Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C@H:9]2[CH2:11][C@@H:10]2[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[N:16][CH:17]=2)[CH:2]=1.[H-].[Na+].[C:21]([O:25][C:26]([N:28]1[CH2:31][CH2:30][C@H:29]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22].[NH4+].[Cl-]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:21]([O:25][C:26]([N:28]1[CH2:31][CH2:30][C@H:29]1[CH2:32][O:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C@H:10]2[CH2:11][C@@H:9]2[CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:13]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1cncc([C@H]2C[C@@H]2COc2cccnc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2COc2cccnc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 5-[(1S,2S)-2-[(3-pyridyloxy)methyl]cyclopropyl]-3-pyridinol (92 mg, 0.38 mmol) in anhydrous DMF (5 mL) in a 25 mL round-bottom flask was added NaH (60% dispersion in mineral oil, 23 mg, 0.57 mmol, 1.5 equiv.). The flask was equipped with a condenser, and the atmosphere was exchanged with Ar (3 times). The suspension was heated to 100° C. (oil bath) and stirred for 1 h. After cooling to room temperature, 1-(tert-butoxycarbonyl)-2(S)-[(4-toluenesulfonyloxy)methyl]azetidine (195 mg, 0.57 mmol, 1.5 equiv.) in dry DMF (2 mL) and tetra-n-butylammonium iodide (14 mg, 0.04 mmol, 0.1 equiv.) were added. The resulting mixture was again protected with Ar and stirred at 100° C. overnight. After the reaction mixture was cooled to room temperature, saturated NH4Cl solution (15 mL) was added to quench excessive NaH. The product was extracted into EtOAc (3×15 mL). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated. The residue was purified by CC on SiO2 (10×1.0 cm, EtOAc) to give the crude product, which was further purified by preparative HPLC in two portions (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 22.0-23.2 min) to give a yellowish oil (123 mg, 79%). 1H NMR (CDCl3, 500 MHz) δ 8.35 (s, 1H), 8.26 (d, 1H, J=3.8 Hz), 8.18 (s, 1H), 8.10 (s, 1H), 7.29-7.22 (m, 2H), 6.95 (s, 1H), 4.53 (d, 1H, J=4.6 Hz), 4.33 (s, br, 1H), 4.15 (dd, 1H, J=10.0, 2.4 Hz), 4.10 (dd, 1H, J=9.9, 6.6 Hz), 4.03 (dd, 1H, J=9.8, 6.8 Hz), 3.92 (t, 2H, J=7.6 Hz), 2.39-2.28 (m, 2H), 2.02-1.97 (m, 1H), 1.67 (dd, 1H, J=12.6, 5.8 Hz), 1.44 (s, 9H), 1.19-1.13 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.C([O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][N:12]=1)=O)C>C(O)C>[CH2:1]([NH:3][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][N:12]=1)=[O:8])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CCO
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of ethylamine in methanol solution (2.0M; 40 mL; 80 mmol) was added to a stirred suspension of 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethyl ester (4.40 g; 9.51 mmol) in absolute ethanol (50 ml). The reaction mixture was heated to 80° C. (oil-bath temperature) for five hours. The reaction mixture was allowed to cool to ambient temperature and left to stand overnight. A colourless solid product formed and the reaction mixture was further cooled in an ice-water bath, filtered and washed with cold ethanol (2×20 ml). The colourless product was dried in vacuo to afford 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethylamide 3.42 g (78%) LCMS: [M+H]+ 465, 463 (37Cl; 35Cl). 1H NMR (400 MHz, CDCl3) δ 1.25 (t, 3H), 3.48 (m, 2H), 5.10 (s, 2H), 5.2 (s, 2H), 6.59 (s, 1H), 6.83 (bit, 1H), 7.08 (s, 1H), 7.30-7.41 (m, 10H), 7.97 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][CH:37]([C@@H:39]1[N:44]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:43][CH2:42][N:41]([C:51]2[CH:57]=[CH:56][C:54]([NH2:55])=[C:53]([O:58][CH3:59])[CH:52]=2)[CH2:40]1)[CH3:38].Cl.N>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:55][C:54]3[CH:56]=[CH:57][C:51]([N:41]4[CH2:42][CH2:43][N:44]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[C@@H:39]([CH:37]([CH3:38])[CH3:36])[CH2:40]4)=[CH:52][C:53]=3[O:58][CH3:59])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1N
Agent: Cl
Agent: N
Solvent: CO
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
To 5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.241 g, 0.490 mmol) and 4-{(3S)-3-(1-methylethyl)-4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-2-(methyloxy)aniline (0.174 g, 0.489 mmol) were dissolved in 5 mL of trifluoroethanol with stirring in a pressure vessel. Hydrogen chloride (0.49 mL, 4N in dioxane, 2.0 mmol) was added, and the vessel was sealed. The reaction was heated to 80° C. for 3 days and subsequently cooled to rt. The reaction was poured into 10 mL of 7N NH3 in MeOH and concentrated onto silica gel. The compound was purified by flash chromatography, and the fractions containing the desired compound were concentrated in vacuo. The material was triturated with diethyl ether, filtered, and washed with diethyl ether. The solid was collected to afford the title compound (0.191 g, 0.236 mmol, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.33 (br. s., 1H), 8.42 (s, 1H), 8.17 (d, J=5.1 Hz, 1H), 8.03-8.09 (m, 1H), 7.70-7.78 (m, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.29-7.43 (m, 3H), 7.25 (d, J=8.8 Hz, 1H), 7.10-7.19 (m, 2H), 6.87-6.95 (m, 1H), 6.61 (s, 1H), 6.43-6.52 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.43-3.51 (m, 1H), 3.30-3.41 (m, 2H), 3.27 (s, 3H), 2.99 (s, 3H), 2.91-2.98 (m, 1H), 2.68-2.85 (m, 2H), 2.51-2.60 (m, 1H), 2.22-2.30 (m, 1H), 2.05-2.16 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.87 (d, J=7.0 Hz, 3H). MS (M+H, ES+) 811.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)(O)[O-].[Na+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 50.8 %

Procedure:
1-(4-Nitrophenyl)piperazine (4.14 g), 4-nitrophenethyl bromide (4.6 g) and sodium bicarbonate (3.4 g) in acetonitrile (75 ml) were stirred under reflux for 1 day, and then evaporated to dryness. The residue was then triturated with water (300 ml), filtered, washed with water (300 ml), and the resulting solid was crystallized from ethyl acetate, yielding the title compound, (3.62 g), m.p. 143°-5°.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[Na+].[C:9]1([S:15]([O-:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH:7]1([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=S([O-])c1ccccc1
Reactant: BrC1=CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)C1C=CCCC1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Bromocyclohexene (35.9 ml, 310.5 mmol) is dissolved in 1 l of DMF, cooled down to 0° C. and after addition of benzenesulfinic acid sodium salt (86.6 g, 527.8 mmol) the mixture is stirred for 17 h at room temperature. Then the mixture is evaporated under high vacuum. The residue is diluted with ether, washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (1:9), 1 kg silicagel).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[CH3:22][C:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.O>O1CCCC1>[CH3:22][C:23]([NH:26][C:27]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:20])[F:21])=[CH:19][CH:18]=2)[CH2:17]1)=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 18 h
Yield: 79 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml of tetrahydrofuran was treated with 2 g (0.022 mole) of 1,1-dimethylethyl isocyanate and after 0.5 hr 5 ml of triethylamine was added. The reaction slurry quickly turned to a pale yellow solution which was stirred for 18 hr, then treated with 10 ml of water. After 20 min, the tetrahydrofuran portion was separated, dried over magnesium sulfate and concentrated on a rotary evaporator. The solid residue was recrystallized from isopropyl ether to yield 5 g (79.0%) of fine white crystals, m.p. 145°-146° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[NH:27][C:26](=[O:28])[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1.CO.[C:32]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:32][N:27]1[C:26](=[O:28])[O:25][N:24]=[C:23]1[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:14]2[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]3[N:29]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[C:15]2=[O:16])[CH:18]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)[nH]3)c1)C2=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)n3C)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
(S)-3-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (150 mg, 0.37 mmol) obtained in Step 1 was suspended in THF (2.0 mL), and the mixture was stirred at room temperature for 2 hours after adding methanol (0.022 mL, 0.55 mmol), triphenylphosphine (144 mg, 0.55 mmol), and diethyl azodicarboxylate (40% toluene solution, 0.25 mL, 0.55 mmol). The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-4-methyl-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (127 mg, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][CH3:26])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[C:43]([SiH:47]([CH3:49])[CH3:48])([CH3:46])([CH3:45])[CH3:44].O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][CH3:26])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:17][CH2:16]1)[O:14][Si:47]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:49])[CH3:48])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[SiH](C)C(C)(C)C
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(O)C1(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}-1-hydroxybutyl)cyclopropanecarboxylate (914.8 mg) and 2,6-lutidine (0.632 mL) in tetrahydrofuran (20 mL) was added under ice-cooling tert-butyldimethylsilane trifluoromethanesulfonate (0.934 mL) and, after warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/1) to give the title compound as a colorless oil (yield: 1.18 g, 98%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]1)=[O:11].Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]2)=[O:11])=[N:30][CH:31]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 477 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[OH:1][CH2:2][C@H:3]([N:8]([CH3:19])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C

Procedure:
A solution of 2E (2 g, 7.35 mmol) in DMF (15 mL) was added with an .K2CO3 (1.5 mol eq, 1.52 g) and, after few minutes, iodomethane (1.2 mol eq, 0.81 ml) was added and the mixture was heated at 50° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (120 mL) and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 3E as a pale yellow oil (2.1 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 2.38 (s, 3H), 2.87 (s, 3H), 3.64 (s, 3H), 3.70 (t, 2H), 4.58 (t, 1H), 5.11 (t, 1H), 7.40 (d, 2H, J=8), 7.61 (d, 2H, J=8).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:8]([CH2:26][C:27]2[O:28][CH:29]=[C:30]([CH3:32])[N:31]=2)[CH:7]=1)=O>[NH4+].CO>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:8]([CH2:26][C:27]2[O:28][CH:29]=[C:30]([CH3:32])[N:31]=2)[CH:7]=1
Reactant: Cc1coc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)n1
Agent: [NH4+]
Solvent: CO
Product: Cc1coc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)n1
Yield: 36.9 %

Procedure:
A solution of 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-((4-methyloxazol-2-yl)methyl)phenyl)acetamide (200 mg, 0.40 mmol) in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 4 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid (59 mg, yield 37%). 4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-((4-methyloxazol-2-yl)methyl)benzenesulfonamide MS calcd for (C18H18BN3O5S): 399.2. MS found (ESI negative): (M−H)−=398.1. 1H NMR (DMSO-d6) δ (ppm): 9.93 (s, 1H), 9.10 (s, 1H), 7.62 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.37 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 6.12 (s, 1H), 4.80 (s, 2H), 4.25 (s, 2H), 1.98 (s, 3H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]([I:24])[N:18]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C.O1CCCC1>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[Cl:16][C:17]1[C:22]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=[C:19]([I:24])[N:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(I)nc1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(I)nc3Cl)c2cc1OC
Yield: 48.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.23 g, 10.0 mmol), 2-chloro-6-iodopyridin-3-ol (2.55 g, 22.0 mmol) and diisopropylethylamine (1.29 g, 10.0 mmol) were heated and stirred in dimethylformamide (5 ml) at 130° C. for 3 hours. The reaction solution was distributed between an ethyl acetate-tetrahydrofuran mixed solvent and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (2.16 g, 4.88 mmol, 49%) as colorless crystals.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][C:12](=[O:28])[C:11]=1[C:29]1[NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]=1)[CH2:2]2.[OH-].[Na+]>Br.CC(O)=O>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][C:12](=[O:28])[C:11]=1[C:29]1[NH:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=1)[CH2:2]2
Reactant: COc1ccc(-c2ccc3[nH]c(=O)c(-c4nc5ccccc5[nH]4)c(N[C@@H]4CN5CCC4CC5)c3c2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(-c3ccc(O)cc3)cc2c(N[C@@H]2CN3CCC2CC3)c1-c1nc2ccccc2[nH]1
Temperature: 60 °C

Procedure:
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-6-(4-methoxyphenyl)quinolin-2(1H)-one (Example 70) was dissolved in 30% HBr/AcOH and heated at 60° C. until the reaction was complete. The resulting mixture was allowed to cool, and it was then neutralized with 2 M NaOH. The resulting mixture was extracted with EtOAc, and the organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by reverse phase HPLC to give the desired product. MS m/z 478.6 (M+H).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li+:13].[Cl-:14].[CH:15]12[O:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2>C(O)(C)C>[OH:21][CH:16]1[CH:17]([N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH:17]3[CH:16]([OH:21])[CH2:15][CH2:20][CH2:19][CH2:18]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:18][CH2:19][CH2:20][CH2:15]1.[Li+:13].[Cl-:14]
Reactant: C1CCC2OC2C1
Reactant: C1CNCCNCCNCCN1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)O
Product: OC1CCCCC1N1CCNCCN(C2CCCCC2O)CCNCC1
Temperature: 0 °C

Procedure:
10 g (58.08 mmol) of 1,4,7,10-tetraazacyclododecane, 4.85 g (116.16 mmol) of LiCl and 56.5 g (580.0 mmol) of cyclohexene oxide (7-oxabicyclo[4.1.0]heptane) are suspended in 20 ml of isopropanol and refluxed for 20 hours. Then, the reaction mixture is mixed with 30 ml of isopropanol and slowly cooled to 0° C. The crystals that are obtained are suctioned off, washed with 30 ml of methyl-tert-butyl ether and dried in a vacuum. 19.5 g (82% of theory) of 1,7-bis(6-hydroxycyclohexyl)-1,4,7,10-tetraazacyclododecane LiCl complex is obtained as white crystals. Melting point 170-178° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][OH:17])[C@H:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@H:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)OCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 217, 13.7 g, 36.67 mmol) in dichloromethane (20 mL) at 0° C. was added pyridine (5.93 mL, 73.35 mmol) followed by dropwise addition of ethyl chloroformate (3.87 mL, 40.34 mmol). The reaction was allowed to warm to room temperature over 3 hours. Diluted with dichloromethane and washed with saturated NH4Cl. Extracted with dichloromethane three times, combined and dried over Na2SO4. Removed solvent to give title compound as a yellow oil (14.5 g, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])(C)(C)C.[CH3:19][C:20]12[CH:29]([CH:30]=[O:31])[CH2:28][CH2:27][CH:26]=[C:25]1[CH2:24][C:23]1([S:35][CH2:34][CH2:33][S:32]1)[CH2:22][CH2:21]2>CCOCC>[CH3:19][C:20]12[CH:29]([CH:30]([C:2]3[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=3)[OH:31])[CH2:28][CH2:27][CH:26]=[C:25]1[CH2:24][C:23]1([S:32][CH2:33][CH2:34][S:35]1)[CH2:22][CH2:21]2
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: CC12CCC3(CC1=CCCC2C=O)SCCS3
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cc(C(O)C2CCC=C3CC4(CCC32C)SCCS4)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution 5-bromo-1,2,3-trimethoxy-benzene (276 mg, 1.12 mmol) dissolved in 6 mL anhydrous ether is cooled to −78° C. and tert-butyllithium (1.7 M in pentane, 1.32 mL, 2.24 mmol) is added. The mixture was stirred at −78° C. for 15 minutes, then at room temperature for 3 hours. Aldehyde 241 (100 mg, 0.373 mmol) was added dropwise over 10 minutes in 10 mL ether at −30° C. The mixture was stirred for 0.5 hours and the reaction quenched with dropwise addition of saturated aqueous NH4+Cl−. The phases were separated and the aqueous phase was extracted with ether (4×10 mL). The pooled organic extracts were washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography over silica gel (25% ethyl acetate-hexanes) to yield 243(119 mg, 73%).