Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:5]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[CH2:29](I)[CH2:30][CH2:31][CH3:32]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:26])[C@:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[N:5]=[C:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCI
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[C@@](Cc1ccccc1)(N=C(c1ccccc1)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-methyl-N-(diphenylmethylene)phenylalaninate (0.50 g, 1.4 mmol) (for synthesis see: O'Donnell et al, J. Org. Chem. 1982, 47, 2663-2666) in 6 mL DMF at 0° C. was added 95% NaH (0.14 g, 5.6 mmol). After 30 min, butyl iodide was added via syringe to the dark red reaction. After 30 min at 0° C., the reaction was warmed to rt for 14 h, then quenched by the addition of water. The aqueous layer was extracted with EtOAc (2×), the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (40 g silica, 0->8% EtOAc/hexanes) afforded methyl-α-butyl-N-(diphenylmethylene)phenylalaninate as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.57 (m, 2H), 7.37-7.17 (m, 11H), 7.05-7.03 (m, 2H), 3.36 (d, J=11.5 Hz, 1H), 3.32 (d, J=11.5 Hz, 1H), 3.24 (s, 3H), 1.78 (m, 2H), 1.41 (m, 2H), 1.29-1.24 (m, 2H), 0.89 (t, J=7.2 Hz, 3H). LC/MS M+H=400.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9].[C:13]1([CH:23]=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[C:23]([C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=1)[NH:10][C:8]2=[O:9]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: O=Cc1cccc2ccccc12
Product: COc1ccc2nc(-c3cccc4ccccc34)[nH]c(=O)c2c1

Procedure:
Compound 17 was synthesized from 5-methoxy-2-aminobenzamide (9) (1.2 g, 7.3 mmol) and 1-naphthaldehyde (14) (1.1 g, 7.3 mmol): yield 1.5 g (70%); pale yellow needles; mp 174 to 175° C.; 1H NMR (DMSO-d6) δ 3.87 (3H, s, OCH3), 7.22-7.34 (2H, m, 2×ArH), 7.53-7.72 (5H, m, 5×ArH), 7.95-8.22 (3H, m, 3×ArH), 12.62 (1H, br s, NH) ppm; MS (ESI) m/z 302; Anal. (C19H14N2O2): C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)[CH3:2].[C:35](Cl)(=[O:37])[CH3:36]>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:16]=2[CH2:25][N:26]([C:35](=[O:37])[CH3:36])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1
Reactant: CC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(benzylamino-methyl)-4-trifluoromethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[Cl:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[Cl:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:1]([C:4]12[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:10][CH2:11]2)=[O:3]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)c(Cl)c1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-chloro-4-methylaniline (41.8 μL) were used to obtain (2S,4S)-1-[[N-[4-[N-(2-chloro-4-methylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (22.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Cn2cnnc2[C@H]2CCCN2)cc1

Procedure:
De-Boc by TFA procedure: A solution of Boc-protected triazole from Example 3 (0.35 g, 0.9645 mmol) in 10 mL of TFA and 10 mL of CH2Cl2 was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and then treated with saturated aqueous Na2CO3 (30 mL), extracted with CH2Cl2 (4×40 mL), dried over Na2SO4, and concentrated in vacuo. The desired product was obtained as a pale yellow oil (0.13 g, 51.3%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([O:35][CH3:36])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:6]3[CH:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:23]=[C:22]([O:35][CH3:36])[N:21]=1
Reactant: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3ccc(NC4CCCC(O)C4)cn23)cc(Cl)n1
Temperature: 95 °C

Procedure:
To a solution of 3-trans-RS/RS(3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol [intermediate J step 2] (1 eq, 10.1 mmol, 3.4 g), 2-Chloro-6-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.05 eq, 10.1 mmol, 2.9 g), Na2CO3 (2 eq, 19 mmol, 2 g) in dioxane (45 ml) and water (13.5 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.96 mmol, 224 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=343/345.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:25][CH2:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(-c2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccccc2)c1CBr
Yield: 79.3 %

Procedure:
Ethyl 4-methyl-3-phenylisoxazole-5-carboxylate (0.2 g, 0.87 mmol), NBS (0.17 g, 0.95 mmol), and benzoyl peroxide (21 mg, 0.087 mmol) were added to 5 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The mixture was diluted with CH2Cl2, and 5 g of silica gel was added. The solvent was removed in vacuo and the crude was purified by flash chromatography (0-20% EtOAc/hexanes) to give 214 mg of the title compound. MS: (+) m/z 310.31, 312.28 (M+1, 79Br/81Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[N:24][C:25]=1[CH3:26].O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:30]1[CH2:31][CH:32]=[C:27]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([CH3:26])[N:24]=2)[CH2:28][CH2:29]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Cc1ccc(C2=CCNCC2)nc1C
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C2=CCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CC2)nc1C
Yield: 44.7 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.83 g, 3.3 mmol) and 5,6-dimethyl-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (5.18 g, 27.5 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (7.48 g, 46.6 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.67 g of the intended substance (yield 44.7%).
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(OCCC#C)(=O)=O)=[CH:3][CH:2]=1.[F:16][C:17]([F:29])([F:28])[CH2:18][CH2:19][S:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:22])=[O:21].[H-].[Na+].Cl>CS(C)=O>[F:29][C:17]([F:16])([F:28])[CH2:18][CH2:19][S:20]([CH:23]([CH2:3][CH2:2][C:1]#[CH:6])[C:24]([O:26][CH3:27])=[O:25])(=[O:21])=[O:22]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Reaction time: 96 h
Yield: 35.3 %

Procedure:
To a solution of 2.0 g of 3-butynyl p-toluenesulfonate and 2.1 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide, 0.4 g of sodium hydride (60% in oil) was added at room temperature, and stirred at the same temperature for 4 days. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.90 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-5-hexynoate (hereinafter referred to as the present compound (8)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].P(Br)(Br)[Br:13].CCOC(C)=O.C([O-])(O)=O.[Na+]>COCCOC>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]([CH2:10][Br:13])[CH:3]=1
Reactant: COc1ncc(CO)cc1Br
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncc(CBr)cc1Br
Reaction time: 0.25 h

Procedure:
To (5-bromo-6-methoxy-pyridin-3-yl)-methanol (2.86 g, 13.1 mmol) in DME (30 mL) was added phosphorus tribromide (1.9 mL, 19.7 mmol), and the reaction was stirred for 15 minutes. The mixture was worked up with EtOAc and saturated aqueous NaHCO3, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give 3-bromo-5-bromomethyl-2-methoxy-pyridine.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22](O)=[O:23])[C:4]=2[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([CH2:22][OH:23])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2c(CO)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To the mixture of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 20 (70 mg, 0.174 mmol) in Tetrahydrofuran (THF) (5 mL) was added in LiAlH4 (19.85 mg, 0.523 mmol) at 0° C. and the reaction mixture was stirred at rt for 1 h. Then LiAlH4 (19.85 mg, 0.523 mmol) was added in and the reaction mixture was stirred at rt for another hour. The reaction mixture was cooled to 0° C. and quenched with water (0.04 ml), NaOH (15%, 0.04 ml) then water (0.12 ml). After the resultant mixture was stirred at room temperature for 2 h, anhydrous MgSO4 was added and the reaction mixture was filtered through celite and washed with EtOAc. Evaporation of the solvent gave the crude product. The crude product was purified on a silica column (0˜4% MeOH/DCM) to give the solid (12 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 2.91-3.05 (m, 4H), 3.64-3.74 (m, 4H), 4.89 (d, J=5.56 Hz, 2H), 5.12 (t, J=5.81 Hz, 1H), 5.95 (s, 2H), 6.33 (d, J=6.82 Hz, 1H), 6.81 (d, J=2.02 Hz, 1H), 6.97 (d, J=1.77 Hz, 1H), 7.34 (t, J=7.71 Hz, 1H), 7.54-7.74 (m, 2H), 7.85 (d, J=8.08 Hz, 1H), 8.01 (d, J=7.58 Hz, 1H), 8.25 (d, 1H). MS(ES+) m/z 388.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N+:11]#[C-:12])[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=[O:20])=CC=1.CCOCC>CS(C)=O>[O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N:11]=[C:12]=[O:20])[CH2:4][CH2:3]1
Reactant: [C-]#[N+]C1CCC(=O)c2sccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C=NC1CCC(=O)c2sccc21

Procedure:
A solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylisocyanide (9.5 g) in dry dimethylsulfoxide (4.63 g) is stirred under a nitrogen atmosphere while anhydrous p-toluenesulfonic acid (0.93 g) is added in small portions over an hour. The mixture is heated below 50° C. After 1.25 hours the reaction mixture is cooled and ether (3 × 3 ml) added, and the ether solution is then decanted. The ether solution contains the title isocyanate, and is used as is.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:16][C:15]([C:14]1[CH:13]=[CH:12][O:11][C:10]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:17]
Reactant: O=C(O)c1ccoc1-c1cccc([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccoc1-c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid (1.2 g) in methanol (200 mL) containing concentrated sulfuric acid (5 drops) was heated under reflux for 18 h. The reaction solution was evaporated to dryness under reduced pressure to give the title compound as a yellow solid (0.66 g). m.p.=93–94° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=O)[NH:8][N:7]=1)=[O:5])[CH3:2].CS(O)(=O)=O>C(O)(=O)C.C1(C)C=CC=CC=1>[N:7]1[N:8]2[C:9]([O:11][C:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=32)=[CH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc(OC2CCCCC2=O)[nH]n1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2oc3c(n2n1)CCCC3
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of ethyl-5-[(2-oxocyclohexyl)oxy]-1H-pyrazole-3-carboxylate (127.6 mg, 0.5 mmol) and methane sulfonic acid (95 mg) in 5 ml of acetic acid and toluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap to remove water. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and aqueous bicarbonate solution. The organic layer was washed with water and dried over MgSO4. After removal of the ethyl acetate, the residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate/hexane to give 69.7 mg (59%) of the desired product as white solid. Mp; 55-57° C.; Electrospray-MS m/z 235.0 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][C:17]#[N:18]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:16][C:17]#[N:18])[CH:5]=[N:4][CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCOc1cncc(Br)c1
Temperature: 0 °C
Yield: 57.7 %

Procedure:
A dry, 250 mL one neck round bottom flask was charged with 3-bromo-5-hydroxypyridine 3 (4.9470 g, 28.4 mmol), 40 mL dry ACN, cesium carbonate (CS2CO3) (3.41 ml, 42.6 mmol) and a stirbar. The flask was fitted with an Ar inlet, and cooled to 0° C. To the solution was added 2-chloroacetonitrile (2.34 ml, 37.0 mmol) dissolved in 10 mL dry ACN over 15 minutes via an addition funnel. The reaction warmed to room temperature overnight. The slurry was filtered through a 0.22 μm PTFE filter membrane, and concentrated under a stream of nitrogen. The residue was loaded onto 100 g of SiO2 wet-packed with ACN, and eluted with 500 mL ACN. The eluent was concentrated in vacuo, and the residue was sublimed at 0.5 mm Hg in a 90° C. oil bath to afford 2-(5-bromopyridin-3-yloxy)acetonitrile (3.49 g, 57.6% yield). 1H NMR (300 MHz, MeOH) δ ppm 5.12 (s, 2H) 7.81 (dd, J=2.63, 1.83 Hz, 1H) 8.35 (d, J=2.63 Hz, 1H) 8.38 (dd, J=1.83, 0.29 Hz, 1H). 13C NMR (75 MHz, MeOH) δ ppm 55.24 (s, 1 C) 116.18 (s, 1 C) 121.90 (s, 1 C) 126.59 (s, 1 C) 137.86 (s, 1 C) 145.61 (s, 1 C) 155.29 (s, 1 C). HPLC-MS: retention time=1.42 min (99.0%@215 nm; 98.9% @254 nm; m/z=212.8, calculated for C7H579Br2N2O+H+=213.0, m/z=214.8, calculated for C7H581Br2N2O+H+=215.0).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1.[Br:17]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: Cc1ccc2oc3ncccc3c(=O)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=c1c2cc(CBr)ccc2oc2ncccc12
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A mixture of 42 g of 7-methyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine, 36 g of N-bromosuccinimide, 0.4 g of benzoyl peroxide and 420 ml of carbon tetrachloride is refluxed with stirring under ultraviolet light for 2 hours. The reaction mixture is filtered rapidly while it is hot. The crystals thus obtained are suspended in hot water (about 60°C). The suspension is stirred thoroughly, and filtered. The crystals are recrystallized from dioxane to give 47.1 g of 7-bromomethyl-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine melting at 211°-212.5°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:4][C:3]=1[F:13].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>COC(OC)(C)C>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([CH2:8][C@@H:9]2[CH2:10][O:11][C:15]([CH3:20])([CH3:16])[O:12]2)=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OC[C@H](O)Cc1cnc(Cl)c(F)c1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC1(C)OC[C@@H](Cc2cnc(Cl)c(F)c2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 967.5 %

Procedure:
A suspension of 3 (2.50 g, 12.2 mmol) in dimethoxypropane (25 mL) was cooled with an ice bath and treated with paratoluene sulfonic acid monohydrate (0.23 g, 1.22 mmol). The ice bath was removed and the solution was stirred at room temperature for 16 hrs, cooled to 5° C. and treated with aqueous sat. NaHCO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to afford 2.90 g of 31 (97%) as an oil. 1HNMR (CDCl3) δ 1.34 (3 H, s), 1.42 (3 H, s), 2.87 (2 H, d, J=6.0 Hz), 3.62 (1 H, t, J=7.0 Hz), 4.08 (1 H, t, J=6.0 Hz), 4.30 (1 H, q, J=6.0 Hz), 7.46 (1 H, d, J=9.0 Hz), 8.12 (1 H, s). LC/MS (M+1) 247.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)=[O:17])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)N2CCN(c3ccc(CN)cc3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(N2CCN(C(=O)N[C@H]3CC[C@H](C(=O)O)CC3)CC2)cc1

Procedure:
400 mg of 1-(4-aminomethylphenyl)-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-piperazine-hydrochloride and 3 ml of a 1.4 molar aqueous lithium hydroxide solution in 3 ml of tetrahydrofuran and 2 ml of water is stirred at ambient temperature for 2 hours. Then 3.2 ml of 1N hydrochloric acid are added dropwise and some of the solvent is evaporated off under reduced pressure. The precipitate is suction filtered, triturated with acetone, suction filtered again and dried. Yield: 330 mg (94% of theory), Rf value: 0.47 (silica gel; methylene chloride/methanol/conc. ammonia=2:1:0.25) Mass spectrum: M+ =360
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.CC(C)([O-])C.[K+].Cl[C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1[CH:23]=[O:24]>C1COCC1>[CH3:18][N:17]1[C:13]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[C:14]([CH:23]=[O:24])[C:15]([C:19]([F:20])([F:21])[F:22])=[N:16]1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: OC1COC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)c(C=O)c1OC1COC1
Yield: 99.9 %

Procedure:
Oxetane-3-ol (6.12 g, 82.7 mmol) was added dropwise to potassium tert-butoxide (1M in THF) (69.6 ml, 69.6 mmol) at room temperature. 5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde (9.86 g, 46.4 mmol) was dissolved in THF (40 ml) and added slowly to the solution. After 25 minutes the mixture was concentrated and the residue partitioned between ethyl acetate and water. The two phases were separated and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to yield the product as brown oil (11.6 g) which was used in the next step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH:9]([C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:10][CH3:11])[CH3:5]>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[C:9]([CH2:10][CH3:11])=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(CC)C(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c(-c2ccc(Cl)cc2)c1CC
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Hydrazine monohydrate (0.13 ml, 3 mmol) was added at ambient temperature to a solution of 3-(4-chloro-benzoyl)-2-oxo-pentanoic acid ethyl ester (740 mg, 3 mmol) in ethanol (4 ml) under an argon atmosphere. The solution was stirred for 8 h at reflux temperature, the solvent was removed under reduced pressure and the residue partitioned between 1 M HCl/ice water and ethyl acetate. The aqueous layer was extracted two times with ethyl acetate, the combined extracts were washed with brine (3 times) and dried over sodium sulfate. Removal of the solvent under reduced pressure left an orange oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 355 mg (1.27 mmol, 49%) of the title compound as yellow crystals.