Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:47])[C@:10]3([C:18]4([CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]4)[N:17]4[C@@H:12]([C:13](=[O:38])[O:14][C@@H:15]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C@H:16]4[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:11]3[C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=3[F:46])[C:5]2=[CH:4][CH:3]=1.[NH2:48][C@H:49]1[CH2:54][CH2:53][C@H:52]([CH2:55][OH:56])[CH2:51][CH2:50]1>>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:47])[C:10]3([C@@H:11]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=4[F:46])[C@H:12]([C:13]([NH:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([CH2:55][OH:56])[CH2:51][CH2:50]4)=[O:38])[N:17]([C@H:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:15]([OH:14])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:18]43[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]4)[C:5]2=[CH:4][CH:3]=1
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cccc(Cl)c1F)[C@@]21C(=O)Nc2nc(Cl)ccc21
Reactant: N[C@H]1CC[C@H](CO)CC1
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)N[C@H]1CC[C@H](CO)CC1)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2nc(Cl)ccc21

Procedure:
The compound (260 mg, 0.39 mmol) obtained in Step 1 above and (trans-4-aminocyclohexyl)methanol (100 mg, 0.77 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 1 to give 260 mg (83%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])=[N+:12]=[N-:13]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:20])=[N+:12]=[N-:13]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: [N-]=[N+]=NCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCCCCN=[N+]=[N-])C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (6.31 g, 43.8 mmol) and 4-dimethylaminopyridine (5.60 g, 45.9 mmol) in 100 ml of CH2Cl2 was added dropwise a solution of crude 6-azidohexanoic chloride (7.32 g, 41.7 mmol) in 30 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr then at room temperature for 1 hr. The solution was washed with 0.5N aqueous HCl (100 ml), water (100 ml) followed by brine (100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 5-(6-azidohexanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light red oil (12.0 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20]C)[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(OC)ccc2C)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(Oc2cc(O)ccc2C)cc1C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
The compound of 3-[4-(5-Methoxy-2-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (1.02 g, 3.10 mmol) is dissolved in DCM (15 mL) under nitrogen at −78° C., and BBr3 (1M, CH2Cl2) (4.64 mL, 4.64 mmol) is added. The mixture is stirred at that temperature for 10 minutes and the bath is removed. The mixture is stirred at rt for 2 h, and water is added. The mixture is neutralized to pH=7 with NaOH (10%). The mixture is extracted with DCM. The organic layer is dried with Na2SO4 and filtered, and then the solvent is evaporated in vacuo. Purification by flash chromatography by eluting with hexane:ethyl acetate 5:1 to afford the title compound (0.48 g, 50%). Rf=0.13 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.26 (t, 3H, J=7.3 Hz), 2.16 (s, 3H), 2.26 (s, 3H), 2.57 (t, 2H, J=7.3 Hz), 2.89 (t, 2H, J=7.5 Hz), 4.15 (q, 2H, J=7.3 Hz), 6.44 (d, 1H, J=2.4 Hz), 6.58 (dd, 1H, J=2.4, 8.1 Hz), 6.68 (dd, 1H, J=2.4, 8.3 Hz), 6.75 (d, 1H, J=2.2 Hz), 6.92 (s, 1H), 7.04 (t, 2H, J=8.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20](O)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20]([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2ccnc(Cl)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3ccnc(Cl)c3)n(-c3cccc(Cl)c3)n2)CCN1

Procedure:
100 mg (0.30 mmol) of the compound of Example 69A is reacted analogously to the synthesis of the compound of Example 4 with 32 mg (0.32 mmol) of 2-oxopiperazine. 111 mg (890% of theory) of the title compound is obtained.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].[CH3:11]I>CO>[CH3:11][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: CI
Reactant: Oc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
2-Mercaptophenol (0.80 mL, 7.9 mmol) was added to a solution of sodium hydroxide (0.290 g, 7.2 mmol) in methanol (5.0 mL). The resulting light green solution was stirred for 30 minutes before methyl iodide (0.45 mL, 7.2 mmol) was added carefully over 1 minute. The reaction was stirred at ambient temperature for 2 hours, and was evaporated to dryness. The residue was partitioned between ether and water. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to yield an oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.49 (dd, J=7.6 Hz, J′=1.6 Hz, 1H), 7.25 (m, 1H), 6.98 (dd, J=8.2 Hz, J′=1.4 Hz, 1H), 6.88 (td, J=7.4 Hz, J′=1.3 Hz, 1H), 6.65 (bs, 1H), 2.33 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N:13]([O-])=O.[Na+].[ClH:17]>O>[ClH:17].[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][NH2:13])=[CH:6][CH:5]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
A suspension of p-trifluoromethoxyaniline (5.0 g, 28 mmol) in 33 mL of concentrated HCl was diazotized at 0°-10° C. with a solution of sodium nitrite (2.0 g, 29 mmol) in H2O (17 mL). After stirring for 15 minutes at -5° C., the turbid solution was made clear by the addition of a few drops of water. A solution of stannous chloride (12.6 g, 56 mmol) in concentrated HCl (11 mL) was added in one portion. The mixture was stirred for 3 hours (with the ice bath removed after 1 hour), basified with 50% NaOH and extracted with EtOAc (2×). The organic phase was washed with 1N NaOH and brine, dried (KOH pellets) and acidified with anhydrous HCl. The precipitate was filtered and dried to give the title product as the white solid hydrochloride salt [4.83 g, mp 231° C. (dec.)]. A second crop was obtained by concentration of the mother liquors (0.62 g). Combined yield 5.45 g (85%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6](=[O:14])[N:5]1[C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].[C:18]([O:21][C:22](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:18][O:21]/[CH:22]=[C:7]1\[C:6](=[O:14])[N:5]([C:15](=[O:17])[CH3:16])[N:4]([C:1](=[O:3])[CH3:2])[C:13]2[C:8]\1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CC(=O)N1C(=O)Cc2ccccc2N1C(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: CO/C=C1\C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 1,2-diacetyl-1,4-dihydro-3(2H)cinnolinone (0.34 g, 1.5 mmol) in dimethylformamide (3.6 mL) is added acetic anhydride (5 mL), followed by trimethylorthoformate (0.64 mL). The mixture is heated at reflux for 12 hours. After cooling to room temperature, the mixture is purified by semi-preparative reverse-phase HPLC, employing a gradient elution from 5% acetonitrile in water with 0.1% trifluoroacetic acid to 100% acetonitrile over 60 minutes. The desired fractions were concentrated under reduced pressure to afford 0.18 g of (Z)-1,1′-(4-(methoxymethylene)-3-oxo-3,4-dihydrocinnoline-1,2-diyl)diethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH:20]=[CH2:21])[CH:15]=3)[S:11][C:7]=2[C:6]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1>CO.ClCCl.[Pd]>[CH2:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][N:17]=1)[C:13]([NH:12][C:10]1[S:11][C:7]2[C:6]([CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:22])[CH3:21]
Reactant: C=Cc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a stirred solution of 90 mg (0.23 mmol) N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-vinyl-isonicotinamide in 10 ml methanol and 10 ml dichloromethane was added a spatula end of 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo and triturated in ether to afford 80 mg (88%) 2-ethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide as a yellow solid. ES-MS m/e (%): 398 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=O)[CH2:4][C:5](OCC)=O.ClC1[C:20]([N+:21]([O-])=O)=[CH:19][C:18]([F:24])=[CH:17][N:16]=1.Cl>CN(C)C=O>[F:24][C:18]1[CH:19]=[C:20]2[C:5]([CH2:4][C:3](=[O:11])[NH:21]2)=[N:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Cc2ncc(F)cc2N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a dry flask was placed sodium hydride as a 60% suspension in oil (3.1 g, 77.5 mmol). Most of the oil was removed by washing twice with hexanes. The remaining solid sodium hydride was then suspended in dry dimethylformamide (DMF) (100 mL) and cooled to 0° C. Diethyl malonate (11.8 mL, 77.7 mmol) was then added dropwise with stirring. The mixture was stirred at 0° C. for 1 hour after which a solution of 2-chloro-5-fluoro-3-nitropyridine (5.21 g, 29.5 mmol) in DMF (40 mL) was added. Stirring at room temperature was continued overnight and the reaction mixture was poured into ice/water. Following acidification to pH 3 with 6N HCl solution, the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to leave a red oil. This was subjected to flash chromatography on silica gel using 3:7 ethyl acetate/hexanes, as eluant. All fractions containing the desired product were combined and concentrated to yield an oil containing 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine and diethyl malonate in a molar ratio of approximately 11:9 weighing 11.5 g. The yield of 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine was calculated to be approximately 8 g (90%).
Reaction SMILES: [N:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[CH:19]=[C:18]1[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([OH:33])[CH:32]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[CH:19]=[C:18]1[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([O:33][S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])[CH:32]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cncc(O)c2)cc2ccc(Cl)cc21
Product: CC(C)(C)OC(=O)n1c(-c2cncc(OS(=O)(=O)N3CCCC3)c2)cc2ccc(Cl)cc21

Procedure:
1-Pyrrolidine-sulfonyl chloride and 6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester (Example 160a) are processed according to the method described in Example 160b to give 6-chloro-2-[5-(pyrrolidine-1-sulfonyloxy)-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester, which is taken onto the next step without further purification. MS (ESI) m/z 478.1 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2CO)c1
Reaction time: 0.25 h

Procedure:
To 2-[3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-propionic acid (0.1 g, 0.30 mmol) in MeOH (3 mL) was added sodium borohydride (0.013 g. 0.36 mmol), and the mixture was stirred at mom temperature for 15 minutes. The solution was concentrated, and the residue was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](O)([C:20]([F:23])([F:22])[F:21])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:19].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:19])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C#N)cc2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2ccc(C#N)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 1-(4-cyanophenyl)-2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: C(O[CH:4](OCC)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])C.C(C1C=CC(C(=O)C(C)(O)C)=CC=1)CCCCCCCCCCC>>[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:4]
Reactant: CCOC(OCC)C(=O)c1ccccc1
Agent: CCCCCCCCCCCCc1ccc(C(=O)C(C)(C)O)cc1
Product: CC(=O)c1ccccc1

Procedure:
2,2-diethoxy acetophenone, 2-hydroxy-2-methyl-1-phenyl-on, 1-(4-isopropylphenyl)-2-hudroxy-2-methyl propane-1-on, 1-(4-dodecylphenyl)-2-hydroxy-methyl propane-1-on
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH2:15]>CCOCC>[CH3:14][NH:15][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Product: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a suspension of 4-nitrobenzenesulfonyl chloride (5 g, 22.56 mmol) in ether (250 ml), methylamine (5 ml, 40% aq. solution, 56.4 mmol) was added, and the mixture was stirred at room temperature. After 16 hr, the reaction mixture was concentrated to remove the solvent and the residue was resuspended in methylene chloride. After washing with 2N HCl and brine, the organic fractions were dried (MgSO4), filtered and concentrated to give N-methyl-4-nitrobenzenesulfonamide (4.8 g, 98%): mp (DSC) 109° C. Anal Calc'd. for C7H8N2O4S: C, 38.89; H, 3.73; N, 12.96. Found: C, 38.83; H, 3.72; N, 12.96.
Reaction SMILES: Cl[CH2:2][C:3](=[N:17][OH:18])[CH2:4][O:5][C:6]1[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:9][S:8][N:7]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][CH2:2][C:3](=[N:17][OH:18])[CH2:4][O:5][C:6]1[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:9][S:8][N:7]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N
Reactant: ON=C(CCl)COc1nsnc1N1CCOCC1
Solvent: C1CCOC1
Product: CC(C)NCC(COc1nsnc1N1CCOCC1)=NO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 200 mL round-bottomed flask were placed 3-chloro-1-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanone oxime 4b (3.53 g, 12.1 mmole), isopropylamine (3.56 g, 60.3 mmole), and THF (71 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo at room temperature. The residue was triturated with isopropyl ether and precipitated crystals were filtered with suction. The crystals were dissolved in dil. HCl solution. To the solution were added ether and NaHCO3 in small portions under vigorous stirring conditions. The organic layer was washed with water and dried over anyydrous MgSO4, and concentrated in vacuo. Yield: 0.42 g (11.6%) from isopropyl ether.
Reaction SMILES: [Na].[C:2]([C:4]1[C:10]([C:11]#[N:12])=[C:9]([OH:13])[CH:8]=[CH:7][C:5]=1[OH:6])#[N:3].[O-]CC.[I-].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>C(O)C.O>[C:2]([C:4]1[C:10]([C:11]#[N:12])=[C:9]([O:13][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:8]=[CH:7][C:5]=1[OH:6])#[N:3]
Reactant: N#Cc1c(O)ccc(O)c1C#N
Reactant: CCCCCCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(O)c(C#N)c1C#N
Yield: 33 %

Procedure:
Sodium (1.15 g, 50 mmoles) was reacted with anhydrous ethanol (200 mL) under a nitrogen atmosphere. 2,3-dicyanohydroquinone (8.01 g, 50 mmoles) in anhydrous ethanol (50 mL) was added dropwise to the ethoxide solution. Upon completion of the addition, potassium iodide (0.5 g) in 5 mL water was added. This solution was brought to reflux and octyl bromide (9.66 g, 50 mmoles) was added dropwise. The reaction was then refluxed under nitrogen atmosphere for one day. The mixture was acidified with 0.5N aqueous HCl and the solvents were removed under reduced pressure. The crude reaction mixture was flash chromatographed using silica gel and methylene chloride as eluent. The appropriate fractions containing the desired product, 2,3-dicyano-4-octyloxyphenol, were combined and the solvent removed under reduced pressure on a rotary evaporator. The crude product was recrystallized from ethanol/water to give 4.5 g 2,3-dicyano-4-octyloxyphenol.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.[CH2:12]([N:14](CC)CC)C.O>C(#N)C>[O:1]1[C:10]2[C:5](=[N:6][C:7]([C:12]#[N:14])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1cccc2c1OCCO2
Reactant: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc2c(n1)OCCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Under an argon atmosphere, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine 5-oxide (102 mg, 666 μmol) was dissolved in actonitrile (700 μL), added triethylamine (202 mg, 2.00 mmol) and trimethylsilylnitrile (529 mg, 5.33 mmol) at room temperature, and the mixture was stirred at 100° C. overnight. Under ice-cold conditions, water was added, and the reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform/methanol), and the title compound (105 mg (yield 97%)) was obtained as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C(C)C)=[C:12]([CH3:20])[CH:11]=2)=[N:3]1>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:20])[CH:11]=2)=[N:3]1
Reactant: COc1c(C)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Agent: O=S(=O)(O)O
Product: COc1c(C)c(-c2ccc(O)c(C)c2)nn1C
Temperature: 0 °C
Yield: 102.2 %

Procedure:
A mixture of 1,4-dimethyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1H-pyrazole (described in Reference Preparation example 98) 7.4 g and 306 aqueous sulfuric acid solution 100 ml was stirred with heating under reflux for fifteen hours. Next, the following work-up treatments was carried out. The reaction mixture was cooled to 0° C., and the resulting precipitates were filtered and were washed with cool water to give some solids. Again, the filtrate were concentrated under reduced pressure to about a half volume and were cooled to 0° C., and the resulting precipitates were filtered and were washed with cool water to give some solids. These work-up treatments were carried out four times and the resulting all solids were dried under reduced pressure to give 4-(1,4-dimethyl-5-methoxy-1H-pyrazol-3-yl)-2-methyl-phenol 6.4 g.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A mixture of 4-nitrobenzyl bromide (0.500 g, 2.31 mmol), 1H-pyrazole (0.362 g, 5.23 mmol), and potassium carbonate (0.704 g, 5.09 mmol) in acetonitrile (30 mL) was stirred at rt overnight. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.380 g, 76%) as a white solid. MW=203.20. 1H NMR (CDCl3, 500 MHz) δ 8.21-8.19 (m, 1H), 8.19-8.16 (m, 1H), 7.61-7.57 (m, 1H), 7.48-7.44 (m, 1H), 7.32-7.28 (m, 2H), 6.35 (t, J=2.1 Hz, 1H), 5.44 (s, 2H); APCI MS m/z 204 [M+H]+.
Reaction SMILES: C([O:8][N:9]1[C:13](=[O:14])[CH2:12][C@@H:11]([NH:15][S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:10]1=[O:35])C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[OH:8][N:9]1[C:13](=[O:14])[CH2:12][C@@H:11]([NH:15][S:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)(=[O:17])=[O:18])[C:10]1=[O:35]
Reactant: O=C1C[C@@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1C[C@@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1O
Reaction time: 1 h

Procedure:
4-(4Trifluoromethyl-phenyl)-piperazine-1-sulfonic acid ((3R)-1-benzyloxy-2,5-dioxo-pyrrolidin-3-yl)-amid (76 mg; 0.15 mmol) was dissolved in EtOAc (5 ml)+MeOH (5 ml). A slurry of 10% Pd/C (35 mg) in MeOH (1 ml) was added under a stream of nitrogen. The mixture was hydrogenated at room temperature at 1 atm. pressure of H2 for 1 h. The reaction mixture was filtered through celite and the filtercake was washed with EtOAc and MeOH. Evaporation of solvent, the crude product was purified by flash chromatograohy through 10 g of Si-60-gel using a gradient of 100% Heptane to 100% (EtOAc+1% AcOH), gradient time=30 min, then isocratic system 100% (EtOAc+1% AcOH) for 15 min. flow=20 ml/min. The fractions containing the product was evaporated and the residue was trituated with Et2O and the resulting colourless solid was dried to give the title compound. Obtained 47 mg (74% yield) of the title compound.