Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].CCOC=[CH:19][C:20](=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[CH2:29](O)C>>[CH2:25]([O:24][C:22]([C:21]1[CH:29]=[N:14][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[C:20]=1[CH3:19])=[O:23])[CH3:26]
Reactant: CCOC=CC(=O)CC(=O)OCC
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Reaction time: 4 h

Procedure:
[2,6-Dichloro-4-(trifluoromethyl)phenyl]hydrazine (5 g) and ethyl (2-ethoxymethylene)acetoacetate (3.8 g) synthesized according to the method described in J. Chem. Soc. Perkin trans. I, p. 1875 (1988) were added to a mixed solvent of 1 N hydrochloric acid aqueous solution (90 ml) and ethanol (100 ml), and stirred for 4 hours under reflux. After completion of the reaction, the mixture was allowed to cool, ethanol was evaporated, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.83 g) as a yellow oil. MS (ESI) m/z: 367, 369 (M+H)+.
Reaction SMILES: Cl.[S:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7](=[NH:9])[NH2:8].[F:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O.O=[C:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[F:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH3:28])[NH:8][C:7]([C:3]2[S:2][CH:6]=[N:5][N:4]=2)=[N:9]1
Reactant: O=Cc1ccc(F)cc1F
Reactant: N=C(N)c1nncs1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1F
Yield: 41.1 %

Procedure:
1,3,4-thiadiazole-2-carboximidamide hydrochloride (1.43 g, 8.69 mmol) was reacted with 2,4-difluorobenzaldehyde (1.23 g, 8.69 mmol) and ethyl 3-oxobutanoate (1.36 g, 10.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (1.3 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([C:18]1[CH:22]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[F:23])=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)csc1C
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-chloro-2-fluorobenzoyl chloride (30.9 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.95 (t, 3 H) 1.31-1.41 (m, 2 H) 1.57-1.77 (m, 2 H) 2.28-2.34 (m, 3 H) 3.95-4.02 (m, 2 H) 6.37-6.41 (m, 1 H) 6.55-6.68 (m, 1 H) 7.28-7.35 (m, 1 H) 7.48-7.54 (m, 1 H) 7.76-7.80 (m, 1 H); MS (ESI) positive ion 326 (M+H).
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].Cl.NC[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH-:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([N:32](CC)CC)C>>[O:14]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[CH:3][NH:32][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:5](=[O:15])[NH:6]1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: [NH-]S(=O)(=O)c1ccc(CCN)cc1
Reactant: CCN(CC)CC
Agent: Cl
Product: NS(=O)(=O)c1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (507 mg, 2.5 mmol) in N,N-dimethylformate (250 μL) is added 4-aminoethylbenzene sulfonylamide hydrochloride (556 mg, 2.5 mmol) and triethylamine (525 μL). The reaction mixture is shaken at 115° C. for 1.5 hours, then concentrated. Ethyl acetate is added to the solid residue that remained and the solid is recovered by filtration, rinsing with diethyl ether, and drying to yield 660.8 mg of 4-{[(1,3-Dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-methyl}benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=O)=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])[CH:2]([CH3:4])[CH3:3].S(O)(O)(=O)=O.[NH2:23][C:24]1[C:29]([NH2:30])=[C:28]([NH2:31])[N:27]=[CH:26][N:25]=1.O>O1CCOCC1.[OH-].[Na+]>[NH2:31][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[C:29]=1[NH:30][C:10]([C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=1)=[N:23]2
Reactant: Nc1ncnc(N)c1N
Reactant: CC(C)COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)COc1ccc(-c2nc3ncnc(N)c3[nH]2)cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 21 %

Procedure:
A solution of 4-isobutoxy-3-nitrobenzoyl chloride (538 mg, 2.09 mmol) in 1,4-dioxane (2 mL) was dropwise added to a suspension of 4,5,6-triaminopyrimidine sulfate (466 mg, 2.09 mmol) in aqueous 1M sodium hydroxide (4.18 30 mL) under cooling with ice. The resulting mixture was stirred for 4 hours at the same temperature. Water (12 mL) was added to the reaction mixture. The precipitated solid product was collected by filtration, dried in air, and subjected to silica gel column chromatography. The elute using chloroform/methanol (10/1) gave 144 mg (yield 20%) of the desired compound in the form of a yellow powdery product.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]=[C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[S:26][C:27]([C:35]([OH:37])=O)=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH:16]=[CH:15]1.N>CN(C=O)C>[O:13]=[C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[S:26][C:27]([C:35]([NH2:3])=[O:37])=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH:16]=[CH:15]1
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
1,1′-Carbonyidiimidazole (51 mg, 0.32 mmol) was added to the compound of Example 59 (100 mg, 0.29 mmol) in DMF (2 mL). After 15 min aq. ammonia (0.190 mL, 25% solution, 3.0 mmol) was added and the solution stirred at r.t. overnight. The mixture was concentrated in vacuo and azeotroped twice with heptane. The crude product was purified by column chromatography on silica (3% MeOH in DCM) to give the title compound as a white solid (74 mg, 74%). δH (DMSO-d6) 7.87–7.76 (3H, m), 7.75–7.68 (5H, m), 7.64–7.61 (2H, m), 7.54 (1H, d, J 9.6 Hz), 6.69 (1H, d, J 9.6 Hz), 6.25 (2H, br s). LCMS (ES+) RT 2.95 minutes, 347.0 (M+H)+.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[Li]CCCC.[CH:36]([C:39]1[CH:40]=[C:41]([CH:45]([CH3:49])[CH2:46][CH:47]=O)[CH:42]=[CH:43][CH:44]=1)([CH3:38])[CH3:37].O>C1COCC1>[CH:36]([C:39]1[CH:40]=[C:41]([CH:45]([CH3:49])[CH2:46][CH:47]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH:42]=[CH:43][CH:44]=1)([CH3:38])[CH3:37]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Reactant: c1ccc([P+](Cc2ccc3c(c2)OCO3)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)CC=Cc2ccc3c(c2)OCO3)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
A solution of (benzo[d][1,3]dioxol-5-ylmethyl)triphenylphosphonium bromide (4.77 g, 10.0 mmol, 1.0 equiv.) in THF (20 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 6.3 mL, 10.0 mmol, 1.0 equiv.) at 0° C., the dark red suspension was stirred at 0° C. for 10 min. 3-(3-Isopropylphenyl)butanal (1.90 g, 10.0 mmol, 1.0 equiv.) in THF (10 mL) was added, and the mixture was stirred at 0° C.→25° C. for 16 h. After addition of H2O at 25° C., the aqueous layer was extracted with hexanes and MTBE, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexanes/EtOAc 4:1) to yield 2.35 g (75%) of the title compound as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)(=O)C>[C:20]([C:19]1[C:13]2[CH:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Yield: 16.6 %

Procedure:
A solution of 1.0 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran in a mixed solvent of 50 ml of ethyl acetate and 2 ml of acetic acid was vigorously stirred with 1.0 g of 10% palladium on carbon for 20 hours in a hydrogen atmosphere. After the palladium on carbon was filtered out, the filtrate was concentrated and the concentrate was purified by silica gel column chromatography (in n-hexane containing 20% ethyl acetate) to give 0.11 g of 4-t-butyl-5-hydroxy-2-methylbenzofuran as a white crystal (yield 17%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[C@@H:20]2[O:24][C:23](=[O:25])[NH:22][C@H:21]2[CH3:26])[CH:9]=1)([CH3:3])[CH3:2].[H-].[Na+].[F:31][C:32]([F:46])([F:45])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:36]Br>CN(C=O)C.CCOC(C)=O.O>[F:31][C:32]([F:45])([F:46])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:36][N:22]1[C@@H:21]([CH3:26])[C@H:20]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:27][CH3:28])[O:24][C:23]1=[O:25]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1OC(=O)N[C@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 30 mg of trans-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one in 1 mL of DMF was added 8 mg of sodium hydride. The mixture was stirred 10 min at room temperature, and then 32 mg of 3,5-bis(trifluoromethyl)benzyl bromide was added. The mixture was stirred overnight at room temperature, then diluted with 10 mL of EtOAc and 10 mL of water. The phases were separated and the aqueous phase was extracted with 5 mL of EtOAC. The combined organics were washed with 5 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 4 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 620.2 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([C:29](O)=[O:30])[C:25](=[O:32])[N:24]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:29]([C:26]4[C:25](=[O:32])[N:24]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:23]([CH3:22])[C:27]=4[CH3:28])=[O:30])=[CH:3][CH:4]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Temperature: 60 °C
Reaction time: 10 h
Yield: 93.6 %

Procedure:
To a solution of 4-(4-aminophenoxy)-6-methoxyquinolin-7-ol (3.61 g, 12.8 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.85 g, 12.27 mmol) in DMF (50 mL) was added EDCI (2.81 g, 14.66 mmol) and HOAT (0.33 g, 2.4 mmol). The reaction was stirred at 60° C. for 10 hours, cooled to room temperature and diluted with H2O (200 mL). The solid was collected by filtration and dried in vacuo at 60° C. overnight to give the title compound as a white solid (5.7 g, 89.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of (5-bromo-pyridin-3-yl)-methanol (0.5 g, 2.68 mmol) in DCM (10 mL) was added thionyl chloride (0.5 mL). The resulting solution was stirred at room temperature for 2 h. After this time, the reaction mixture was quenched with water and extracted into DCM. The organic extracts were washed with brine filtered and concentrated under reduced pressure to give 3-bromo-5-chloromethyl-pyridine (0.45 g, 82%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][CH2:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].N>N1C=CC=CC=1>[CH2:1]([NH:3][C:4](=[O:5])[O:6][CH2:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[CH2:9][NH:10][C:11]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:17])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(CO)c1cccc(C(F)(F)F)c1
Reactant: CCN=C=O
Agent: N
Solvent: c1ccncc1
Product: CCNC(=O)OCC(CNC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mg (42 μmol) of 4-N,N-dimethylaminopyridine and 66 μl (0.84 mmol) of ethyl isocyanate were added to a solution of 134 mg (0.42 mmol) of the compound of Example 17A in 2.5 ml of pyridine. The mixture was stirred at RT overnight. A further 66 μl of ethyl isocyanate were then added, and the mixture was heated at 50° C. for 24 h. After cooling to RT, 0.5 ml of ammonia solution (35% in water) was added. The volatile components were removed on a rotary evaporator. A little acetonitrile and 1 N hydrochloric acid were added to the residue, and the solution was separated by preparative HPLC [Method 9]. This gave 110 mg (67% of theory) of the title compound.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+:23]>C(O)(=O)C.ClCCl>[N+:1]([CH:4]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:23][C:7](=[O:9])[CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1CCC([N+](=O)[O-])C(c2ccccc2)N1
Temperature: 5 °C

Procedure:
A solution of methyl 4-nitrobutyrate (23g) and benzaldehyde (16ml) in acetic acid (39ml) containing ammonium acetate (12.12g) was heated at reflux under nitrogen for 2h. The reaction mixture was cooled to 5° C., whereby a pale-yellow solid crystallised. This was isolated by filtration, then dissolved in dichloromethane, washed cautiously with saturated aqueous sodium bicarbonate solution (2×), then dried (MgSO4) and concentrated to leave a yellow solid. Recrystallisation from ethyl acetate provided 5-nitro-2-oxo-6-phenylpiperidine (12.5g) as a crystalline, white solid. 1H NMR (CDCl3) δ7.46-7.26 (m), 6.0 (br s), 5.24 (dd, J=1.4, 7.0Hz), 4.70 (m), 2.70-2.50 (m), 2.38-2.24 (m).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].C1O[C@@H]1CO.[N+:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].C(N(CC)CC)C>C1(C(C)C)C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([S:20]([O:5][CH2:4][C@H:2]2[O:3][CH2:1]2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: OCC1CO1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: OC[C@@H]1CO1
Solvent: CC(C)c1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1

Procedure:
To demonstrate that the heterogeneous distillate obtained as described hereinabove may be subsequently employed in the synthesis of aromatic sulfonate derivates of optically active glycidol, the distillate containing 84% (R)-glycidol in cumene was reacted with stoichiometric amounts of 3-nitrobenzene sulfonyl chloride and triethylamine to obtain optically pure (S)-glycidyl 3-nitrobenzene sulfonate as follows: 3-nitrobenzenesulfonyl chloride (10 g) was dissolved in toluene (100 g) and then combined with triethylamine (4.6 g). After cooling the solution to 5° C., the 84% (R)- glycidol distillate (3.96 g) was added. After 2 hours at 5° C. and 2 hours at 25° C., the reaction mixture was washed with water (100 g) to remove the triethylamine hydrochloride salt. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the bulk of the solvent removed under vacuum. On cooling to 0° C., (S)-glycidyl 3-nitrobenzenesulfonate crystallized out of solution. The crystalline derivative (8.2 g; 69% overall yield) was collected by filtration and washed with a small quantity of hexanes. The derivative had a melting point of 57°-59° C. and an optical purity of 96% e.e.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@H]1C#N>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][C@H:23]2[C:32]#[N:33])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: N#C[C@@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@H]2C#N)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidine-2-carbonitrile hydrochloride and isolated as light-yellow solid (11.5 mg, 65%). MS (m/e): 396.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[Cl:15])[CH3:2].[CH:18](OCC)(OCC)[O:19][CH2:20][CH3:21]>C(OC(=O)C)(=O)C>[Cl:15][C:8]1[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=1[C:6](=[O:16])[C:5](=[CH:18][O:19][CH2:20][CH3:21])[C:4]([O:3][CH2:1][CH3:2])=[O:17]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl

Procedure:
In accordance with the above reaction scheme, a solution of 2-chloro-4,5-difluorobenzoic acid (V) in acetonitrile containing a catalytic amount of dimethylformamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride (VI) which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, followed by the addition to ice water and acidification to pH 2.5, giving (2-chloro-4,5-difluorobenzoyl)propanedioic acid diethyl ester (VII). A solution of compound (VII) in p-dioxane and water is heated at reflux, then evaporated and distilled, giving 2-chloro-4,5-difluoro-β-oxobenzenepropanoic acid ethyl ester (VIII). A solution of compound (VIII) and triethyl orthoformate in acetic anhydride is heated at 150° C. for 2 hours, giving 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (IX). Cyclopropylamine is added to a solution of compound (IX) in ethanol, giving 2-chloro-α-[(cyclopropylamino)methylene]-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (X). Compound (X) is reacted with sodium hydride in dry dimethylformamide under an inert atmosphere with heat, giving 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester (XI). Ester (XI) is then refluxed with acid, giving the desired 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XII).
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.C(N)[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1>>[CH2:4]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)[C:3]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CN(C)CCNc1nc2ccc([N+](=O)[O-])cc2s1
Product: O=[N+]([O-])c1ccc2nc(NCc3ccccc3)sc2c1

Procedure:
The title compound was prepared following the procedure for N,N-dimethyl-N′-(6-nitrobenzothiazol-2-yl)-ethane-1,2-diamine, using benzylamine. Modified workup: Solid that had precipitated during course of reaction (amine salt) was filtered; no aqueous workup was conducted. 1H NMR (400 MHz, CDCl3): δ=4.70 (s, 2H), 6.07 (s, br, —NH), 7.33-7.39 (m, 1H), 7.39-7.42 (m, 4H), 7.51 (d, J=8.8 Hz, 1H), 8.21 (dd, J=8.8, 2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 286.03 (100) [MH+]. HPLC: tR=3.47 min (ZQ2000, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:12](Br)[CH3:13].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:15]([CH:12]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:13])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Br)c1nc2sccn2c(=O)c1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
A mixture of 6-bromo-7-(1-bromoethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (3.7 g, 11 mmol) and sodium azide (1.4 g, 22 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 1.5 hour. After diluted with ethyl acetate, the mixture was washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-60% ethyl acetate/hexanes) to give the desired product (2.16 g). LCMS calculated for C8H7BrN5OS (M+H)+: m/z=300.0. Found: 300.0.