Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)=[CH:2]1.[Br:19][C:20]1C=C(CC=O)C=C[CH:25]=1>C(Cl)Cl.CO>[Br:19][C:20]1[CH:2]=[C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)[CH:4]=[CH:5][CH:25]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: O=CCc1cccc(Br)c1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(Nc2ncc(-c3cccc(Br)c3)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (3-bromophenyl)-acetaldehyde. The title compound: ES-MS: 348.9 [M+2]+; single peak at tR=3.92 min (System 2); Rf=0.47 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [CH3:1][C:2]1[C:6]([Cr:8][CH:9]=[C:10](C)[CH:11]=[CH:12][CH3:13])([CH3:7])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[CH3:17].C1([Na])C=CC=C1.C1([Li])C=CC=C1>>[CH3:15][C:5]1[C:6]([Cr:8][CH:9]2[CH:10]=[CH:11][CH:12]=[CH:13]2)([CH3:7])[C:2]([CH3:1])=[C:3]([CH3:17])[C:4]=1[CH3:16]
Reactant: CC=CC(C)=C[Cr]C1(C)C(C)=C(C)C(C)=C1C
Agent: [Li]C1C=CC=C1
Agent: [Na]C1C=CC=C1
Product: CC1=C(C)C(C)([Cr]C2C=CC=C2)C(C)=C1C

Procedure:
The preparation was substantially the same as that described in Example 1 for [Cr(C5 (CH3)5)(C6H9)] except that cyclopentadienyl sodium was used in place of 2-methyl pentadienyl lithium. (Cyclopentadienyl lithium could also have been used). The crystalline product isolated from this preparation was purified by sublimation. Excess [Cr(C5H5)2 ] was removed by sublimation at 40° C. and about 1 Pa. [Cr(C5 (CH3)5)(C5H5)] was then sublimed at 70° C. and about 1 Pa.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[Mg]Br.CO>C1COCC1.C(Cl)Cl>[CH:40]1[C:41]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:39]=1[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: Br[Mg]c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4ccccc4c3)sc2c1
Yield: 75.1 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]methanone (1.58 g, 3.6 mmol) in THF (12 mL) was reacted with a 0.65M THF solution of 2-naphthylmagnesium bromide (15 mL, 9.8 mmol) to provide, after chromatography (silica gel, 5% methanol in methylene chloride) 1.41 g (75%) of the title compound as a green/yellow foam: 1H NMR (300 MHz, CDCl3) δ1.43 (m, 2H), 1.59 (m, 4H), 2.45 (m, 4H), 2.70 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 4.02 (t, J=6.0 Hz, 2H), 6.72 (d, J=8.7 Hz, 2H), 7.01 (dd, J=2.1 Hz, 8.8 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.44-7.47 (m, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.60 (d, J=9.3 Hz, 1H), 7.67-7.79 (m, 4H), 7.82 (d, J=8.7 Hz, 2H), 7.94 (d, J=1.6 Hz, 1H); MS (FD) m/e 521 (M+); Anal. calc'd. for C33H31NO3S: C, 75.98; H, 5.99; N, 2.68. Found: C, 76.27; H, 6.10; N, 2.74.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:17]1[CH2:22][CH2:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:19]4[CH2:20][CH2:21][CH:22]([CH:17]=[CH:18]4)[CH:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]3=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1=CCCC=C1
Reactant: CN1C(=O)C=C(c2ccc(F)c(F)c2)C1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C2C3C=CC(CC3)C2(c2ccc(F)c(F)c2)C1=O
Temperature: 25 °C

Procedure:
A 5.0 g amount of 3-(3,4-difluorophenyl)-1-methyl-1H-pyrrole-2,5-dione was dissolved in 25 ml of chloroform with warming. The solution was cooled to room temperature and 2.0 g of cyclohexadiene was added. After prolonged standing another 11/2 ml of diene was added with a small amount of butylated hydroxytoluene. The solution was heated at reflux for 24 hours. The reaction mixture was subjected to high pressure liquid chromatography using a silica gel column and 20% ethyl acetate in hexane as eluent giving 4.9 g of 3a-(3,4-difluorophenyl)-3a,4,7,7a-tetrahydro-2-methyl-4,7-ethano-1H-isoindole-1,3(2H)-dione as a white solid, mp 125°-127° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+].[NH4+].[Cl-].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26]5[N:36]=[N:37][NH:38][N:27]=5)[CH:23]=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C#N)ccn4c3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5nn[nH]n5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 150 °C
Yield: 55 %

Procedure:
A mixture of {1-[4-(7-cyano-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.43 mmol), sodium azide (336 mg, 5.16 mmol, 12 equiv), NH4Cl (276 mg, 5.16 mmol, 12 equiv) and DMF (4.3 mL) was heated under an argon atmosphere for 3.5 h at 150° C. in a microwave apparatus. The reaction mixture was added to a saturated aqueous NaHCO3 solution (10 mL). The resulting mixture was extracted with a 4:1 CH2Cl2/isopropanol mixture (25 mL). The combined organic phases were dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 25 g SNAP cartridge: 80% hexane/20% EtOAc for 3.0 min., gradient to 70% hexane/30% EtOAc over 13.7 min.) to give (1-{4-[3-Phenyl-7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (0.12 g, 52%):
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].[CH2:6]([O:8][C:9]([C:11]1[C:12]([Cl:21])=[C:13]2[S:20][CH:19]=[CH:18][C:14]2=[N:15][C:16]=1Cl)=[O:10])[CH3:7]>C(O)(=O)C>[CH2:6]([O:8][C:9]([C:11]1[C:16](=[O:3])[NH:15][C:14]2[CH:18]=[CH:19][S:20][C:13]=2[C:12]=1[Cl:21])=[O:10])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1c(Cl)nc2ccsc2c1Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O
Temperature: 140 °C
Yield: 55.8 %

Procedure:
Ammonium acetate (161 mg, 2.1 mmol) was added to a stirred solution of 5,7-dichloro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (3) (530 mg, 1.9 mmol) in glacial acetic acid at room temperature. The solution was heated at 140° C. for 48 h. The hot solution was poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was recrystallized by CH2Cl2 to yield 273 mg (60%) of 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as white solids. MP 206° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 7.10 (d, J=5.2 Hz, 1H), 8.13 (d, J=5.2 Hz, 1H) ppm; MS m/z=240 amu (M++1).
Reaction SMILES: C([N:9]1[C:56](=[O:57])[CH:55]=[CH:54][N:11]([C@@H:12]2[O:53][C@H:27]([CH2:28][O:29][C:30]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C@@H:25]([OH:26])[C@H:13]2[O:14][CH2:15][CH2:16][C:17]([O:19]CC(F)(F)F)=O)[C:10]1=[O:58])(=O)C1C=CC=CC=1.[CH3:59][NH:60][CH3:61].O1CCCC1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([O:29][CH2:28][C@H:27]2[O:53][C@@H:12]([N:11]3[CH:54]=[CH:55][C:56](=[O:57])[NH:9][C:10]3=[O:58])[C@H:13]([O:14][CH2:15][CH2:16][C:17](=[O:19])[N:60]([CH3:61])[CH3:59])[C@@H:25]2[OH:26])([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1
Reactant: CNC
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)n(C(=O)c4ccccc4)c3=O)[C@H](OCCC(=O)OCC(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCCC(=O)N(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To N3-benzoyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-[2-(2,2,2-trifluoroethoxy)carbonylethyl]uridine (120 mg, 0.15 mmol) synthesized in Example 15 was added 2 M dimethylamine/tetrahydrofuran (4 mL), followed by stirring at room temperature for 15 hours. Then, the reaction was carried out at 40° C. for 2 hours. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography eluting with chloroform to give the title compound as a white foam-like material (80 mg, 83%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2C.Br[C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[C:48]1([C:80]3[C:71](=[CH:72][C:73]4[O:78][CH2:77][CH2:76][O:75][C:74]=4[CH:79]=3)[O:70][CH2:69]1)[C:49](=[O:68])[N:50]2[CH:55](C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:55][N:50]1[C:51]2[C:47](=[C:46]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)[CH:54]=[CH:53][CH:52]=2)[C:48]2([C:80]3[C:71](=[CH:72][C:73]4[O:78][CH2:77][CH2:76][O:75][C:74]=4[CH:79]=3)[O:70][CH2:69]2)[C:49]1=[O:68]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: OB(O)c1cc[nH]n1
Agent: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: OB(O)c1cnc2ccccc2c1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3cc[nH]n3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 1H-pyrazol-3-boronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-methyl-4′-(1H-pyrazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (63%) as a colorless solid: mp 201-202° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.46-7.35 (m, 2H), 7.25-7.20 (m, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.40 (s, 1H), 6.24 (s, 1H), 5.94 (d, J=2.0 Hz, 1H), 4.74-4.61 (m, 2H), 4.20-4.07 (m, 4H), 3.27 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.6, 144.7, 144.5, 137.8, 129.2, 128.0, 124.6, 121.6, 111.0, 108.2, 105.5, 99.5, 77.4, 64.5, 63.9, 58.4, 26.9; MS (ES+) m/z 375.9 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:6][CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)([C:4]#[CH:5])[CH3:3].C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].[Cl-].[NH4+]>CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[CH3:3][C:2]([O:6][CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)([C:4]#[C:5][CH2:18][CH2:19][CH2:20][Cl:21])[CH3:1]
Reactant: ClCCCBr
Reactant: C#CC(C)(C)OC1CCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C#CCCCCl)OC1CCCO1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a dried flask (500 ml volume), the inside of which had been flushed with nitrogen, were charged 15.4 g (0.10 mol.) of 2-methyl-2-tetrahydrofuranoxy-3-butyne, 150 ml of tetrahydrofuran and 20 ml of hexamethylphosphoric triamide, and the resulting mixture was cooled to −70° C. Subsequently, 65 ml of n-butyllithium (1.55 mol./l n-hexane solution, 0.10 mol.) was added to the mixture and the resulting mixture was stirred at 70° C. for 30 minutes. After adding 15.8 g (0.10 mol.) of 1-bromo-3-chloropropane, the reaction solution was warmed to 0° C. over 2 hours and further stirred at 0° C. for 2 hours to complete the reaction. After the completion of the reaction, the reaction mixture was added to 500 ml of an aqueous saturated ammonium chloride solution, cooled by ice, and then subjected to extraction with two 200 ml portions of ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated by distillation of the solvent through a rotary evaporator to give 22.8 g of a crude product. The crude product was purified by distillation under reduced pressure to give 2-methyl-2-tetrahydrofuranoxy-7-chloro-3-heptyne (19.2 g, purity 97.0%, yield 80.8%) having the following physical data:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].S([O-])(O)=O.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: Clc1cccc(C=Cc2ccccc2OCc2ccccc2)c1
Agent: [Rh]
Agent: O=S([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: CCO
Solvent: c1ccccc1
Product: Clc1cccc(CCc2ccccc2OCc2ccccc2)c1
Yield: 98.5 %

Procedure:
5.4 g of this 2-benzyloxy-3'-chlorostilbene were treated with hydrogen in the presence of 300 mg of tris(triphenylphosphine)rhodium (I) chloride in a mixture of 60 ml of benzene and 40 ml ethanol at room temperature for one day. At the end of this time, aqueous sodium hydrogensulfite containing a small amount of sodium metabisulfite was added to the reaction mixture and allowed to react. Insoluble materials were removed by filtration. Ethyl acetate was added to the filtrate, and the mixture was washed once with water and twice with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.35 g (yield 98%) of benzyl 2-[2-(3-chlorophenyl)ethyl]phenyl ether.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[OH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.[K+].[Br-].[O-]Cl.[Na+]>C(Cl)Cl>[O:12]=[CH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1ccc(CCCO)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(CCC=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TEMPO (0.02 equiv, 6 mg, 0.038 mmol) was added to a solution of methyl 2-(4-(3-hydroxypropyl)phenyl)acetate in CH2Cl2 (5 mL) and cooled to 0° C. KBr (2.2 equiv, 1.6 mL, 2.7M) and KHCO3 (5.5 equiv, 6.6 mL, 1.6M) solutions were then added followed by the dropwise addition of 10% aq. NaOCl (1.34 equiv, 1.9 g, 2.6 mmol). Once the addition was complete, the reaction was stirred for an additional 10 min. at 0° C. The reaction was quenched with sat. aq. sodium thiosulfate solution (3 mL) and then partitioned between H2O (10 mL) and CH2Cl2 (10 mL). The organic phase was separated and the remaining aqueous phase was extracted with EtOAc (2×2 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting aldehyde was carried forward to the subsequent reaction without further purification. LRMS: 206.1 (calc) 207.2 (found)(MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].NC(N)=[O:23].OO.C1(=O)OC(=O)C2=CC=CC=C12.[O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O>[C:1]([O:5][C:6]([C:7]1[CH:8]=[C:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N+:14]=2[O-:23])[CH:10]=[CH:11][CH:12]=1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(N)=O
Reactant: Cc1cccnc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: O=C1OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc[n+]([O-])c1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 45 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
tert-Butyl-3-(3-methylpyridin-2-yl)benzoate (1.0 eq) was dissolved in EtOAc (6 vol). Water (0.3 vol) was added, followed by urea-hydrogen peroxide (3 eq). Phthalic anhydride (3 eq) was then added portionwise to the mixture as a solid at a rate to maintain the temperature in the reactor below 45° C. After completion of the phthalic anhydride addition, the mixture was heated to 45° C. After stirring for an additional 4 hours, the heat was turned off. 10% w/w aqueous Na2SO3 (1.5 eq) was added via addition funnel. After completion of Na2SO3 addition, the mixture was stirred for an additional 30 minutes, and the layers separated. The organic layer was stirred, and 10% wt/wt aqueous. Na2CO3 (2 eq) was added. After stirring for 30 minutes, the layers were allowed to separate. The organic phase was washed 13% w/v aq NaCl. The organic phase was then filtered and concentrated to afford crude 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (95%) that was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]([C:15]([O-:17])=O)=[CH:5]1)[CH3:3].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:15]([C:6]2[C:7](=[O:14])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([N:2]([CH3:1])[CH3:3])[CH:5]=2)=[O:17])=[CH:21][CH:20]=1
Reactant: CN(C)n1cc(C(=O)[O-])c(=O)c2ccccc21
Reactant: NCc1ccc(Cl)cc1
Product: CN(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccccc21

Procedure:
Ethyl 1-(dimethylamino-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.21 g) of Preparation No. 59 and 4-chlorobenzylamine (1.2 mL) are heated to 180° C. for 10 hrs under nitrogen. The product is precipitated from the cooled reaction mixture by dilution with a mixture of toluene and hexanes. The crude product is then recrystallized from aqueous acetic acid to give 0.030 g of the title compound.
Reaction SMILES: [Br-:1].O[C@@H]1C2CC[N+](CC(=O)NC3C=CON=3)(CC2)C1.[Br-].[OH:21][C@@H:22]1[CH:27]2[CH2:28][CH2:29][N+:24]([CH2:30][C:31](=[O:39])[NH:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)([CH2:25][CH2:26]2)[CH2:23]1.[CH:40]1([C:46]([OH:56])([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:47](O)=[O:48])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[Br-:1].[CH:50]1([C:46]([OH:56])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:47]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N+:24]([CH2:30][C:31](=[O:39])[NH:32][C:33]4[CH:38]=[N:37][CH:36]=[CH:35][N:34]=4)([CH2:25][CH2:26]3)[CH2:23]2)=[O:48])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCCC1)C2)Nc1cnccn1

Procedure:
This compound is prepared as a diastereomeric mixture using an method analogous to Example 4, by replacing (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) with (R)-3-Hydroxy-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate H) and 2,2′-diphenylpropionic acid with cyclohexyl-hydroxy-phenyl-acetic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1.[ClH:35]>CO>[ClH:35].[NH:25]1[CH2:26][CH2:27][CH:22]([C:17]2[C:16]([O:15][CH:13]3[CH2:14][N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:12]3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc2nc(N3CC(Oc4nccnc4C4CCNCC4)C3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To tert-butyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidine-1-carboxylate (400 mg, 0.86 mmol) was added 4 M HCl in MeOH (20 mL). The reaction mixture was stirred at room temperature for 30 min and concentrated. The residue was dried under high vacuum to give 2-(3-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)azetidin-1-yl)quinoline hydrochloride (310 mg, 0.86 mmol, 100% yield) as a white solid. ESI-MS (M+1): 362 calc. for C21H23N5O 361.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH3:22].O>C(C(C)=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:19]([O:11][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=1[F:10])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCOc1c(F)c(F)cc(F)c1F
Yield: 91.3 %

Procedure:
To 20.0 g of 2,3,5,6-tetrafluorophenol (1) dissolved in 100 mL of methyl ethyl ketone (MEK) there were added 18.3 g of potassium carbonate, 4.26 g of tetrabutylammonium bromide (TBAB) and 18.1 g of bromobutane dissolved in 50 mL of MEK, with heating under reflux for 4 hours. After cooling and addition of water, the organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 24.4 g (110 mmol) of 4-butoxy-2,3,5,6-tetrafluorobenzene (2).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1>CN(C=O)C.CO.[Pd]>[NH2:1][CH2:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(CBr)n1
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
Sodium azide (0.280 g, 4.32 mmol) was added to a solution of 6-bromomethyl-pyridine-2-carbonitrile (0.610 g, 2.88 mmol) in DMF (12 ml) and the resulting pale yellow solution was stirred at rt for 16 h. Standard basic workup gave the crude product as a tan solid in quantitative yield (0.501 g). The crude solid was dissolved in MeOH (15 ml), treated with 10% Pd/C (0.050 g) and placed under 40 psi H2 on a Parr shaker for 30 minutes (Note: it is imperative that this reduction is stopped at 30 minutes or reduction of the nitrile also occurs). The mixture was filtered through Celite®, the cake was washed with MeOH and the combined filtrate was concentrated under reduced pressure to give a yellow oil. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 83:15:2, v/v/v) afforded 6-aminomethyl-pyridine-2-carbonitrile (0.178 g, 46%) as a white crystalline solid. 1H NMR (CDCl3) δ 1.96 (br s, 2H), 4.02 (s, 2H), 7.53 (d, 1H, J=9.0 Hz), 7.59 (d, 1H, J=9.0 Hz), 7.80 (t, 1H, J=9.0 Hz).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12]([OH:14])=O)[CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+:19].O>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12]([NH2:19])=[O:14])[CH2:6][CH2:5]2
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)[C@H]1CCc2cc(I)ccc2O1
Reaction time: 3 h

Procedure:
The crude carboxylic acid of Example 7 (30.4 g, 100 mmol) and CDl (19.5 g, 120 mmol) were stirred in N,N-dimethylformamide (300 mL) at room temperature for 2 hours to obtain a yellow solution. To this solution was then added ammonium acetate (23.1 g, 300 mmol). The resulting mixture was stirred for 3 hours. It was then cooled in an ice-water bath and water (400 mL) was then added dropwise to the reaction mixture to obtain a fine white precipitation which was stirred for 12 hours. The solid was collected by vacuum filtration, washed with water and dried by suction (25.8 g, 85%): 1H NMR (DMSO-d6) δ1.75-1.90 (m, 1H), 2.00-2.15 (m, 1H), 2.55-2.80 (m, 2H), 4.43-4.47 (dd, J=8.7, 3.3 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 7.35 (m, 2H). CI-MS m/z 304 (M +H+).