Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:5]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:18][CH:17]([CH3:19])[CH:12]([N:6]1[C:5](=[O:20])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[CH:3]=2)[C:7]1=[O:11])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: COC(=O)C(C(C)C)N1C(=O)c2ccc(Br)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(C)C)N1C(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Temperature: 80 °C

Procedure:
The compound of example 660 (2.5 g, 7.35 mmol); 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (2.19 g, 8.82 mmol) and bis-Pinacolato diborane (180 mg, 0.22 mmol) were taken in dry DMF under argon atmosphere. Degassed 2M solution of sodium carbonate (1.94 g, 18.37 mmol) was added and the reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled and the solvent was removed by distillation. The residue was taken in water and this aqueous mixture was extracted with ethyl acetate. The crude material was purified through column chromatography (silicagel, 30% dichloromethane in petroleum ether) to afford the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19].C(N(CC)CC)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cccc(I)c1NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C#C[Si](C)(C)C)c1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 98 %

Procedure:
To tert-butyl 2-iodo-6-methoxyphenylcarbamate (10.36 g, 29.67 mmol), ethynyltrimethylsilane (3.20 g, 32.63 mmol), copper(I) iodide (0.28 g, 1.48 mmol), and PdCl2(PPh3)2 (1.04 g, 1.48 mmol) in THF (100 mL) was added triethylamine (3.60 g, 35.6 mmol), followed by overnight stirring. The crude reaction was then concentrated and the mixture was flashed through silica gel with 10:1 Hex/EtOAc to give the desired product (98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH2:9]([O:8][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][N:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1cc(Cl)cc[nH]1
Reactant: BrCc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(COc2ccccn2)cc1

Procedure:
Reaction of 4-chloropyridone (XXXXII) with an aryl halide, such as benzyl bromide in benzene and in the presence of Ag2CO3 as described in Scheme 13 (Smith A. M.; et al. J. Med. Chem. 36, 8, 1993) and at temperature ranges of 30-80° C. afforded the corresponding 2-benzyloxypyridine (XXXXVII). This was coupled with an arylboronic acid, ArB(OH)2 under palladium-catalyzed conditions to give (XXXXIX). The benzyloxy group can be removed by treatment with a strong acid, such as trifluoroacetic, triflic, sulfuric, HCl, etc. to give pyridone (L). This was converted to the 2-halopyridine with the action of POX3, PX5 or the corresponding triflate, tosylate or mesylate, which was displaced with a primary amine RNH2 to give (LI). The nitro group was reduced under conditions described in scheme 13 and the aminopyridine was cyclized to the imidazolo[4,5-b]pyridine (LII) under conditions described in scheme 13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:24]([CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27])[C:10]2=[O:12]
Reactant: O=C(O)c1cccc(OCc2cc(Cl)cc(Cl)c2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cc(Cl)cc(Cl)c4)c3C2=O)C(=O)N1
Yield: 76.9 %

Procedure:
A mixture of 3-(3,5-dichloro-benzyloxy)-phthalic acid (0.3 g, 0.9 mmol), alpha-amino-glutarimide hydrochloride (0.15 g, 0.92 mmol) in pyridine (10 mL) was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3,5-dichloro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.30 g, 84% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 70/30 CH3CN/0.1% H3PO4, 3.6 min (98.0%); mp, 278-280° C.; 1HNMR (DMSO-d6) δ 2.01-2.08 (m, 1H, CHH), 2.54-2.63 (m, 2H, CH2), 2.84-2.96 (m, 1H, CHH), 5.13 (dd, J=6, 12 Hz, 1H, CH), 5.40 (s, 2H, CH2), 7.50-7.89 (m, 6H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.95, 30.92, 48.79, 68.37, 115.90, 116.79, 120.02, 125.58, 127.45, 133.25, 134.18, 137.14, 140.61, 154.93, 165.34, 166.73, 169.88, 172.73. Anal Calcd For C20H14N2O5Cl2: C, 55.45; H, 3.26; N, 6.47; Cl, 16.37. Found: C, 55.20; H, 3.13; N, 6.38; Cl, 16.63.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][C:18]#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]#[N:19]
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#CCn1c(C(F)F)cc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, bromoacetonitrile (2 eq) and Cs2CO3 (2 eq): MS (ES) m/z 264 (M−1).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:25]([C:29]1[CH:30]=[C:31]([CH:52]=[C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:54]=1[OH:55])[C:32]([O:34][C:35]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][C:36]=1[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:33])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:39](=[O:40])[C:38]1[CH:42]=[C:43]([C:44]([CH3:45])([CH3:47])[CH3:46])[C:35]([O:34][C:32](=[O:33])[C:31]2[CH:52]=[C:53]([C:56]([CH3:57])([CH3:59])[CH3:58])[C:54]([OH:55])=[C:29]([C:25]([CH3:27])([CH3:28])[CH3:26])[CH:30]=2)=[C:36]([C:48]([CH3:51])([CH3:49])[CH3:50])[CH:37]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCNCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCN(CCCCCCCC)C(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4.83 grams of di-n-octylamine and 2.0 grams of triethylamine dissolved in 40 ml of toluene was added dropwise at 35° to 40° over a period of 10 minutes 10.0 grams of 4-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)-3,5-di-tert-butyl-benzoyl chloride dissolved in 30 ml of toluene. The reaction mixture was stirred at 85° to 90°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered to remove the precipitated triethylamine hydrochloride. The filtrate was washed with water and dried over anhydrous sodium sulfate. After removal of the toluene by distillation, the product was isolated as white crystals (m.p. 145°-146°) by successive crystallization from acetonitrile and isopropanol.
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29])=[NH:6]>[Ni].CO.O>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])(=[NH:4])[NH2:6]
Reactant: Cc1ccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)cc1
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cn(N=C3CCc4c(C(=N)N)cccc43)c(N)n2)cc1

Procedure:
Analogously to Example 2, 0.2 g of Raney nickel is added to a solution of 0.9 g (1.917 mmol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(4-tolyl)-imidazole dihydrochloride in 60 ml of methanol/water (1:1), and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered, and the filtrate is acidified to pH 3 with 3N methanolic hydrochloric acid and is concentrated to a volume of approximately 20 ml. The product that has crystallized out is filtered off and recrystallized from ethanol/water, yielding the title compound with a water content of 11.81%, m.p. 220°-225° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.33 (d, 1H); 7.98 (s, 1H); 7.83 (d, 1H); 7.61-7.71 (m, 3H); 7.29 (d, 2H); 3.37 (s, 4H); 2.34 (s, 3H).
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12]([CH3:29])=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[Cl:23])[N:15]=2)[N:9]=1)(=O)C.Cl>>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12]([CH3:29])=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[Cl:23])[N:15]=2)[N:9]=1
Reactant: CCOC(=O)C1=C(C)NC(c2csc(NC(C)=O)n2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2csc(N)n2)=NC1c1ccc(F)cc1Cl
Yield: 79 %

Procedure:
0.35 g Ethyl 2-(2-acetylaminothiazol-4-yl)-4-(2-chloro-4-fluorophenyl)-6-methyl-1,4-dihydro-pyrimidin-5-carboxylate (Example 30) reacted with 2 ml 6 mol/L hydrochloric acid solution at 50° C. for 2 hr. The reaction product was extracted with ethyl acetate, dried, and separated by a column chromatography to obtain 0.25 g of amorphous yellow solid with mp 95-110° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.01-1.04 (3H, m); 2.39 (3H, s); 3.89-3.95 (2H, m); 5.91 (1H, br); 7.02-7.38 (6H, m, br); 8.83 (1H, br); MS (EI) 394.0 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.Cl.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[C:10]1([NH:16][N:17]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccncc1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C(=NNc1ccccc1)c1ccncc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
4-Pyridinecarboxaldehyde (1.75 g, 16 mmol), phenylhydrazine hydrochloride (2.26 mL, 16 mmol) and triethylamine (1.65 g, 16 mmol) were dissolved in ethanol (50 mL) and heated for 1 h. The reaction mixture was cooled to room temperature. The resulting precipitates were collected and washed with petroleum ether to afford 3.04 g (94%) of 1 as a solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[C:26]([F:38])=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:28]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(Cl)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(Cl)c2F)n1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-chloro-2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.321 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.066 g (40% yield) of pure product: MS (ES) m/z 530 (M+).
Reaction SMILES: [CH2:1](OC1C=C(I)C=C(OCC)C=1OCC)C.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:30][CH2:31]C)[C:26]=1OCC)[NH2:23])C>>[CH3:31][O:30][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:17])[C:26]=1[CH3:1])[NH2:23]
Reactant: CCOc1cc(N)cc(OCC)c1OCC
Reactant: CCOc1cc(I)cc(OCC)c1OCC
Product: COc1cc(N)cc(OC)c1C

Procedure:
Following the procedure of the synthesis of 3,4,5-triethoxy-1-iodobenzene from the oil containing 3,4,5-triethoxyaniline in Reference Example 5,1-iodo-3,5-dimethoxy-4-methylbenzene was obtained as a pale yellow amorphous powder (7.59 g, yield: 87%) from 3,5-dimethoxy-4-methylaniline (J. Chem. Soc., 497-506 (1963)) (5.23 g, 31.3 mmol).
Reaction SMILES: O1CC[C@@H]([O:6][C:7](=[O:34])[NH:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)C1.[ClH:35].[CH3:36][CH2:37][O:38][CH2:39][CH3:40]>C(Cl)Cl>[ClH:35].[O:38]1[CH2:39][CH2:40][C@@H:36]([N:8]([CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)[C:7](=[O:34])[OH:6])[CH2:37]1
Reactant: CCOCC
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@H](CN(C(=O)O)[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
(R)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (116 mg, 0.251 mmol) was suspended in 8 mL anhydrous CH2Cl2 and gently heated until an homogenous solution was formed. After the reaction was cooled to room temperature, a 2.0 M solution of HCl in Et2O (0.126 mL, 0.251 mmol) was added in one portion. The reaction mixture was diluted with 25 mL Et2O, and the product precipitated from solution. The reaction was stirred for an additional 30 minutes before the solid was filtered and dried to obtain (R)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride as a light yellow solid (99 mg, 70%). LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J=7.7 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.75 (s, 1H), 7.42-7.49 (m, 3H), 6.97-7.08 (m, 2H), 5.08 (dd, J=6.1, 4.6 Hz, 1H), 4.52-4.54 (m, 2H), 3.66-3.78 (m, 3H), 3.58-3.60 (m, 1H), 3.48 (t, J=10.7 Hz, 1H), 3.23 (t, J=11.5 Hz, 1H), 3.00 (t, J=6.3 Hz, 2H), 2.53 (s, 3H), 2.05-2.14 (m, 1H), 1.80-1.91 (m, 4H), 1.72 (d, J=9.0 Hz, 1H), 1.34-1.43 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8])([CH3:4])[CH3:3].[S:13](Cl)([CH3:16])(=[O:15])=[O:14]>N1C=CC=CC=1.C(Cl)Cl>[C:2]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][O:11][S:13]([CH3:16])(=[O:15])=[O:14])=[O:12])([CH3:1])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Hydroxyethyl)methylcarbamic acid 1,1-dimethylethyl ester (350 mg, 2.0 mmol) was dissolved in pyridine (2 ml). Mesyl chloride (0.229 ml, 2.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with methylene chloride, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over MgSO4 and concentrated under reduced pressure to give methanesulfonic acid 2-(tert-butoxycarbonyl-methyl-amino)-ethyl ester. This was used in the next reaction without complete purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)=[CH:8][CH:7]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20].CCN(CC)CC>C(Cl)Cl>[CH3:22][S:19]([O:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:11][CH:10]=2)[CH2:13]1)(=[O:21])=[O:20]
Reactant: OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(4-(oxazol-2-yl)phenyl)piperidin-3-ol (85 mg, 0.348 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise mesyl chloride (0.033 mL, 0.418 mmol), followed by Et3N (0.058 mL, 0.418 mmol). The reaction was stirred at 0° C. for 5 min, and then at rt for 30 min. After this time, HPLC and LC/MS showed that the desired product formed and there was no starting material remaining. The reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with water, saturated aqueous NaHCO3, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give the desired product 1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl methanesulfonate (110 mg, 0.341 mmol, 98% yield) as an off-white foam. Anal. Calcd. for C15H18N2O4S m/z 322.3, found: 323.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:18]([O:20][C:21](=[O:25])[CH:22]=[N+]=[N-])[CH3:19].B(F)(F)F.CCOCC>CCOCC>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH2:3][CH:22]1[C:21]([O:20][CH2:18][CH3:19])=[O:25]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A dry 500 ml 3-neck flask was charged with benzyl 4-oxo-1-piperidinecarboxylate (35.08 g, 150 mmol). It was dissolved in 130 ml Et2O and cooled to −45° C. Ethyldiazoacetate (20.5 ml, 195 mmol) and boron trifluoride ethyl ether (19.4 ml, 158 mol) were added simultaneously by syringe pump over 45 minutes. The temperature was kept below −25° C. The reaction was stirred for 30 minutes longer, and then quenched with sat. NaHCO3. The ice bath was removed. The reaction was diluted with EtOAc (250 ml) and H2O (150 ml). The layers were separated, and the organic phase was dried over MgSO4. It was concentrated under reduced pressure to an orange oil. The product was purified by flash chromatography (silica gel, 40% EtOAc/hexane), yielding product as pale yellow oil (42.1 g, 88%). 1H NMR (CDCl3)δ 67.39-7.31, 5.15-5.12, 4.42-4.17, 3.96-3.83, 3.75-3.70, 3.65, 3.54-3.37, 2.08-2.03, 1.29-1.24; IR (liq.) 1743, 1702, 1476, 1455, 1443, 1425, 1371, 1318, 1295, 1238, 1213, 1178, 1098, 1068, 1028 cm−1.
Reaction SMILES: [Cl-].[CH3:2][NH:3][C:4](=O)[CH3:5].N1C(C)=CC=CC=1C.C(OC([N:22]1[CH2:29][CH2:28][C@:27]2([CH3:32])[C@H:30]([CH3:31])[C@H:23]1[CH2:24][C:25]1[CH:36]=[CH:35][C:34]([C:37]([NH:39][NH2:40])=O)=[CH:33][C:26]=12)=O)(C)(C)C>ClCCl>[CH3:2][N:3]1[C:4]([CH3:5])=[N:40][N:39]=[C:37]1[C:34]1[CH:35]=[CH:36][C:25]2[CH2:24][C@@H:23]3[C@@H:30]([CH3:31])[C@:27]([CH3:32])([C:26]=2[CH:33]=1)[CH2:28][CH2:29][NH:22]3
Reactant: CNC(C)=O
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)NN)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1nnc(-c2ccc3c(c2)[C@]2(C)CCN[C@H](C3)[C@H]2C)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalylic chloride (0.12 mL) is added to a solution N-methylacetamide (102 mg) and 2,6-lutidine (0.33 mL) in dichloromethane (5 mL) chilled in an ice bath. After stirring the solution for 15 min, (2R,6R,11S)-8-hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.50 g) is added and the cooling bath is removed. The resulting solution is stirred at ambient temperature for 1 h and then neutralized with aqueous NaHCO3 solution. The resulting mixture is extracted with dichloromethane, the combined organic extracts are dried (MgSO4), and the solvent is evaporated. The residue is taken up in acetic acid (3 mL) and stirred at 120° C. for 2.5 h. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is taken up in trifluoroacetic acid (1 mL) and dichloromethane (5 mL) to cleave off the tert-butoxycarbonyl group. The solution is stirred at room temperature overnight and then concentrated. The residue is dissolved in little methanol/acetonitrile, neutralized with aqueous ammonia, and purified by HPLC on reversed phase (MeCN/H2O/NH4OH) to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:3]2[N:4]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[N:5]=1
Reactant: CCOC(=O)c1cn2nc(Cl)cc(Br)c2n1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2nc(Cl)cc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 5a (10.6 g, 34.8 mmol) in acetonitrile (150 mL) was added DIEA (10.9 mL, 62.6 mmol) and morpholine (3.60 mL, 42.0 mmol). The reaction mixture was stirred at rt for 1 h, during which time the entire solution solidified. The resulting mixture was left at rt for 3 h, then was poured into ice water (200 mL), and the precipitates were collected by filtration, and dried under high vacuum. Compound 5b was obtained as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.25 (s, 1H), 6.10 (s, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.99-4.17 (m, 4H), 3.86-3.96 (m, 4H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]=[CH:3][CH3:4].[C:5]1([CH2:11][CH:12]2[O:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:2]([NH:1][CH2:13][CH:12]([OH:14])[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=[CH2:4]
Reactant: CC=CN
Reactant: c1ccc(CC2CO2)cc1
Solvent: CO
Product: C=CCNCC(O)Cc1ccccc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A solution of 1-aminopropylene (10.6 grams, 0.186 mol) in methanol was added to a methanolic solution of 3-phenylpropyleneoxide (5.07 grams, 0.037 mol) and the mixture heated to reflux for 30 minutes. The mixture was allowed to warm to room temperature and concentrated in vacuo to yield 7.2 grams (99%) of N-allyl-3-phenyl-2-hydroxypropylamine. 1H NMR (CDCl3, dTMS) 7.24-7.18 (5H, m, Ar-H), 5.84 (1H, ddt, 3JHH =17.1 Hz, 3JHH =10.2 Hz, 3JHH =6 Hz, CH2CH), 5.2-5.0 (2H, m, CH=CH2), 3.86 (1H, m, CHOH), 3.19 (2H, m, NCH2CH=CH2), 2.76-2.66 (3H, m, NCH2CH(OH)CHHPh), 2.50 (1H, dd, 2JHH =12 Hz, 3JHH =9 Hz). 13C NMR (CDCl3) 138.4, 136.5, 129.3, 128.4, 126.3, 116.0, 70.6, 54.0, 51.9, 41.7.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][CH:11]=O.[CH2:13]([O:20][C:21]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21](=[O:22])[CH:23]=[CH:11][CH2:10][CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CCC1Cc2ccccc2C1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: ClCCl
Product: O=C(C=CCC1Cc2ccccc2C1)OCc1ccccc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
3.97 g (24.8 mmol) of (indan-2-yl)acetaldehyde was dissolved in 50 ml of methylene chloride, to which was added 12.2 g (29.8 mmol) of benzyloxycarbonylmethylene triphenyl phosphorane and stirred for 1.5 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain 6.45 g colorless oil. Yield: 89%