Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[CH:13]=[CH:12][CH:11]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:10]1([CH2:9][OH:8])[C:15]2[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc2c1C=CCCCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2c1C=CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl(5,6,7,8-tetrahydrobenzo[a]cycloocten-1-ylmethoxy)dimethylsilane (10.94 g, 36.16 mmol) in tetrahydrofuran (100 ml) was added a solution (43.4 ml, 43.4 mmol) of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran at room temperature and the mixture was stirred at room temperature for 15 min. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[CH2:24]([N:26]([CH2:31]C)[CH2:27][CH2:28][CH2:29][NH2:30])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:24][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6]
Reactant: CCN(CC)CCCN
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN(C)C)c1
Yield: 68 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.5 g, 1 eq, prepared according to Example A1), 3-diethylamino-propylamine (877 mg, 1.1 eq) and potassium carbonate (2.13 g, 2 eq) in acetonitrile (80 ml) is heated under reflux for 5 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (130 ml) and water (50 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: dichloromethane/methanol 9:1) produces the expected compound in the form of a yellow oil (2.1 g mg; 68% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][OH:13].[N+:14]([O-])([OH:16])=[O:15].CCO>C(O)(=O)C>[OH:1][C:2]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][OH:13]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(O)c(OCCO)c1
Solvent: CCO
Solvent: CC(=O)O
Product: O=Cc1cc(OCCO)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 88.7 %

Procedure:
To the solution of 4-hydroxy-3-(2-hydroxyethoxyl)benzaldehyde in acetic acid (5 mL) was added 65% nitric acid (34.6 mg, 0.55 mmol) at 0° C., and the mixture was stirred at 0° C. 4 hours. The reaction mixture was poured into ice water followed by a standard aqueous/EtOH workup. Isolated 110 mg, yield 88.7% of Intermediate 10.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.Br[C:11]([CH3:23])([CH3:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C(#N)C>[F:1][C:2]1([F:8])[CH2:7][CH2:6][N:5]([C:11]([CH3:23])([CH3:22])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:4][CH2:3]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(Br)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C(=O)OCc1ccccc1)N1CCC(F)(F)CC1
Temperature: 85 °C
Yield: 11.3 %

Procedure:
A stirred mixture of 4,4-difluoropiperidine/HCl (158 mg), benzyl 2-bromo-2-methylpropanoate (257 mg) and TEA (0.279 mL) in acetonitrile (1.5 mL) in a capped vial was heated at 85° C. overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in ether, washed with satd. NaHCO3, water, brine and dried (MgSO4). The crude product was purified by silica gel FCC (0-1% MeOH in DCM) to afford benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate as a viscous oil (33.7 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.31-7.46 (5H, m), 5.18 (2H, s), 2.66 (4H, t, J=5.40 Hz), 1.86-2.08 (4H, m), 1.36 (6H, s). Benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate was debenzylated by hydrogenation (10% Pd/C, EtOAc) to afford Cap P-16 as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.00 (4H, br. s.), 2.18-2.43 (4H, m), 1.45 (6H, s).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C@H:7]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:26]([O:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C@H:7]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8]2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: Oc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
(R)-(-)-3,4-Dihydro-2-(4-hydroxybenzyl)-2H-benzopyran (5.0 g, 20 mmol), 4-dimethylaminopyridine (240 mg, 2 mmol), triethylamine (2.6 g, 25 mmol) and acetic anhydride (2.9 g, 28 mmol) were dissolved in methylene chloride (75 ml) and stirred at room temperature for 2 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue purified on silica gel using hexanes/ethyl acetate (3:1) as eluent to afford an oil which was crystallized from hexanes to yield 4.0 g of the title product, m.p. 64°-65° C.; [α]D -98.9° (c 1.3, MeOH);
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(CN2CC[C@H](N3CCNCC3)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a mixture of 1-benzyl-3-phenyl-piperidin-4-one (10.0 g, 37.7 mmol) and piperazine (13.0 g, 151 mmol) was added tetraisopropyl-orthotitanate (42.8 mL, 151 mmol) at room temperature. After stirring at room temperature overnight the reaction mixture was diluted with ethanol (300 mL) and sodium cyanoborohydride (10.5 g, 151 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (10 mL). The inorganic precipitate was filtered off and washed with ethanol. The solvent was evaporated and the residue was taken up in ethylenglycol (130 mL) and sodium hydroxide (13.6 g, 37.7 mmol) was added. The reaction mixture was stirred at 130° C. for 15 min. After cooling water (200 mL) was added and the mixture was extracted twice with 200 mL diethylether. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with methylene chloride/triethyl amine 99:1 gave rac-cis-1-(1-benzyl-3-phenyl-piperidin-4-yl)-piperazine (4.63 g, 36%), as a yellow oil, MS: m/e=336.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:16][C@@H:17]([CH2:25][CH2:26][S:27][CH3:28])[C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])=[CH:12][CH:11]=[C:10]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:31][N:32]3[CH:36]=[CH:35][N:34]=[CH:33]3)[N:9]=2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:16][C@@H:17]([CH2:25][CH2:26][S:27][CH3:28])[C:18]([OH:20])=[O:19])=[O:15])=[CH:12][CH:11]=[C:10]([O:29][CH:30]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[CH2:31][N:32]3[CH:36]=[CH:35][N:34]=[CH:33]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CSCC[C@H](NC(=O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)nc1-c1ccc(F)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)nc1-c1ccc(F)cc1)C(=O)O

Procedure:
A solution of tert-butyl (2S)-2-{2-(4-fluorophenyl)-6-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]pyrid-3-oylamino}-4-methylsulfanylbutyrate (0.1 g.) in TFA(20 ml.) was stirred at ambient temperature under an inert atmosphere for 30 minutes. The TFA was evaporated away and the residue was converted to the hydrochloride salt to give (2S)-2-{2-(4-fluorophenyl)-6-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]pyrid-3-oylamino}-4-methylsulfanylbutyric acid as a white solid (0.092 g.).
Reaction SMILES: C[C@@H:2]1[NH:10][CH2:9][C@H:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3]1.C(N1CCC[C@H]1C(O)=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl.COC(=O)[C@H](C)N>>[N:4]12[CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:9][NH:10][CH2:2][CH2:3]2
Reactant: C[C@H]1CN2CCC[C@H]2CN1
Agent: COC(=O)[C@H](C)N
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Product: C1C[C@H]2CNCCN2C1
Yield: 14 %

Procedure:
(3S,6S)-3-methyl-1,4-diazabicyclo[4.3.0]nonane, 14% yield, from N-Fmoc-L-proline and L-alanine methyl ester hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][CH3:25])[C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC(N(CCC)C2C([N+]([O-])=O)=CC=CN=2)CC1)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][CH3:25])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(c1ncccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Agent: CCCN(c1ncccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Product: CCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 204, Part B), and making non-critical variations but substituting 1-benzyl-4-[N-ethyl-N-(3-nitro-2-pyridinyl)amino]piperidine (EXAMPLE 204, Part A) for 1-benzyl-4-[N-propyl-N-(3-nitro-2-pyridinyl)amino]piperidine, the title compound is obtained, NMR (CDCl3) 7.84, 7.31, 7.26, 6.96, 6.85, 3.97, 3.50, 3.18, 3.07, 2.89, 2.02, 1.75 and 0.89δ.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)=O)[CH2:3][CH2:2]1.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[Cl:13][C:8]1[CH:7]=[C:6]([C:4]2[C:17]3[N:16]([C:15]([CH3:14])=[N:19][CH:18]=3)[CH2:2][CH2:3][CH:1]=2)[CH:11]=[CH:10][C:9]=1[Cl:12]
Reactant: O=C(c1ccc(Cl)c(Cl)c1)C1CC1
Reactant: Cc1ncc[nH]1
Product: Cc1ncc2n1CCC=C2c1ccc(Cl)c(Cl)c1

Procedure:
Combine 10 g (46.5 mmol) of cyclopropyl-(3,4-dichlorophenyl)methanone with 20 g (0.24 mol) of 2-methylimidazole and heat to 175° C. under nitrogen for 70 hr. The title compound is isolated by column chromatography on silica gel using methylene chloride as the solvent.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=2)[C:31](O)=[O:32])[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([C:28]2[CH:29]=[C:30]([C:31]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]3[CH2:16][O:15][C:14]3[C:4]4[C:3]([NH2:2])=[N:8][S:7](=[O:9])(=[O:10])[NH:6][C:5]=4[CH:11]=[CH:12][CH:13]=3)=[O:32])[CH:34]=[CH:35][N:36]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=C(O)c1ccnc(-n2ccnc2)c1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3ccnc(-n4ccnc4)c3)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(1H-imidazol-1-yl)isonicotinic acid (Example 52a) (22% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.47-1.91 (m, 6H), 3.02 (m, 1H), 3.35 (m, 1H), 4.28 (dd 1H, J=10.4, 4.4 Hz), 4.65 (t, 1H, J=10.4 Hz), 5.24 (m, 1H), 6.63 (d, 1H, J=8.2 Hz), 6.90 (d, 1H, J=8.5 Hz), 7.31 (d, 1H, J=5.2 Hz), 7.48 (d, 1H, J=8.2 Hz), 7.77 (s, 1H), 7.84 (br s, 1H), 8.00 (s, 1H), 8.44 (br s, 1H), 8.52-8.59 (m, 2H), 10.95 (br s, 1H). MS 482 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[C:20]([CH3:22])[O:19][C:18](=[O:23])[CH:17]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:7]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[O:19][C:18](=[O:23])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(O)cc(=O)o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(=O)o1
Reaction time: 4.5 h

Procedure:
124.4 g (0.900 mol) potassium carbonate and 63 ml (0.547 mol) benzyl chloride were added in succession to a solution of 56.7 g (0.450 mol) 4-hydroxy-6-methyl-2H-pyran-2-one and 1.0 g (0.004 mol) 18-crown-6 in 900 ml anhydrous dimethyl-formamide. It was stirred vigorously for 4.5 hours at an internal temperature of 70°-75° C. It was suction filtered and the residue was washed well with ethyl acetate. The combined filtrates were extensively evaporated in a vacuum and subsequently poured onto ice water. The aspirated precipitate was recrystallized from t-butylmethyl ether after drying. 69.0 g (71%) V, melting point 92°-93° C.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[CH2:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:30][CH3:31]>C1COCC1>[CH2:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2]#[N:3])=[CH:34][CH:33]=1)[CH2:30][CH3:31]
Reactant: N#CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(C=CCCCCCC#N)cc1
Yield: 67.3 %

Procedure:
This compound was synthesized from 6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) and p-propylbenzaldehyde (2.96 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the product (3.25 g, 67%) as a colorless liquid (bp 144-148° C./0.05 torr). IR 2290 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.55 (m, 8H), 2.40 (m, 6H), 5.60 (m, 1H), 6.40 (d, 1H), 7.10 (s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[O-]CC.[Na+]>[C:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: N#CCc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(F)cc1

Procedure:
By employing the procedures described in Example 1, p-fluorophenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide to give ethyl 3-cyano-3-(p-fluorophenyl)pyruvate. The latter is reacted with phenylacetonitrile and subsequent synthetic steps yield 4-fluoropulvinic acid lactone. The lactone ring is opened with 2-aminothiazole as described above to give 4-fluoro-N-(2-thiazolyl)pulvinic acid amide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1>>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]2[CH:2]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: N#Cc1ccc(N)nc1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(C#N)ccc2n1
Yield: 11 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-5-cyanopyridine instead of 2-aminopyridine, to the title compound (17 mg, 11%) which was obtained as a light yellow foam. MS: m/e=301.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:12][CH2:13][CH2:14][OH:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:12][CH2:13][CH2:14][OH:15])[C:5]#[N:6]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCO)c(Br)c1
Temperature: 50 °C
Reaction time: 0.59 h
Yield: 55.7 %

Procedure:
3-Bromo-4-hydroxy benzonitrile (10.0 g, 50.5 mmol) was dissolved in acetone and successively treated with 1-bromo-3-propanol (19.0 g, 138 mmol) and K2CO3 (20.9 g, 151 mmol) at ambient temperature. The resulting suspension was warmed to 50° C. and maintained 3 d. After cooling to ambient temperature, the solids were removed by filtration, exhaustively was with acetone and the filtrate concentrated. Purification by chromatography on SiO2 (A: hexanes; B: EtOAc; 0-100% B over 35.4 min; 200 mL/min; 330 g column) afforded a solid. Further purification by recrystallization from hot MTBE (131 mL) and pentane (130 mL), with cooling at −20° C. (12 h) to induce precipitation, afforded a solid (7.2 g, 58%). 1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.56 (d, J=9 Hz, 1H), 6.94 (d, J=6 Hz, 1H), 4.23 (t, J=6 Hz, 2H), 3.88 (t, J=6 Hz, 2H), 2.08 (m, J=6 Hz, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:24]2[CH:23]=[CH:22][C:21]3[O:16][CH2:17][CH2:18][O:19][C:20]=3[CH:25]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methy ester hydrochloride salt, of Preparation 44, and 2,3- dihydro-benzo[1,4]-dioxine-6-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.26-7.16 (m, 3H), 7.07 (d, 1H), 6.85-6.78 (m, 3H), 4.24 (s, 4H), 3.75 (s, 2H), 3.68 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.62 (t, 2H); MS 342 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([CH2:15][CH2:16][OH:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([CH2:15][CH2:16][O:17][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(O)(CCO)c1ccc(Cl)c(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)C(O)(CCOS(=O)(=O)c1ccc(C)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To the solution of Example 135C (8.8 g, 30 mmol) in CH2Cl2 was added tosyl chloride (2 equivalents) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 equivalents) and the mixture stirred overnight at room temperature. Purification by column chromatography on silica gel provided title compound (3.3 g, 25%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].CO>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(F)c1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cc(F)c(F)c(CO)c1

Procedure:
To a stirring solution of 2,3-difluoro-5-nitrobenzoic acid (Butt Park Ltd.; 9.00 g; 44.3 mmol) in THF at 0° C. was added a 1M solution of borane-tetrahydrofuran complex in THF (177.3 mL; 177.3 mmol). The mixture was allowed to react at RT overnight. Then, MeOH was cautiously added to the stirred mixture while cooling with an ice bath. The batch was diluted with ethyl acetate and washed with aqueous sodium hydroxide solution (1N) and saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulfate), filtered and concentrated. The residue was purified by chromatography (hexane to hexane/ethyl acetate 1:2) to give the pure product (8.20 g; 43.4 mmol).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:5]=2[N:6]=1.N([O-])=O.[Na+].[Na+].[Cl-:18]>OP(O)(O)=O.O>[Cl:18][C:2]1[S:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:5]=2[N:6]=1
Reactant: Cc1ccc(Cl)c2sc(N)nc12
Reactant: [Cl-]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)c2sc(Cl)nc12
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a slurry of 2-amino-4-methyl-7-chlorobenzothiazole (77.2) (6.37 g) in H3PO4 (85%, 213 ml) in a 500 ml 3-necked flask with mechanical stirring and an internal temperature of <−10° C., was added dropwise a solution of NaNO2 (6.87 g) in water (11 ml). The mixture was warmed to 0° for 30 minutes and then recooled. The slurry was then slowly added to a cold (˜−5° C.) solution of CuSO4.5H2O (32 g) and NaCl (40 g) in water (128 ml) with vigorous mechanical stirring. After the foaming subsides and warming to RT, the solids were collected by filtration and rinsed with water. The solids were dissolved in ether leaving some insoluble residue. The ether solution was washed with water, and sodium bicarbonate solution. After the organic layer was concentrated, the residue was purified by flash chromatography with 10% methylene chloride in hexane to afford 2-chloro-4-methyl-7-chlorobenzothiazole (77.3) (4.48 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:6]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)N[C@H](CO)Cc1ccccc1
Yield: 86.4 %

Procedure:
5 g (27.6 mmol) of 2-methyl-5-nitrobenzoic acid were reacted with 4.2 g (27.6 mmol) of (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.5 g (87%) of the product were obtained.