Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(N(CC)CC)C.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[OH:39])[N:23]=1>C(Cl)Cl>[F:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])[N:23]=[C:22]2[N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Reaction time: 1 h

Procedure:
At 0° C. under an N2 atmosphere, a solution of tert-butyl(R)-pyrrolidin-3-ylcarbamate (264 mg, 1.42 mmol) and triethylamine (0.33 mL, 2.36 mmol) in CH2Cl2 was rapidly added to a stirring solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (325 mg, 1.18 mmol) in 15 mL CH2Cl2. The reaction mixture was stirred for 1 h before it was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 yielded tert-butyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 425.5 (M+H)+ at 2.74 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[S:14])=[CH:8][CH:7]=1)=[O:5])C.Br[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=O>C(O)C>[CH3:1][O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[S:14][C:25]3[CH2:26][CH2:27][CH2:28][CH:23]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:17][CH:18]=4)[C:24]=3[N:15]=2)=[CH:8][CH:7]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: CCOC(=O)c1ccc(NC(N)=S)cc1
Solvent: CCO
Product: COC(=O)c1ccc(Nc2nc3c(s2)CCCC3c2ccccc2)cc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A suspension of 1-(4-ethoxycarbonylphenyl)-2-thiourea (105 mg, 0.5 mmol) and of 2-bromo-6-phenyl-cyclohexanone (253.1 mg, 1.00 mmol) in ethanol (4 mL) was heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The product was precipitated with diethyl ether and heptane as an oil, which was purified on silica gel with dichloromethane as eluent to yield the title compound (120 mg, 63%) as a pale-yellow solid. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.42 (s, 1H), 7.77 (d, 2H), 7.50 (d, 2H), 7.28 (t, 2H), 7.27 (t, 1H), 7.12 (d, 2H), 4.23 (q, 2H), 4.06 (m, 1H), 2.73 (m, 2H), 2.12 (m, 1H), 1.70-1.90 (m, 3H), 1.27 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[NH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17](=[O:19])[CH3:18].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:17]([C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[NH:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:7])(=[O:19])[CH3:18]
Reactant: O=Cc1nccs1
Reactant: COc1ccc(C(C)=O)c(N)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2nccs2)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 2-thiazolecarboxaldehyde (500 mg, 3.87 mmol) in 35 mL of pyridine, 1-(2-amino-4-methoxyphenyl)ethanone (640 mg, 3.87 mmol) was added and the solution was cooled to −30° C. before POCl3 (750 μl, 8.13 mmol) was added drop wise. The reaction mixture was stirred at −10° C. for 1 hour and then at room temperature for 2 hours. The mixture was concentrated under vacuum and the residue was triturated with NaHCO3 to pH 7. The precipitate was filtrated, washed with water and dried. The amide was pure enough for the next step without purification (972 mg, 91%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[NH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([NH:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CC(C)(CN)CO
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Product: Cn1ncc2c(NCC(C)(C)CO)cc(-c3cccc4[nH]ncc34)nc21

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (70 mg) and 3-amino-2,2-dimethyl-1-propanol (3 equiv.) were heated in microwave at 170° C. for two hours. Volatiles were removed in vacuo; the residue was purified by prep HPLC to give 114 as a white solid (55 mg). NMR (CDCl3): 1.11 (6H, s), 1.72 (1H, br, OH), 3.42 (2H, d), 3.64 (2H, d), 4.19 (3H, s), 5.70 (1H, br, NH), 6.78 (1H, s), 7.49-7.58 (2H, m), 7.71 (1H, d), 7.94 (1H, s), 8.82 (1H, s), 10.10 (1H, br, NH). MS: MH+ 351
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: 32 °C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
Add a solution of 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (600 mg, 2.15 mmol) dropwise to a mixture of Dess-Martin periodinane (1.06 g, 2.5 mmol) in dichloromethane (6.5 mL). Stir the exothermic reaction mixture (32° C.) for 20 min without additional heat. To the reaction mixture add diethyl ether (12 mL) and saturated aqueous sodium bicarbonate (12 mL). Separate the layers and wash the aqueous layer with diethyl ether (2×12 mL). Combine the organics and wash with saturated aqueous sodium bicarbonate (12 mL), saturated aqueous sodium chloride (12 mL), dry (magnesium sulfate), concentrate, and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound as an oil (0.54 g, 91%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=O)[N:9]=[CH:8]2)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[Cl:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2[nH]c(=O)ncc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Temperature: 105 °C
Yield: 74 %

Procedure:
In a 100 mL flask equipped with a reflux condenser, 6-acetoxyquinazolone 3.06 g (15 mmol), phosphoryl chloride (35 mL) were added. The mixture was refluxed at 105° C. for 2 h, and then was taken out and poured into 150 mL of ice water carefully. A large amount of solid was deposited slowly, which was filtered, dried, and identified as the title compound. Yield: 74%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[C:26]4[NH:30][N:29]=[CH:28][CH:27]=4)=[O:18])[CH2:15]3)[CH2:10]2)[N:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[C:26]4[CH:27]=[CH:28][N:29]([CH3:33])[N:30]=4)=[O:18])[CH2:15]3)[CH2:10]2)[N:3]=1
Reactant: CI
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4ccn[nH]4)C[C@@H]32)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4ccn(C)n4)C[C@@H]32)n1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
A solution of the (1R,6S)-8-(4,6-dimethylpyrimidin-2-yl)-3-{[5-fluoro-2-(1H-pyrazol-3-yl)phenyl]carbonyl}-3,8-diazabicyclo[4.2.0]octane (Example 171) in DMF was treated with NaH at RT and stirred for 15 minutes until no more gas evolution occurred. The solution was cooled to −5° C. and then treated with MeI. Reaction allowed to stir for 20 min and then worked up by the addition of water followed by multiple extractions with EtOAc. Purified on 12 g SiO2 with 0-3.5% NH3 MeOH in CH2Cl2. MS (ESI) mass calcd. for C23H25FN6O, 420.5; m/z found, 421.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH2:4]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[F:27][C:2]([F:26])([F:1])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cc(C4=CCC(C(F)(F)F)CC4)ncn3)cccc2s1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(C4=CCC(C(F)(F)F)CC4)ncn3)cccc2s1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[6-(4-trifluoromethyl-cyclohex-1-enyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, Example 1(e), (85 mg, 0.22 mmol) in toluene was added acetic anhydride (82 μL, 0.86 mmol). The mixture was heated at 90° C. with stirring for 1 h. The reaction mixture was allowed to cool to room temperature and evaporated in vacuo to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 435 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH2:11][NH:10][CH2:9]1.[Na]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:10]1[CH2:9][CH:8]=[C:13]([C:14]([OH:16])=[O:15])[CH2:12][CH2:11]1
Reactant: O=C(O)C1=CCNCC1
Reactant: Clc1ncccn1
Agent: [Na]
Solvent: O
Product: O=C(O)C1=CCN(c2ncccn2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloropyrimidine (0.570 g, 4.98 mmol), and isoguvacine, sodium salt (1.2 g, 8.2 mmol) in water (7 mL) was heated to 90° C. and stirred for 4 hour. Additional isoguvacine, sodium salt (0.52 g, 3.3 mmol) was then added and stirred overnight. The mixture was diluted with water and extracted with CH2Cl2. The aqueous layer was acidified with conc HCl (pH˜3) and extracted with CHCl3. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid a white solid (0.564 g, 2.75 mmol, 55%): 1H NMR (300 MHz, CD3OD) δ 8.43 (d, J=4.8 Hz, 2 H), 7.02 (sept, J=1.7 Hz, 1H), 6.74 (t, J=4.8 Hz, 1H), 4.39 (q, J=3.0 Hz, 2H), 3.97 (t, J=5.8 Hz, 2H), 2.49 (m, 2H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:16])([F:15])[C:10](=[O:14])[CH2:11][C:12]#[N:13]>C(OCC)C>[F:8][C:9]([F:16])([F:15])[C:10]([O:14][CH3:1])=[CH:11][C:12]#[N:13]
Reactant: N#CCC(=O)C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=CC#N)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(Trimethylsilyl)diazomethane (21 mL, 2M in diethyl ether) was added dropwise to a solution of 4,4,4-trifluoro-3-oxobutanenitrile (3.79 g, 26 mmol) in anhydrous diethyl ether (25 mL) previously cooled to 0° C. The resulting mixture was allowed to slowly warm to room temperatureand stirred overnight. The solvent was removed under reduced pressure to give 4,4,4-trifluoro-3-methoxybut-2-enenitrile, which was directly used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.00 (s, 1H), 4.16 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])/[NH:7]1.C(N(CC)CC)C.[C:30]1([CH2:36][S:37](Cl)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:30]1([CH2:36][S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]2[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]3[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=3)=[O:13])/[NH:7]2)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCCNS(=O)(=O)Cc3ccccc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-(4-amino-butyl)-imidazolidin-(2E)-ylidene]-amide (Intermediate T) (0.023 g, 0.071 mmol) in DMF (2 ml) is added triethylamine (0.010 ml, 0.071 mmol) followed by alpha-toluenesulfonyl chloride (0.014 g, 0.071 mmol). The suspension is stirred at room temperature for 30 minutes. Purification by reverse phase chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA) followed by catch and release resin (SCX-2) eluting with MeOH and 7M NH3 in MeOH gives the title compound as a yellow solid; [M+H]+ 481.0
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:18])[N:10](C(OC(C)(C)C)=O)[C:3]=12.[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:20]=[O:21]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:22]([NH:19][C:20]([N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]2[NH:10][C:9]1=[O:18])=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cc1ccnc2[nH]c(=O)n(C(=O)OC(C)(C)C)c12
Reactant: CCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCNC(=O)n1c(=O)[nH]c2c(C)ccnc21

Procedure:
Analogously to Example 1, tert-butyl 7-methyl-2-oxo-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (300 mg, 1.2 mmol), 1-isocyanatohexane (183.8 mg, 1.44 mmol) and 4-dimethylaminopyridine (14.7 mg, 0.12 mmol) were reacted in toluene. Yield: 8 mg (2%), M+H+: 277.16.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([C:35]2[C:30]([O:29][CH3:28])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1Cl
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1ccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c(Cl)n1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a pink solid (yield=40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:18]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N+:11]2([O-])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([CH:18]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NCC[N+]2([O-])CCOCC2)ncc1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NCCN2CCOCC2)ncc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The 4-[2-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine-N-oxide (78 mg, 0.14 mmol) obtained in Example 349 was dissolved in a mixed solvent of acetic acid (2.0 ml) and water (2.0 ml). The resulting mixture was heated to 60° C. Iron powder (40 mg, 0.72 mmol) was added and the mixture was stirred for 30 minutes. After cooling, the reaction mixture was poured into a saturated aqueous solution of potassium carbonate, followed by extraction with ethyl acetate (60 ml). The solution was washed with brine, dried and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% methanol/chloroform solution), whereby the title compound (30 mg, 40%) was obtained.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[NH2:2].CS(O)(=O)=[O:15].OO>>[C:1]([NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([O:11][OH:15])=[O:10])(=[O:3])[NH2:2]
Reactant: CS(=O)(=O)O
Reactant: NC(=O)NC(=O)CCCC(=O)O
Agent: OO
Product: NC(=O)NC(=O)CCCC(=O)OO

Procedure:
11.3 g (0.065 mol) of N-carbamoylglutaramic acid, 21 g of methanesulfonic acid and 7.8 g (0.2 mol) of hydrogen peroxide (85% strength by weight) are reacted and worked up as described in Example 3.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:13]=1)=[N+:7]([O-])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].O=P(Cl)(Cl)[Cl:16].[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:16][C:8]1[N:7]=[C:6]2[N:13]=[C:3]([CH2:1][CH3:2])[NH:4][C:5]2=[C:10]([CH3:11])[CH:9]=1
Reactant: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2nc(Cl)cc(C)c2[nH]1
Temperature: 80 °C

Procedure:
A mixture of the N-oxide (29.75 g, 0.168 mol), CHCl3 (25 mL) and POCl3 (160 mL) was heated to 80° C. for 1 hours. After pouring over ice, the mixture was neutralized by careful addition of NH4OH and extracted with EtOAc. Concentration gave 23.8 g of 5-chloro-2-ethyl-7-methylimidazo[4,5-b]pyridine as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)=[CH:12][C:11]=1[OH:33])C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:17]2[CH2:22][C:21]([CH3:23])([CH3:24])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)=[CH:12][C:11]=1[O:33][CH2:6][C:5]([O:4][CH2:3][CH3:2])=[O:7]
Reactant: CC(=O)OCCBr
Reactant: CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)ccc1C
Temperature: 100 °C
Yield: 99 %

Procedure:
Bromoethylacetate (187 mg, 1.12 mmol), compound 41 (150 mg, 0.449 mmol), and K2CO3 (185 mg, 1.34 mmol) were combined with dry acetone (5 mL) in a sealed microwave vessel. The mixture was heated at 100° C. for 20 minutes in a Personal Chemistry Emrys Optimizer microwave. The reaction was allowed to cool to room temperature and the solids filtered. The solids were rinsed twice with acetone and the solvent was removed in vacuuo to give 187 mg (99%) of compound 42. The crude material was used without additional purification. 1H NMR (400 MHz, CDCl3): δ 0.88 (s, 6H), 0.91 (s, 6H), 1.20-1.25 (m, 5H), 1.75 (s, 2H), 1.90 (s, 2H), 2.23 (s, 3H), 4.22 (m, 3H), 4.46 (s, 2H), 6.73 (d, J=8.3 Hz, 1H), 6.75-7.05 (m, 2H), 7.09-7.46 (m, 5H).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:44])=[C:20]([CH:43]=1)[CH2:21][N:22]1[CH2:26][CH2:25][CH:24]([NH:27][S:28]([C:31]2[S:32][C:33]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)(=[O:30])=[O:29])[C:23]1=[O:42])#[N:15]>CN(C=O)C.CCOC(C)=O>[C:6]([Si:10]([CH3:13])([CH3:12])[O:44][C:19]1[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:43][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]2[S:32][C:33]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)(=[O:30])=[O:29])[C:23]1=[O:42])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(O)c(CN2CCC(NS(=O)(=O)c3ccc(-c4cccnc4)s3)C2=O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C#N)cc1CN1CC[C@H](NS(=O)(=O)c2ccc(-c3cccnc3)s2)C1=O
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Imidazole (0.094 g, 1.37 mol) and t-butyldimethylchlorosilane (0.099 g, 0.66 mmol) are added to a solution of 5-pyridin-3-yl-thiophene-2-sulfonic acid {1-[5-cyano-2-hydroxy-benzyl]-2-oxo-pyrrolidin-3-yl}-amide (0.25 g, 0.55 mmol) in 10 mL of DMF. The resulting mixture is stirred overnight, and then diluted with EtOAc and washed with saturated NaHCO3 (aq) and brine. The organic layer is dried over MgSO4, filtered and concentrated. The product is purified by column chromatography eluting with 3% MeOH/CH2Cl2 to give a brown oil (0.236 g, 0.41 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:19].[O:20]([NH2:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[CH3:21][O:20][N:22]=[CH:17][C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:10]#[C:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:12]=1
Reactant: CON
Reactant: O=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Yield: 80 %

Procedure:
Prepare in a similar manner as described in EXAMPLE 6 using 5-(3,4-difluorophenylethynyl)-pyridine-3-carbaldehyde, (prepared essentially as described in EXAMPLE 101), (0.28 g, 1.15 mmol), methoxylamine hydrochloride (0.77 g, 9.21 mmol) and potassium carbonate (0.80 g, 5.76 mmol) to give the title compound (0.28 g, 80%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:21]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:43])([O:38][Si](C)(C)C)[CH3:37])=[CH:32][CH:31]=2)=[C:26]([CH3:44])[CH:25]=1)[CH2:22][CH3:23])[CH3:20].C(OCC)(=[O:62])C>O1CCCC1>[CH2:19]([C:21]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@H:51]([OH:62])[CH2:52][CH2:53][C:54]([OH:55])=[O:56])=[C:47]([CH3:59])[CH:46]=1)([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])([CH3:37])[CH3:43])=[CH:32][CH:31]=2)=[C:26]([CH3:44])[CH:25]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CCOC(C)=O
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2ccc(C(C)(C)O[Si](C)(C)C)cc2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OC[C@H](O)CCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(C)(C)O)cc2)c(C)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.1 mL, 0.1 mmol) was added to a solution of (R)-5-(4-{1-ethyl-1-[2-methyl-4′-(1-methyl-1-trimethylsilanyloxy-ethyl)-biphenyl-4-yl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(4); 16 mg, 0.028 mmol) in tetrahydrofuran (0.1 mL) at room temperature, and the mixture was stirred at 75° C. for two hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with a potassium bisulfate aqueous solution and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol=10/1, developed three times) to give the title compound (11.3 mg, 78%).