Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]([OH:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]([OH:22])[CH3:21]
Reactant: CC(O)c1ccncc1Br
Reactant: OB(O)c1cc2ccccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)c1ccncc1-c1cc2ccccc2o1
Yield: 23.4 %

Procedure:
A mixture of benzofuran-2-boronic acid (178 mg, 1.100 mmol), 1-(3-bromopyridin-4-yl)ethanol (202 mg, 1 mmol), sodium carbonate 2N in water (1 mL, 2.000 mmol), PdCl2(dppf).CH2Cl2 adduct (40.8 mg, 0.050 mmol) in DMF (5 mL) was heated to 100° C. for 3 hrs. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (25M column, 20-60% EtOAc/heptane, v/v) giving the title compound (56 mg, 23%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.56 (d, J=6.4 Hz, 3H), 5.53 (q, J=6.4 Hz, 1H), 7.03 (d, J=0.7 Hz, 1H), 7.31 (td, J=7.3, 0.9 Hz, 1H), 7.38 (td, J=8.0, 1.2 Hz, 1H), 7.54 (dd, J=8.2, 0.7 Hz, 1H), 7.66 (dd, J=7.6, 0.6 Hz, 1H), 7.85 (d, J=5.4 Hz, 1H), 8.63 (bs, 1H), 8.91 (bs, 1H). LC-MS (M+1) 240.2, t=1.25 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:14](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:14])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
6-Chloro-1Hbenzo[d][1,3]oxazine-2,4-dione (22.88 g, 116 mmol) was dissolved in dimethylformamide (150 mL), and sodium carbonate (14.73 g, 139 mmol) was added. Methyl iodide (10.86 mL, 174 mmol) was then added dropwise. The reaction was stirred at room temperature overnight. Water (150 mL) was then added, and the mixture was stirred for 1 hour. The solid was collected by filtration. The impure solid was sonicated in methyl-tert-butyl ether for several minutes, and then collected by filtration yielding the product as a white solid (19.38 g, 79%). 1HNMR (300 MHz, DMSO-d6) δ 3.45 (s, 3H), 7.47 (d, 1H), 7.89 (dd, 1H), 7.94 (d, 1H).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[NH2:25][C@@H:24]1[C:23](=[O:26])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[CH:18][CH2:19][S:20][C@H:21]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.17 h

Procedure:
A total of 0.380 g of 7β-amino-ceph-3-em-4-carboxylic acid diphenylmethyl ester is treated with 2 ml of anisole and 8 ml of absolute trifluoroacetic acid, the clear solution is allowed to stand for 10 minutes at room temperature and then diluted with about 20 ml of absolute toluene. The mixture is evaporated under reduced pressure; the residue is taken twice to dryness with toluene and then suspended in 5 ml of methanol, 5 ml of diethyl ether and 0.5 ml of water. The pH-value of the suspension is adjusted to 3.5 by adding dropwise a 5% solution of triethylamine in methanol; the reaction mixture is allowed to stand for 30 minutes in the ice-bath and the fine precipitate is filtered off with the use of a suitable glass suction filter. The slightly beige-coloured filter residue is washed with a mixture of methanol and methylene chloride, then with diethyl ether and dried at 35° under reduced pressure. The 7β-amino-ceph-3-em-4-carboxylic acid, which is obtained as a fine microcrystalline powder, decomposes at 215° C.; thin-layer chromatogram (silica gel: development with iodine): Rf=0.12 (system: n-butanol/acetic acid/water 67:10:23), Rf=0.28 (system: n-butanol/pyridine/acetic acid/water 40:24:6:30) and Rf=0.21 (system: ethyl acetate/n-butanol/pyridine/acetic acid/water 42:21:21:6:10); infrared absorption spectrum (in mineral oil): characteristic bands at 3.12μ, 3.80μ, 4.12μ (shoulder), 4.92μ, 5.54μ, 6.05μ (shoulder), 6.19μ, 6.55μ, 7.05μ, 7.42μ, 8.23μ, 8.79μ, 9.55μ, 12.08μ, 12.69μ and 13.04μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18]C(Cl)Cl.Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]([C:6]1[C:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1cc2cccc(OC)c2o1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C=O)ccc(OC)c2o1
Reaction time: 0.5 h

Procedure:
Ethyl 7-methoxybenzofuran-2-carboxylate (10 g) was dissolved in anhydrous methylene chloride (200 ml), to which were dropwise added dichloromethyl methyl ether (8.2 ml) and titanium tetrachloride (10 ml) with cooling with ice, and directly stirred for 30 minutes. After having been restored to be at room temperature, the mixture was stirred for further 1.5 hours. Then, an aqueous HCl (1 mol/liter) solution was dropwise added thereto to decompose the remaining titanium tetrachloride, and thereafter the mixture was extracted with chloroform. The extract was washed with an aqueous NaOH (1 mol/liter) solution and a saturated saline solution, and dried over sodium sulfate, and the solvent was thereafter evaporated. The residue was suspended in ether, and taken out therefrom through filtration to obtain Compound IIbz-s (8.9 g, 79%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13].[H-].[Na+].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:30]([F:33])([F:32])[F:31].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:18]1[C:19]([C:30]([F:32])([F:33])[F:31])=[CH:20][C:21]([N+:27]([O-:29])=[O:28])=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:10](=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(=O)Nc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(c1ccc(Cl)cc1Cl)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
Ethyl 2,4-dichlorophenylcarbamate (1.206 g) was dissolved in tetrahydrofuran (15 ml), and to the solution were added sodium hydride (206.0 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (1.161 g). The reaction mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=5:1) to give the title compound (1.4490 g, 72%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][C:21]=1[CH:22]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][C:21]=1[CH2:22][NH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]1[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(-n2cnnn2)cc1C=O
Reactant: COC(=O)[C@@H]1CC[C@H](N)[C@H]1c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CC[C@H](NCc2cc(-n3cnnn3)ccc2OC)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 100 mg of amine from Example 62 in 2 mL of methanol was added 0.040 mL of acetic acid, 1 g of 3A sieves and 90 mg 2-methoxy-5-(1-tetrazolyl)benzaldehyde (prepared according to the procedures given in PCT International Application WO 95/08549, published 30 Mar. 1995; p. 33). The reaction was stirred at room temperature for 30 min and then 0.080 g of sodium cyanoborohydride was added. The reaction was stirred further for 20 h and was then poured into water, made basic with 2N NaOH and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 0 to 3% methanol in methylene chloride to obtain 100 mg of title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]([N:27]1[CH2:30][CH:29](OS(C)(=O)=O)[CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:29]2[CH2:30][N:27]([CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1

Procedure:
The title compound is synthesized by condensation of piperazine-1-carboxylic acid tert-butyl ester and Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (commercially available from Fluorochem Ltd) analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=408.3; HPLC: AtRet=3.84 min.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][C:16]([CH3:21])([CH3:20])[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][C:16]([CH3:21])([CH3:20])[CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2CCOC(C)(C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCOC(C)(C)C3)n(C)c2n1
Temperature: 120 °C
Yield: 65.1 %

Procedure:
A mixture of 2-chloro-8-[2-(2,2-dimethylmorpholin-4-yl)ethyl]-9-methyl-6-morpholin-4-yl-9H-purine (57 mg, 0.14 mmol), 2-ethylbenzimidazole (23 mg, 0.16 mmol), Pd2(dba)3 (3.3 mg, 2.5 mol %), Xphos (6.9 mg, 10 mol %) and Cs2CO3 (71 mg, 0.27 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 120° C., for 16 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-5% MeOH in DCM) to give 392 (46 mg, 63%) as a pale yellow solid. LCMS: (Method G): RT 6.31 min; [M+H]+ 505.3. 1H NMR (400 MHz, CHCl3-d): δ 8.02-7.97 (m, 1 H), 7.78-7.72 (m, 1 H), 7.27-7.22 (m, 2 H), 4.48-4.20 (m, 4 H), 3.89-3.83 (m, 4 H), 3.79 (s, 3 H), 3.77-3.55 (m, 2 H), 3.35 (q, J=7.5 Hz, 2 H), 3.12-2.97 (m, 2 H), 2.91-2.76 (m, 2 H), 2.57-2.43 (m, 2 H), 2.42-2.29 (m, 2 H), 1.44 (t, J=7.5 Hz, 3 H), 1.26 (s, 6 H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[CH:6][C:5]=1[OH:29].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[CH:6][C:5]=1[O:29][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Yield: 82.3 %

Procedure:
A mixture of 2.5 g (5.95 mmol) of 2-hydroxy-5-(octadecyloxy)benzoic acid methyl ester, 0.78 ml (6.54 mmol) of benzyl bromide and 4.1 g (29.8 mmol) of potassium carbonate in 100 ml of acetone and 10 ml of DMF was stirred at reflux under an argon atmosphere for 24 hours. The solvent was removed at reduced pressure and the residue was treated with water. The product was extracted with ethyl ether and the dried extract was concentrated to a solid which was purified by HPLC using 5% ethyl acetate-hexane to give 2.5 g (82% yield, mp 52°-54°) of 5-(octadecyloxy)-2-(phenylmethoxy)benzoic acid methyl ester.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1/[CH:21]=[CH:22]/[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>O1CCCC1>[Cl:8][CH2:9][C:10]([N:26]1[CH2:27][CH2:28][CH:23](/[CH:22]=[CH:21]/[C:15]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])[CH2:24][CH2:25]1)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1/C=C/C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1/C=C/C1CCN(C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under ice cooling, 6.77 ml of triethylamine and 3.87 ml of chloroacetyl chloride were added to a solution of 9.96 g of 4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine in 150 ml of tetrahydrofuran. After stirring at ambient temperature for 20 minutes, 200 ml of water was added to the mixture. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether. The combined organic layer was and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate). The collected crystals were washed with diisopropyl ether-hexane and dried under reduced pressure to give 10.69 g of 1-(chloroacetyl)-4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine.
Reaction SMILES: [CH2:1]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:16]([NH2:18])[CH3:17]>C(O)C>[CH2:16]([NH:18][CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:17]
Reactant: CCN
Reactant: C=C(CCc1ccccc1)C(=O)OCC
Solvent: CCO
Product: CCNCC(CCc1ccccc1)C(=O)OCC
Temperature: 105 °C

Procedure:
17 g of ethyl 2-methylene-4-phenylbutyrate (Example 1.4) and 3.6 g of ethylamine were dissolved in 50 ml of absolute ethanol and heated under 40 atmospheres of nitrogen at 105° C. for 20 hours. After the solvent had been removed, the residue was taken up in 5 normal hydrochloric acid, extracted with ether and the aqueous solution was adjusted to pH 9.5 with potassium carbonate, again extracted with ether, and this was dried with potassium carbonate and evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:11]1([C:17]2[S:18][CH:19]=[C:20]([CH2:22]Cl)[N:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.[I-].[K+]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:22][C:20]1[N:21]=[C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCc2csc(-c3ccccc3)n2)c1
Yield: 81.4 %

Procedure:
To a solution of 6.5 g (0.046 mol) of 3-nitrophenol in 300 ml of acetone are added 11.6 g (0.047 mol) of 2-phenyl-4-chloromethylthiazole hydrochloride2, 15 g (0.046 mol) of cesium carbonate, and 0.5 g of potassium iodide and the slurry is heated to reflux for 20 hours. The hot mixture is filtered and the filtrate is concentrated in vacuo to obtain 11.7 g (82%) crystalline residue. A part is recrystallized from ethyl acetate/pentane to give crystals, m.p. 112°-114° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:38][C:39](O)=[O:40])[N:24]=[C:25]([O:26][C@@H:27]4[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]4[OH:29])[C:18]=23)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:43][NH:44][CH3:45].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:38][C:39](=[O:40])[N:44]([CH3:45])[CH3:43])[N:24]=[C:25]([O:26][C@@H:27]4[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]4[OH:29])[C:18]=23)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)Cn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(OCc4ccccc4)cc3)ccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(OCc4ccccc4)cc3)ccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of 4-[2-(4-benzyloxyphenyl)ethyl]-1-carboxymethyl-3-(β-D-glucopyranosyloxy)-1H-pyrazolo-[3,4-b]pyridine (50 mg) in N,N-dimethylformamide (2 mL) were added dimethylamine hydrochloride (9 mg), 1-hydroxy-benzotriazole (14 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (34 mg) and triethylamine (0.049 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-8/1) to give 4-[2-(4-benzyloxyphenyl)ethyl]-3-(β-D-glucopyranosyloxy)-1-(N,N-dimethylcarbamoylmethyl)-1H-pyrazolo[3,4-b]pyridine (27 mg). This material was dissolved in methanol (4 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (20 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([N:12]3[CH2:15][C:14]([F:17])([F:16])[CH2:13]3)=[CH:10][N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:21][C:22]1([CH2:26][C:27]([NH2:29])=[O:28])[CH2:25][O:24][CH2:23]1>>[NH2:29][C:27](=[O:28])[CH2:26][C:22]1([NH:21][C:18]([C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:11]([N:12]3[CH2:13][C:14]([F:16])([F:17])[CH2:15]3)=[CH:10][N:9]=2)=[O:20])[CH2:25][O:24][CH2:23]1
Reactant: O=C(O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Reactant: NC(=O)CC1(N)COC1
Product: NC(=O)CC1(NC(=O)c2cc(OCC3CC3)c(N3CC(F)(F)C3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 4-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 53e) and 2-(3-Amino-oxetan-3-yl)-acetamide (CAN 1417638-25-5) as starting material and isolated (31 mg, 36%); MS (ESI, m/z): 397.6 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=CCc1ccc(Br)cc1
Temperature: -78 °C

Procedure:
To a cold solution (−78° C.) of 15 g (62 mmol) of ethyl (4-bromophenyl)acetate (Compound A) in 150 ml of CH2Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at −78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5](C(Cl)=O)[C:6]([CH3:9])=[CH:7][CH:8]=1.[H-].C([O:18][Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].O>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:18])=[CH:5][CH:4]=1
Reactant: Cc1ccc(CBr)cc1C(=O)Cl
Reactant: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of the 4-bromomethyltoluoyl chloride (3.48 g. 15 mmol) in dry tetrahydrofuran (15 ml) was added dropwise to a solution of lithium tri-t-butoxyaluminium hydride (3.81 g, 15 mmol) in dry tetrahydrofuran (50 ml) at -70° C., stirred for 2 h, allowed to warm to room temperature and stirred for a further 1 h. The reaction was poured into water, filtered, extracted with ethyl acetate, dried (magnesium sulphate), and evaporated in vacuo to yield 4-bromomethylbenzaldehyde (1.31 g, 44%).
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[S-:14][C:15]#[N:16].[K+].BrBr.O>C(O)(=O)C>[NH2:16][C:15]1[S:14][C:12]2[CH:13]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: N#C[S-]
Reactant: CCCCCCc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCc1ccc2nc(N)sc2c1
Yield: 49.9 %

Procedure:
In a 2 liter-reaction vessel, 50.0 g(0.28M) of p-hexylaniline, 54.8 g (0.56M) of potassium thiocyanate and 400 ml of acetic acid were placed and cooled below 10° C. To the mixture, a solution f 45.0 g of bromine in 135 ml of acetic acid was added dropwise in 40 minutes below 10° C. under strong stirring, followed by reaction for 1.5 hours below 10° C. After the reaction, 500 ml of water was poured into the reaction mixture, followed by heating to dissolve the resultant precipitate. The resultant solution was filtered when hot. Ammonia water was added to the filtrate until the resultant solution became basic, followed by cooling with ice to precipitate a crystal. The crystal was recovered by filtration, followed by washing and drying to obtain a crude product. The crude product was recrystallized from a mixture solvent of n-hexane/benzene (1/1) to obtain 33.0 g of 2-amino-6-hexylbenzothiazole (Yield: 49.9%).