Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[C:14]3[C:9](=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH:8]([OH:19])[CH2:7]2)[N:3]=[CH:2]1.[CH2:20](O)[CH3:21]>Cl>[CH2:20]([O:19][CH:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=2[CH3:18])[CH:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)[CH2:7]1)[CH3:21]
Reactant: CCO
Reactant: COc1cc2c(c(C)c1C)C(O)CC2c1c[nH]cn1
Agent: Cl
Product: CCOC1CC(c2c[nH]cn2)c2cc(OC)c(C)c(C)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1H-imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-ol (cis-isomer, 0.1 g) is dissolved in the mixture of ethanol (20 ml) and concentrated hydrochloric acid (2 ml). The solution is stirred at 25° C. for one hour. Work-up of the reaction mixture gives the crude product, which is purified by flash chromatography using methylene chloride-methanol as eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[N+]([O-])(O)=O.CC1C=C(C)[N:28]([C:32](=N)[NH2:33])N=1.C(N(CC)CC)C.[ClH:42]>CN(C=O)C.C(O)C>[ClH:42].[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH2:33])=[NH:28])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCOC(=O)c1oc2cccc(OCCCN)c2c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1oc2cccc(OCCCNC(=N)N)c2c1C

Procedure:
A mixture of 4-(3-amino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (the compound in Example 109-a: 10 mg), 3,5-dimethyl-1-guanylpyrazole nitrate (14 mg) and triethylamine (100 μl) in DMF (1 ml) was stirred at 40° C. for two days. The solvent was removed under a reduced pressure and the residue was purified by reversed phase column chromatography using Sep-Pak Cartridge C18 (Waters) (H2O-MeOH) to give a white powder. The powder was dissolved in a solution of 1N HCl (0.3 ml) and ethanol (5 ml), and the solution was concentrated in vacuo to give 4-(3-guanidino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester hydrochloric acid salt (9 mg) as a white powder. FAB-MS: m/z 320 (MH+); 1H-NMR (CD3OD): δ 1.40 (3H, t, J=7 Hz), 2.18 (2H, quintet, J=6.5 Hz), 2.75 (3H, s), 3.46 (2H, t, J=7 Hz), 4.22 (2H, t, J=6 Hz), 4.39 (2H, q, J=7 Hz), 6.78 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.39 (1H, t, J=8 Hz).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].C(N(CC)CC)C.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:29]([C:21]1[S:20][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)(=[O:30])=[O:31])[CH3:4]
Reactant: O=S(=O)(Cl)c1nc2ccccc2s1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.10 g, 5.0 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069.), in dichloromethane (50 mL) was slowly added triethylamine (2.02 g, 20 mmol) at room temperature. Then benzothiazole-2-sulfonyl chloride (1.19 g 5.0 mmol) in dichloromethane (10 mL) was added to the reaction mixture at room temperature for 5 min. The resulting reaction mixture was stirred for additional 2 h. at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to remove solvent to give desired product (1.60 g, 92%) as a solid. 1H NMR (500 MHz; DMSO-d6) δ 8.28 (d, 1H), 8.19 (d, 1H), 7.69˜7.63 (m, 2H), 4.03 (q, 2H), 3.24 (s, 2H), 3.13 (t, 2H), 2.62 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.P(Br)(Br)[Br:13].O>CCCCCC>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][Br:13]
Reactant: BrP(Br)Br
Reactant: CC(C)CCCC(C)CCO
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCCC(C)CCBr
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To neat 3,7-dimethyloctanol (5 ml) was added phosphorus tribromide (1.01 ml). The mixture was stirred for 4 hours at 60° C. The reaction mixture was added to a mixture of water and n-hexane. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 3,7-dimethyloctyl bromide (4.40 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[OH-].[Na+]>CO>[CH3:13][S:12][C:10]1[N:11]=[C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:8]=2[N:9]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nc(SC)nc2n1Cc1cccc(F)c1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A mixture of 260 mg (0.564 mmol) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 25 mL of methanol were treated with 0.42 mL of 2 M sodium hydroxide and stirred at reflux for 3 hours. The reaction was cooled to ambient temperature. The product precipitated upon addition of 1 M HCl and was collected by filtration. The solids were washed with water and dried in vacuo to provide 176 mg (73%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a solid. nmr (300 MHz, dmso-d6) δ0.99 (t, 3H), 2.49 (s, 3H), 2.91 (q, 2H), 4.87 (s, 2H), 5.52 (s, 2H), 6.90 (d, 1H), 7.04 (d, 1H), 7.10 (dt, 1H), 7.36 (dt, 1H), 7.60 (br s, 1H), 8.02 (br s, 1H)
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.CO>O>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CCc1ccncc1
Yield: 37.1 %

Procedure:
A solution of potassium cyanide (25 g) in water (133 ml) and of 4-picolyl chloride hydrochloride (30 g) in reagent grade methanol (268 ml) was heated under reflux for 2 hours, concentrated under vacuum, diluted with water (500 ml) and extracted with CHCl3 (4×100 ml). Distillation of the extract afforded a single fraction of 4-pyridylacetonitrile (8.026 g), b.p. 84° C. at 0.15 mm Hg. This was dissolved in dry dimethylformamide (130 ml) and stirred with sodium hydride (3.4 g, 50% w/v dispersion in oil) for 2.5 hours. Ethyl iodide (5.7 ml, 1.93 g/ml) was added slowly with cooling and stirring. After 18 hours, excess solvent was evaporated off, the residue diluted with water (150 ml) and extracted with diethyl ether (3×300 ml). Flash chromatography (Merck Art 9385, CHCl3, 4.5×15 cm column) of the extract afforded a mixture of 2-(4-pyridyl)butyronitrile and 2-ethyl-2-(4-pyridyl)-butyronitrile (9.85 g). Acrylonitrile (4.46 ml) in t-butanol (5.5 ml) was added to a solution of the above mixture in t-butanol (18 ml) and "Triton B" (0.32 ml) with cooling and stirring. ("Triton" is a Registered Trade Mark in the UK and many other countries). After 2 hours, excess solvent was evaporated off, the residue diluted with water (150 ml) and extracted with CHCl3 (2×50 ml). Flash chromatography of the extract (CHCl3, 4.5×15 cm column) afforded a mixture of 2-ethyl-2-(4-pyridyl) butyronitrile and 4-cyano-4-(4-pyridyl)hexanonitrile (8 g). This mixture was heated under reflux with glacial acetic acid (15 ml) and conc. sulfuric acid (3 ml) during 0.5 hours, then with addition of 5N hydrochloric acid (15 ml) for a further 3 hours, cooled, diluted with water, adjusted to pH 7-7.5 with sodium hydrogen carbonate and extracted with methylene chloride. Elution from a column (4.5×30 cm) of silica gel (Merck, Kieselgel 6) with CHCl3 afforded the title compound, 2.95 g; (20% yield based on 4-pyridylacetonitrile) which crystallized from toluene, m.p. 138°-139° C. (corrected); mass spectrum, isobutane chemical ionization [MH+ ] at m/z=219: IR (KC1) cm-1 2990 (CH aromatic phenyl), 2800 (NH), 1720, 1784 (C=0 imide), 1605 (C=C, aromatic phenyl); 1H-NMR (CDCl3), δ0.87 (t,3H,CH3CH2), 1.80-2.82 (m, 6H, CH3CH2, H(4), H(5)), 7.15 (d, 2H, aromatic H(3), H(5), J=4.7 Hz), 8.55 (d, 2H, aromatic H(2), H(6), J=4.7 Hz), 9.13 (br.s., 1H, NH). Anal. C12H14N2O2, 218.25) Calcd: C,66.03; H,6.47; N,12.84, Found: C,66.00, H,6.58; N,12.87%.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c(OC)nc1C
Yield: 70 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=1)[CH3:2].Cl[C:22]1[C:23]2[C@H:31]([CH3:32])[CH2:30][C:29](=[O:33])[NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C.[OH-].[Na+]>C(OCC)(=O)C.O.CN1CCCC1=O>[CH2:1]([C:3]1[N:4]=[C:5]([CH:15]2[CH2:16][CH2:17][N:18]([C:22]3[C:23]4[C@H:31]([CH3:32])[CH2:30][C:29](=[O:33])[NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:19][CH2:20]2)[N:6]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=1)[CH3:2]
Reactant: CCc1cn(CCN2CCCC2)c(C2CCNCC2)n1
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cn(CCN2CCCC2)c(C2CCN(c3ncnc4c3[C@H](C)CC(=O)N4)CC2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
Combine 4-(4-ethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine (7.70 g, 27.86 mmol), (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (6.06 g, 1.1 eq), N-methylpyrrolidinone (25.4 mL) and triethylamine (4.27 mL, 1.1 eq). Stir overnight at 110° C. under nitrogen, then let cool to room temperature. Dilute with ethyl acetate and water. Adjust the pH with 2 M aqueous sodium hydroxide to 10. Separate the layers. Wash the aqueous phase with ethyl acetate. Wash the organics with aqueous saturated sodium chloride. Concentrate the organics in vacuo. Dilute with ethyl acetate and water. Adjust the pH to 5. Separate the layers; discard the organic layer. Adjust the pH of the aqueous phase with 2 M aqueous sodium hydroxide to 11. Wash the aqueous phase with ethyl acetate. Wash the organics with water and aqueous saturated sodium chloride. Concentrate the organics in vacuo. Dilute with 2-methyltetrahydrofuran:hexanes (15:85, 77 mL). Stir overnight at room temperature. Filter and dry the resulting white solid under vacuum to give the title compound, (R)-4-(4-(4-ethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (7.90 g, 65%). MS (ES) m/z=438 [M]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:21](OC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:29]=[C:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[S:24][C:1]([C:3]2[CH:8]=[C:7]([CH:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 61 %

Procedure:
tert-Butyl 2-(2-cyano-4-pyridyl)-1-pyrrolidinecarboxylate (1.6 g, 6.0 mmol) and methyl thiosalicylate (3.0 g, 18.3 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.5 g, 63%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:17]C[CH:15]1[CH2:14][NH:13][CH2:12]2.C(N(CC)CC)C>O1CCOCC1>[CH:15]12[CH2:17][CH:11]1[CH2:12][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:14]2
Reactant: C1CC2CNCC12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CC3CC3C2)nc1
Temperature: 65 °C
Yield: 97.5 %

Procedure:
A mixture of 0.5 g (3.15 mmol) of 2-chloro-5-nitropyridine, 0.452 g (3.78 mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and 1.32 mL (6.94 mmol) of triethylamine in 10 mL of dioxane, is heated at 65° C. for 4 h. The reaction mixture is then poured into 50 mL of ice water. The mixture is stirred until the ice has melted completely, then a yellow precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 0.63 g of the expected product in the form of a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]([NH2:18])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)[CH:5]=[N:6][CH:7]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:18][C:15]2[N:16]=[CH:17][C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)=[N:21][CH:22]=1
Reactant: Nc1ncc(-c2cncc(F)c2)c2cccnc12
Reactant: Clc1ccc(Br)nc1
Product: Fc1cncc(-c2cnc(Nc3ccc(Cl)cn3)c3ncccc23)c1

Procedure:
The title compound, MS: m/e=352.1 (M+H+), was prepared in accordance with the general method of example 15 step 3 from 5-(5-fluoro-pyridin-3-yl)-[1,7]naphthyridin-8-ylamine and 2-bromo-5-chloropyridine.
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7]([CH:9]1[CH2:17][CH2:16][C:12]2[O:13][CH:14]=[CH:15][C:11]=2[C:10]1=O)=O)C>C(O)C>[OH:6][C:7]1[C:9]2[CH2:17][CH2:16][C:12]3[O:13][CH:14]=[CH:15][C:11]=3[C:10]=2[NH:3][N:2]=1
Reactant: NN
Reactant: CCOC(=O)C1CCc2occc2C1=O
Solvent: CCO
Solvent: O
Product: Oc1n[nH]c2c1CCc1occc1-2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Hydrazine monohydrate was added to an ethanol (50 ml) solution of 3.00 g 5-ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]furan, and the mixture was stirred at room temperature for 14 hours. The solvent was evaporated under a reduced pressure, and the residue was washed with hexane/ethyl acetate and dried under a reduced pressure to give 4,5-dihydro-3-hydroxy-1H-furo[2,3-g]indazole. Diazomethane (2 eq.) was added to a mixed solution of 1,4-dioxane (10 ml) and methanol (20 ml) containing 1.50 g of the thus obtained compound, and the mixture was stirred at room temperature for 1 hour. Acetic acid was added to the reaction mixture until gas evolution stopped, and then the solvent was evaporated under a reduced pressure. The residue was extracted with chloroform and washed with saturated sodium bicarbonate aqueous solution, and the thus obtained organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent, the solvent was evaporated and the residue was purified by a silica gel column chromatography to give 0.80 g of 4,5-dihydro-3-methoxy-1H-furo[2,3-g]indazole. From this compound, 3-methoxy-1H-furo[2,3-g]indazole was obtained in the similar manner as described in Reference Example 60.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)C1CCCN1
Yield: 94.8 %

Procedure:
A solution of 3-(3-pyridyl)-1-propyl (2S)-N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.00 g; 9 mmol) in methylene chloride (50 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3×). The combined organic extracts were dried and concentrated to yield 2.00 g (95%) of the free amine as a thick oil, 1H NMR (300 MHz, CDCl3): δ 1.87-2.20 (m, 6H); 2.79 (m, 2H); 3.03 (m, 2H total); 3.07 (m, 2H); 3.84 (m, 1H); 4.24 (m, 2H); 7.32 (m, 1H); 7.60 (m, 1H); 8.57 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[NH:39][C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[N:32]=2)[CH2:27][CH2:26]1>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:26][CH2:27][CH:28]([C:31]5[NH:39][C:34]6=[N:35][CH:36]=[CH:37][CH:38]=[C:33]6[N:32]=5)[CH2:29][CH2:30]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2[nH]c(C3CCNCC3)nc2c1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: c1ccc(-c2cn3nccc3nc2-c2ccc(CN3CCC(c4nc5cccnc5[nH]4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
251.4 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde, a suspension in 10 mL DMF and 238 mg (1 mmol) 2-piperidine-4-yl-3H-imidazo[4,5-b]pyridine hydrochloride salt were stirred and treated as described in example 15.0. After stirring overnight at room temperature, the reaction mixture was worked up as described in example 15. After purification 90 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCN)cc(OC)c1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCNC(=O)CCc2ccc(F)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-(3,5-Dimethoxy-phenyl)ethylamine (1.20 g, 6.62 mmol) is dissolved in anhydrous DMF (50 mL), and 3-(4-fluorophenyl) propionic acid (1.113 g, 6.62 mmol), PyBOP (3.77 g) and DIPEA (2.61 mL, 15 mmol) are added. The mixture is stirred at rt for 14 h. Water (60 mL) is added, and the mixture is extracted with EtOAc (4×60 mL). The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography (EtOAc/Hex, 7:3) to afford the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[NH2:5].C(N(CC)CC)C.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].[OH-].[Na+].[NH4+].[Cl-]>ClCCl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: CCS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
3-Bromo-4-(2,4-difluorophenoxy)aniline (3.24 g, 10.80 mmol) and triethylamine (4.37 g, 43.2 mmol) were stirred in dichloromethane (48.1 mL) at ambient temperature. Ethanesulfonyl chloride (4.16 g, 32.4 mmol) was added dropwise and the solution stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dioxane (24 mL) and sodium hydroxide (10% w/v, 12 mL, 0.427 mmol) were added, and the solution was heated to 70° C. for 1 hour. The solution was neutralized to a pH of about 7 with saturated aqueous NH4Cl (200 mL). The aqueous phase was extracted with ethyl acetate (3×125 mL). The combined organics were washed with brine, dried (anhydrous MgSO4), filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate/petroleum ether gradient,) to afford N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (1.4 g, 3.57 mmol, 33.1% yield).
Reaction SMILES: [C:1]1([C:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([CH2:27][O:28][NH2:29])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:48](Cl)(=[O:50])[CH3:49].Cl>ClCCl.C(OCC)(=O)C>[C:36]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([CH2:27][O:28][NH:29][C:48](=[O:50])[CH3:49])[CH2:10]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NOC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NOC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.42 h
Yield: 88 %

Procedure:
To a solution of (2S,4S)-4-triphenylmethylthio-2-aminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (6), prepared as above A (6), in dichloromethane are added pyridine (93 μl) and acetyl chloride (66 μl), and the mixture is stirred for 25 minutes. To the reaction mixture are added 1N-hydrochloric acid (1 ml) and ethyl acetate. The organic layer brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-triphenylmethylthio-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7:385 mg) as a pale yellow foam. Yield: 88%;.