=O)c(C)cc12
Solvent: CCCCCC
Product: C=CCc1cc(C)c2[nH]c(=O)c(C)cc2c1O
Temperature: 200 °C
Reaction time: 0.67 h
Yield: 89.4 %

Procedure:
N,N-dimethylaniline (10 ml) was added to 5-allyloxy-3,8-dimethylcarbostyril (4.32 g, 18.9 mmol), and stirred for 2 hours and 40 minutes in a bath of 200° C. in the atmosphere of argon. After cooling, hexane was added. Precipitated crystals were collected by filtration, and purified by silica gel chromatography (chloroform:methanol =10:1). The purified product was subjected to recrystallization (chloroform-n-hexane) to obtain 3.86 g of the title compound as colorless crystals (89.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([Br:15])[CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-n2cc(Br)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-methylphenyl)-2-cyanopyrrole (1.274 g) in tetrahydrofuran (25 ml) is added N-bromosuccinimide (1.776 g) in several portions at room temperature. After being stirred for 3 hours at ambient temperature, the mixture is concentrated in vacuo. The residue is treated with diethyl ether. The precipitates are removed by filtration and washed with a small amount of diethyl ether. The filtrates are concentrated in vacuo to give an oily residue, which is purified by silicagel column chromatography (elution by 40% methylene chloride in n-hexane) to yield 1-(4-methylphenyl)-4-bromo-2-cyanopyrrole as a solid.