Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][OH:29].[I-].[K+]>C(#N)C.O>[OH:29][CH2:28][CH2:27][N:26]([CH3:25])[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18]
Reactant: CNCCO
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(CCO)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.861 mmol) and potassium carbonate (1286 mg, 9.30 mmol) in acetonitrile (5 ml) was added 2-(methylamino)ethanol (0.447 ml, 5.58 mmol). The resulting mixture was stirred overnight at room temperature under argon. The reaction mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel using ethyl acetate as eluent, followed by 10% (2M NH3 in methanol) in dichloromethane. A large amount of starting material was recovered and resubjected to the reaction conditions, using potassium iodide, and heating overnight at 80° C. followed by workup and repurification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH2:16]([N:18]1[C:22]([CH3:23])=[C:21](I)[N:20]=[CH:19]1)[CH3:17]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:21]3[N:20]=[CH:19][N:18]([CH2:16][CH3:17])[C:22]=3[CH3:23])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CCn1cnc(I)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1cnc(-c2cc3nccc(Cl)c3s2)c1C
Temperature: 25 °C
Yield: 117.2 %

Procedure:
To a solution of 2 (1.14 g, 6.76 mmol) in THF (60 ml) was added, at −78° C., n-BuLi (3.38 ml, 2.5 M soln in hexanes) and the reaction mixture was stirred at the same temperature for 10 min. A solution of ZnCl2 (16.9 ml, 2.5 ml, 0.5M in THF) was added and the reaction mixture was warmed to room temperature. Then a solution of 1-ethyl-4-iodo-5-methyl-1H-imidazole (800 mg, 3.38 mmol) (Pyne, S. G and Cliff, M. D. Synthesis 1994, 681) and Pd(PPh3)4 (390 mg, 0.34 mmol) in THF (15 ml) were added and the reaction mixture was refluxed for 3 hrs, cooled to room temperature, quenched with conc. ammonium hydroxide solution and made neutral with concentrated aqueous HCl. The neutral solution was extracted with EtOAc, the extract was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated and the residue was purified by column chromatography (eluent MeOH:EtOAc, 1:9) to afford the title compound 87 (1.1 g, 100% yield) as a brown oil. MS (m/z) 278.0/280.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:22]1[C:27]([O:28][CH3:29])=[N:26][C:25](Cl)=[CH:24][N:23]=1)COCCO[Si](C)(C)C)(=[O:11])=[O:10].[C:31]([NH2:35])(=[O:34])[CH2:32][OH:33].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:22]1[N:23]=[CH:24][C:25]([NH:35][C:31](=[O:34])[CH2:32][OH:33])=[N:26][C:27]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: COc1nc(Cl)cnc1N(COCCO[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: NC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(NC(=O)CO)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25 g), glycolamide (0.066 g) and sodium hydride (0.035 g of a 60% dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.075 g.
Reaction SMILES: [BH4-].[Na+].Cl.S([O-])(O)(=O)=O.[K+].[CH2:10]([O:17][N:18]1[C@H:21]([C:22](OC)=[O:23])[C@H:20]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]1=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.O>[CH2:10]([O:17][N:18]1[C@H:21]([CH2:22][OH:23])[C@H:20]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:19]1=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1CO
Yield: 11.4 %

Procedure:
In 20 ml of tetrahydrofuran is dissolved 1.9 g [5.4 mmole) of (3S,4S)-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-methoxycarbonyl -2-azetidinone obtained in the same manner as the method described in The Journll of Organic Chemistry, 48(1983), 3556-3559, and a solution of 410 mg (10.8 mmole) of sodium borohydride in 4 ml of water is added dropwise to the solution over the 10-minute period. After the addition is completed, the reaction solution is stirred under ice-cooling for 20 minutes, and 3 ml of 3N hydrochloric acid is added to stop the reaction. 10 ml of 0.6M aqueous potassium hydrogen sulfate solution is added, followed by extraction with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution successively, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (silica gel, 100 g;h-hexane-ethyl acetate, 2:1, then 1:1). The fractions containing the objective compound are collected the solvent is distilled off under reduced pressure, and after ether and n-hexane are added to the residue, the resulting crystals are recovered by filtration to give 200 mg (11.4%) of (3S,4S)-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-hydroxymethyl-2-azetidinone.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:13][CH2:12]1)=[O:9].[OH-].[Li+].O1CCCC1.Cl>O>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:16]1)=[O:9]
Reactant: COC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 100 %

Procedure:
A stirred solution of the product of Step (a) (902 mg, 2.37 mmol) and lithium hydroxide (171 mg, 7.11 mmol) in a 50% mixture of tetrahydrofuran (12 mL) and water (12 mL) was heated at 30° C. overnight and then acidified with concentrated hydrochloric acid. The resulting mixture was lyophilized to give the title compound (˜100% yield, containing some lithium chloride).
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:32]>CO.ClCCl.O1CCOCC1>[ClH:32].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:30][CH:31]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of tert-butyl 4-(4-((4-(1H-tetrazol-1-yl)phenoxy)methyl)thiazol-2-yl)piperidine-1-carboxylate (0.60 g) in methanol/dichloromethane (1.0 mL/1.5 mL) was added 4N HCl in dioxane (1.7 mL) at 0° C., and then stirred at room temperature for 7 hours. After removal of solvents in vacuo, a crude desired compound HCl salt was obtained as an off-white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:13][OH:14])[NH2:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(C1C=CC(S(N)(=O)=O)=CC=1)#N.[CH3:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][C:35]=1[NH:43][S:44]([CH3:47])(=[O:46])=[O:45]>>[CH3:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:34]1[CH:42]=[CH:41][C:37]([C:38]2[O:14][N:13]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:12]=2)=[CH:36][C:35]=1[NH:43][S:44]([CH3:47])(=[O:45])=[O:46]
Reactant: NC(=NO)c1ccc(S(N)(=O)=O)cc1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1NS(C)(=O)=O
Agent: N#Cc1ccc(S(N)(=O)=O)cc1
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)cc1NS(C)(=O)=O

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from 4-(aminosulfonyl)-N′-hydroxybenzenecarboximidamide, prepared as described in WO 2006/013104 A1 from 4-cyanobenzene-1-sulfonamide (ABCR; CD10716), (322.85 mg; 1.50 mmol) and Intermediate 25 (562.30 mg; 1.80 mmol). The reaction mixture was evaporated under reduce pressure and was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a pale yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.68 (br s, 1H), 8.31-8.27 (m, 2H), 8.22 (d, J=2.0 Hz, 1H), 8.06-8.03 (m, 2H), 7.94 (dd, J=8.2, 1.8 Hz, 1H), 7.57 (br s, 2H), 7.55 (s, 1H), 3.23 (s, 3H), 3.20-3.13 (m, 1H), 2.94-2.87 (m, 1H), 2.66-2.57 (m, 1H), 1.84-1.66 (m, 4H), 1.50-1.44 (m, 2H), 0.82 (d, J=6.1 Hz, 3H). LC/MS (Method B): 490.4 (M−H)−, 492.4 (M+H)+. HPLC (Method A) Rt 4.34 min (Purity: 97.9%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(F)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.3 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(4-fluorophenyl)acetic acid (I49) (725 mg, 2.69 mmol) in THF (20 ml), were added N,N′-methanediylidenedicyclohexanamine (667 mg, 3.23 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (437 mg, 3.23 mmol), and (R)-quinuclidin-3-ol (411 mg, 3.23 mmol). The reaction was stirred at RT for 15 hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 93/7) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-fluorophenyl)acetate (410 mg; 40% yield).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C[O-].[Na+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:22](OC)(=[O:26])[C:23]([CH3:25])=[CH2:24].CC(C1C(O)=C(C(C)(C)C)C=C(CCC(OCC(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)=O)C=1)(C)C>>[OH:2][CH2:1][CH2:3][NH:4][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: NCCO
Reactant: C=C(C)C(=O)OC
Agent: CC(C)(C)c1cc(CCC(=O)OCC(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: C[O-]
Agent: [Na+]
Product: C=C(C)C(=O)NCCO
Reaction time: 23 h

Procedure:
A round-bottom flask with a magnetic stirrer is charged with 61.1 g of ethanolamine, 5.4 g of sodium methoxide and 0.4 g of phenothiazine. The contents are stirred. A mixture of 100.1 g of methyl methacrylate and 0.6 g of Irganox 1010* are added with stirring from a dropping funnel over a period of 90 minutes. The temperature is maintained below 40° C. during the addition. The mixture is left to stand at room temperature for about 23 hours. One gram of Irganox 1010* is added and the mixture is stripped on a rotary evaporator at about 60° C. and 8 mm Hg pressure. Product (125 g) is recovered and analyzed by gas chromatography to be 90 percent HEMA. Proton nuclear magnetic resonance spectra show that about 17 mole percent of the product has addition across the double bond and 83 percent is HEMA.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-n2cnc3cnccc32)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2cnc3cnccc32)cc1

Procedure:
In 20 mL of methanol, 33 mg (0.1237 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine prepared in Step A was dissolved and the solution was stirred on 5 mg of 10% palladium carbon in a hydrogen atmosphere at room temperature at normal pressures for one hour. After removal of the palladium carbon by filtration, the solvent was distilled under reduced pressure, and the obtained product was vacuum dried to obtain 4-(imidazo[4,5-c]-pyridin-1-yl)aniline as a white solid. This product was used in process C without further purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CO>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:3]([C:5]2[N:6]=[C:7]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:8]3[C:9](=[O:12])[C:10]=2[OH:11])=[O:4])=[CH:21][CH:20]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc2ccc(Br)cn2c(=O)c1O
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2ccc(Br)cn2c(=O)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.4 %

Procedure:
7-Bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-2-carboxylic acid methyl ester (20 mg, 0.07 mmol) and p-fluorobenzylamine (19 uL, 0.17 mmol) in dry methanol (4 mL) was heated to reflux with stirring. Reaction progress was monitored by HPLC. After 6 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was triturated with diethyl ether (2 mL) and the precipitate collected by filtration and washed with diethyl ether (10 mL) and dried on the pump to afford 7-bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide (24 mg, 92%) as a yellow brown solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: Nc1ccccc1
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(Nc4ccccc4)cc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (27 mg, 0.057 mmol), aniline (10.4 μL, 0.114 mmol), palladium acetate (1.3 mg, 0.0057 mmol), racemic BINAP (10.6 mg, 0.017 mmol) and toluene (2 mL) was stirred under nitrogen at room temperature for 30 min. Cesium carbonate (37 mg, 0.11 mmol) was added and the mixture was heated at 110° C. under nitrogen for 5 h. The mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-phenylaminophenyl)benzoxazole-4-carboxamide (21 mg, 84%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.66 (d, J=7.5 Hz, 1H), 8.15 (dd, J=8.0, 1.0 Hz, 1H), 8.09 (dd, J=7.5, 2.0 Hz, 2H), 7.66 (dd, J=8.0, 1.0 Hz, 1H), 7.41-7.36 (m, 3H), 7.22 (d, J=7.5 Hz, 2H), 7.12-7.10 (m, 3H), 6.15 (s, 1H), 4.32-4.28 (m, 1H), 3.52 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.10-2.81 (m, 5H), 2.17-2.06 (m, 2H), 1.78-1.64 (m, 3H); MS (ESI+) m/z 439 (M+H); HPLC>99% (AUC), tR=14.32 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19]>O1CCCC1.CCCCCC>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([Sn:18]([CH3:20])([CH3:19])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C[Sn](C)(C)Cl
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To 20.0 g (88.9 mmol) of meta-bromobenzotrifluoride stirring in 200 ml of tetrahydrofuran at 78° C., 61.2 ml of 1.6M n-butyl lithium (97.9 mmol) in hexane was added dropwise. After stirring the reaction 10 minutes at -78° C., 19.5 g (97.8 mmol) of trimethyltin chloride dissolved in 30 ml of tetrahydrofuran was added dropwise and the mixture stirred for 10 minutes at -78° C. before allowing to warm to room temperature. The reaction mixture was quenched with excess saturated sodium bicarbonate and extracted with ethyl acetate (300 ml). The extract was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo to give a crude yield of 20.2 g of the above product, isolated as a oily semi-solid. This aryl stannane was used directly as a crude material in the coupling reactions with heterocycles of Formula II.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][CH:9]([CH3:27])[CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)=[O:14].[F:28][C:29]([F:37])([F:36])[CH2:30][CH:31]([CH3:35])[C:32](O)=[O:33].N12CCCN=C1CCCCC2.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:8][CH:9]([CH3:27])[CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:32](=[O:33])[CH:31]([CH3:35])[CH2:30][C:29]([F:37])([F:36])[F:28])[CH2:23][CH2:22]2)=[CH:19][CH:20]=1)=[O:14]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: CC(CC(F)(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)C(C)CC(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
A mixture of TFA salt of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (100 mg, 0.25 mmol), 4,4,4-trifluoro-2-methylbutyric acid (47.8 mg, 0.31 mmol), 1,8-diazabicylco[5.4.0]undec-7-ene (77.8 mg, 0.51 mmol) and 1-hydroxy-benozotriazole hydrate (41.4 mg, 0.31 mmol) in DMF (2 mL) was stirred at ambient temperature for 15 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (47.6 mg, 0.31 mmol) was added to this solution. The reaction mixture was stirred at ambient temperature overnight and then diluted with ethyl acetate (50 mL) and washed with aqueous saturated NaHCO3 (2×20 mL) and finally with brine (2×20 mL). The organic extract was dried over anhydrous Na2SO4, concentrated, and then purified by column chromatography eluted with hexanesethyl acetate (1:2). The product was obtained as a white flaky solid (80 mg, 75% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.85, 7.01, 3.60-4.00, 3.50, 3.15, 2.80, 2.21, 1.70, 1.50, 1.25, 0.95. MS (ES+) m/z 41 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:41]3[CH2:40][CH2:39][N:38]([S:35]([C:30]4[CH:29]=[CH:28][C:27]5[C:32](=[CH:33][CH:34]=[C:25]([Cl:24])[CH:26]=5)[CH:31]=4)(=[O:37])=[O:36])[CH2:43][CH2:42]3)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-(1-tert-butoxycarbonylpiperidin-4-yl)benzoic acid and l-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14])CC1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][NH:2][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14]
Reactant: CN(CCNS(=O)(=O)c1cccc2cnccc12)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNCCNS(=O)(=O)c1cccc2cnccc12
Yield: 63.6 %

Procedure:
In 100 ml of ethanol was dissolved 2.0 g of N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (65) as obtained in Example 16, and to the solution was added 0.2 g of 10% palladium-carbon. Then the solution was vigorously stirred at a temperature of 20° C. to 25° C. in a hydrogen stream of 2.0 to 2.5 atm. for 5 hours. After the palladium-carbon was separated from the reaction solution by filtration, the reaction solution was concentrated to dryness to give 0.95 g of N-(2-methylaminoethyl)-5-isoquinolinesulfonamide, i.e., Compound (14) in a yield of 64%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[C:11]12([CH:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:11]12([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:6]3[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[C:3]=3[C:4]#[N:5])[CH2:20][CH:15]3[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]3)[CH2:18]1)[CH2:12]2
Reactant: N#Cc1c(F)cccc1Br
Reactant: C1CNC(C23CC4CC(CC(C4)C2)C3)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Br)cccc1N1CCCC1C12CC3CC(CC(C3)C1)C2
Temperature: 130 °C

Procedure:
2-Bromo-6-fluorobenzonitrile (900 mg), 2-adamantan-1-yl-pyrrolidine (924 mg), and potassium carbonate (1244 mg) were added to dimethyl sulfoxide and the mixture was heated at 130° C. for 16 hours. The solution was cooled, diluted with ethyl acetate, washed twice with 1M HCl, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the crude material was concentrated under vacuum and purified on silica gel using 5% ethyl acetate (hexanes) to provide the title compound.