Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:14]1[C:22]([OH:23])=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=1)([CH2:12]O)[C:5](=[O:11])[NH:6]2.ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:22]3[O:23][CH2:12]1)[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCO2
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Yield: 71 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 71% yield as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.19-7.08 (m, 2H), 6.90 (dd, 1H), 6.58 (s, 1H), 6.25 (s, 1H), 5.90 (d, 2H), 4.74 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.5, 157.0, 148.8, 144.5, 141.9, 131.2, 130.6, 126.1, 119.2, 117.5, 109.8, 103.3, 101.8, 93.3, 77.6, 59.7; MS (ES−) m/z 360.4 (M−1), 358.4 (M−1).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C@H:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43]([OH:45])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].[N:53]1([C:59]2[C:60]3[CH:68]=[CH:67][CH:66]=[N:65][C:61]=3[N:62]=[CH:63][N:64]=2)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C1COCC1.CCOC(C)=O>[C:34]([O:38][C:39](=[O:40])[NH:41][CH:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43](=[O:45])[N:56]1[CH2:57][CH2:58][N:53]([C:59]2[C:60]3[CH:68]=[CH:67][CH:66]=[N:65][C:61]=3[N:62]=[CH:63][N:64]=2)[CH2:54][CH2:55]1)([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: c1cnc2ncnc(N3CCNCC3)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ncnc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
DIEA (0.74 mL) and HBTU (1.3 g) was added to the solution of (2R)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid (0.092 g) in THF (5 mL) at 0° C. The mixture was stirred at room temperature for 20 minutes, and then 4-piperazin-1-yl-pyrido[2,3-d]pyrimidine (0.31 g) was added. The reaction was stirred at room temperature for 1 hour. 20 mL of EtOAc was added and the organic layer was separated. The aqueous layer extracted with EtOAc (20 mL). The combined organic layer was washed with saturated sodium bicarbonate (20 mL) and dried over sodium sulfate. After removal of solvent, the residue was purified by flash chromatography (10:1=DCM:MeOH) to give [1-benzyl-2-oxo-2-(4-pyrido[2,3-d]pyrimidin-4-yl-piperazin-yl)-ethyl-carbamic acid tert-butyl ester as white foam solid (0.392 g, 58.9%). 1H NMR (CDCl3, 400 MHz) δ 9.11 (br, 1H), 8.92 (s, 1H), 8.15 (d, 1H), 7.40 (m, 1H), 7.20-7.33 (m, 5H), 5.42 (m, 1H), 4.85 (m, 1H), 3.78-3.82 (m, 2H), 3.61-3.70 (m, 2H), 3.50-3.58 (m, 2H), 3.15-3.20 (m, 1H), 3.08-3.12 (m, 2H), 1.42 (s, 9H). Rt 2.23 min. MS (ESI+) [M+H]+463.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([O:13][CH3:14])[CH:5]=1)([O-:3])=[O:2].Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:12][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:8]([O:10][CH3:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCCN1CCCC1

Procedure:
1-[2-(4-nitro-2,6-dimethoxyphenoxy)ethyl]pyrrolidine was prepared from 4-nitro-2,6-dimethoxyphenol [R F Collins and M Davis, J. Chem. Soc. 1863, (1961)] (0.4 g, 2.39 mmol), 1-(2-chloroethyl)pyrrolidine (612 mg, 0.36 mmol) and caesium carbonate (2.3 g, 0.72 mmol) to give the desired product as a brown oil (232 mg). MS (ES+) 297 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(Cl)c1
Product: COc1ccc(-c2nc3cc(-c4cccc(Cl)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-chlorophenylboronic acid (134 mg, 0.86 mmol) the subtitle compound was obtained, (72 mg, 33%). 1H NMR (DMSO) δ 8.71(d, 1H), 8.53(dd, 1H), 8.19(d, 1H), 7.95(d, 1H), 7.88(t, 1H), 7.83(dd, 1H), 7.79(d, 1H), 7.70(d, 1H), 7.58(t, 1H), 7.52(d, 1H), 4.12(s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH4+].[OH-]>O1CCOCC1.O>[CH:1]1([CH2:4][O:5][CH2:6][CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:10]=3[O:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCC(COCC1CC1)O2
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)OCC(COCC1CC1)O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-((Cyclopropylmethoxy)methyl)-2,3-dihydro-6-nitrobenzo[b][1,4]dioxine (0.33 g, 0.0012 mol) was dissolved in 20 mL dioxane. Sodium dithionite (2.2 g, 0.013 mol) was suspended in water (4 mL) and NH4OH (2 mL) and then added to the dioxane solution. The reaction was stirred at room temp for 6 hrs. The mixture was filtered through filter paper and the filtrate concentrated under vacuum to a white solid. The solid was suspended in 10% EtOAc/hexanes and filtered. The filtrate was concentrated to a white solid and used for the next reaction without further purification. Yield of the title compound is 0.29 g (98%). m/z=235.8 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][OH:27])[CH2:21]1>>[OH:27][CH2:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:18])([F:17])[F:1])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:14])[CH2:21]1
Reactant: OC[C@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](CO)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) and (S)-1-piperidin-3-yl-methanol, hydrochloride (76 mg, 0.5 mmol) by the method used in Example 46 for the achiral isomer. Gummy solid (70 mg, 74%). LC/MS 5.85 min, [M+1]+ 375.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].OC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]([C@H:14]([OH:15])[C@H:13]([OH:16])[CH:12]=[O:17])[C@H:10]([OH:11])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Product: O=C[C@@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)[C@H](O)CO

Procedure:
Through the specification of the present invention, the activity of the cellobiose 2-epimerase was determined as a lactose 2-epimerase activity, which catalyzes epimerization of lactose to form epilactose, using lactose as the substrate obtainable in highly purified form at low cost. The lactose 2-epimerase activity was measured as follows. To 1,000 μl of substrate solution, which contains lactose to give a final concentration of 35.1 mM and acetate buffer (pH 6.0) to give a final concentration of 20 mM of the reaction solution, 200 μl of a enzyme solution was added to give a 1,200 μl of the reaction solution, followed by reaction at 50° C. for 20 minutes. The reaction was stopped by heating for 10 minutes in a boiling water bath. Then reaction mixture was subjected to HPLC chromatography to determine the amount of epilactose produced by the reaction. The HPLC chromatography was conducted at the following conditions;
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[H][H]>O1CCOCC1.[Ni]>[Cl:1][C:2]1[C:3]([S:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Sc1ccc(Cl)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cccc(Cl)c1Sc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-chloro-2-(2,4-dichlorophenylthio)-nitrobenzene (10.04 g) in dioxan (100 ml) is mixed with Raney-nickel (5 g). Following this, the mixture is shaken for 3 hours at room temperature and 3 bar hydrogen pressure in a Parr apparatus. The catalyst is removed by filtration. The filtrate is concentrated in a vacuum and the resulting residue is brought to constant weight in a vacuum. Yield 9.01 g (98.6%) of colourless oil.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reactant: Nc1ccccn1
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(C)O3)nc2ccccn12
Yield: 48.5 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.05 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.2 g) and 2-aminopyridine (2.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.[C:14]([O:17][C:18](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:17][CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc(Br)ccc2C(=O)N1
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-bromo-4H-isoquinoline-1,3-dione (2.4 g, 10 mmol) in 25 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide, respectively, is added trimethylorthoformate (2.2 mL, 20 mmol). The reaction mixture is shaken in a heating block at 125° C. for 1 hour. Upon cooling to room temperature, the product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 2.4 g of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl>O>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N2CCOCC2)CC1
Reaction time: 72 h

Procedure:
273 Grams of 4-chloro-3-morpholinosulfonylbenzoic acid (1.0 mole) were heated under reflux for 5 hours with 0.5 l of N-methylpiperazine. Subsequently the excess base was completely eliminated in vacuo, the residue was dissolved in 2 l of water, and the pH value of the solution was adjusted to 8 by means of 5N HCl. After standing for 3 days at room temperature, the crystalline precipitate was suction-filtered and was recrystallized from water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1C(O)=O)=O.C(=O)=O.[C:22]([C:28]([O:30][CH3:31])=[O:29])#[C:23][C:24]([O:26][CH3:27])=[O:25]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]3[C:8](=[C:22]([C:28]([O:30][CH3:31])=[O:29])[C:23]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14]3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1ccc(Cl)c(Cl)c1
Agent: O=C=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)c(Cl)c2)n2c1CCC2
Yield: 91 %

Procedure:
A solution of N-(3,4-dichlorobenzoyl)proline (28.813 g 0.1 mol) in acetic anhydride (100 mL) and dimethyl acetylenedicarboxylate (50 mL) was stirred in a flask equipped with a reflux condenser and a gas bubbler to monitor CO2 evolution during the reaction. The mixture was heated to 120° C. over a 15-min period, during which time CO2 evolution occurred at an increasingly rapid rate; the temperature was maintained for 1 h after the rate of gas evolution had substantially decreased. The reaction mixture was concentrated in vacuo and the residue, which solidified on cooling, as twice crystallized from hot methanol (500 mL) to yield 33.35 g (91%) of dimethyl 2,3-dihydro-5-(3,4-dichlorophenyl)-1H-pyrrolizine-6,7-dicarboxylate as analytically pure fine white needles.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:4](I)[CH:3]=1.[F:18][C:19]([F:30])([F:29])[CH2:20][S:21][CH2:22][C:23]([OH:28])([CH2:26][CH3:27])[C:24]#[CH:25]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9])[N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[C:24]([C:23]([OH:28])([CH2:26][CH3:27])[CH2:22][S:21][CH2:20][C:19]([F:30])([F:18])[F:29])=[CH:25]2
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(Cl)cc1I
Reactant: C#CC(O)(CC)CSCC(F)(F)F
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc(Cl)c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the standard Sonagashira procedure as described in General Procedures Example C, reacting from N-(4-chloro-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (0.60 g, 1.5 mmol) and 3-(2,2,2-Trifluoro-ethylsulfanylmethyl)-pent-1yn-3-ol (0.32 g, 1.5 mmol) to yield the title compound as a yellow sticky oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=O)[CH2:6][CH:5]([CH2:10][CH3:11])[N:4]1[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=[O:14])=[O:13])[CH3:2].C([C@H]1N[C@@H](CC)CC2(OCCO2)C1)C.Cl.N1C=CC=CC=1S(Cl)(=O)=O.CN(C(OC)OC)C.[NH:54]1[CH:58]=CC=[N:55]1.O.NN>>[CH2:1]([C@H:3]1[C:8]2[CH:58]=[N:54][NH:55][C:7]=2[CH2:6][C@@H:5]([CH2:10][CH3:11])[N:4]1[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=[O:14])=[O:13])[CH3:2]
Reactant: CCC1CC(=O)CC(CC)N1S(=O)(=O)c1ccccn1
Reactant: c1cn[nH]c1
Agent: CC[C@@H]1CC2(C[C@H](CC)N1)OCCO2
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: O
Product: CC[C@@H]1Cc2[nH]ncc2[C@H](CC)N1S(=O)(=O)c1ccccn1

Procedure:
Prepared by treatment of 2,6-diethyl-1-(pyridin-2-ylsulfonyl)piperidin-4-one, which was prepared by sulfonylation of compound 126 using pyridine-2-sulfonyl chloride hydrochloride followed by deprotection as shown in Example 17, with DMF-DMA followed by pyrazole formation using hydrazine hydrate as shown in Example 15,
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12](NNC(C)(C)C)=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.CC1C(C(N(C(C)(C)C)N)=O)=CC=C2C=1CCC[O:26]2.Cl>O>[CH3:1][C:2]1[C:11]([C:12]([OH:13])=[O:26])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2
Reactant: Cc1c(C(=O)NNC(C)(C)C)ccc2c1CCCO2
Reactant: Cc1c(C(=O)N(N)C(C)(C)C)ccc2c1CCCO2
Agent: Cl
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1CCCO2
Yield: 16.8 %

Procedure:
To a mixture of 57.8 g of a solid containing 80% of 1-(5-methylchroman-6-carbonyl)-2-t-butyl hydrazine and 20% of 1-(5-methylchroman-6-carbonyl)-1-t-butyl hydrazine and 900 ml of water was added 100 ml of concentrated hydrochloric acid at room temperature and then the the resultant was heated under reflux for 30 minutes. After cooling with ice and water, the resulting crystals were filtered to obtain 7.11 g of 5-methyl-6-chromanic acid in a yield of 16.8% (which had a purity of 99.5% by peak area from HPLC analysis and a melting point of 207° to 208° C.). An 50% aqueous solution of sodium hydroxide was added to the filtrate to pH 8 followed by extraction with dichloromethane to obtain 45.8 g of 1-(5-methylchroman-6-carbonyl)-2-t-butyl hydrazine in a yield of 79.1% (which had a purity of 99.8% by peak area from HPLC analysis and a melting point of 146° to 148° C. while which contained not more than 0.1% by peak area of 1-(5-methylchroman-6-carbonyl)-1-t-butyl hydrazine from HPLC analysis).
Reaction SMILES: COCCOC[C:7]1([C:20]([O:22]CC)=[O:21])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[Li+].[OH-:26]>C(O)C.O.ClCCl>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][C:7]([O:26][CH2:17][CH2:16][O:15][CH3:13])([C:20]([OH:22])=[O:21])[CH2:12][CH2:11]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1(COCCOC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [OH-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COCCOC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
1-tert-Butyl 4-ethyl 4-((2-methoxyethoxy)methyl)piperidine-1,4-dicarboxylate from step A (1.78 g, 5.15 mmol) was treated with LiOH (0.62 g. 26 mmol) in ethanol (12 mL) and water (24 mL) at 80° C. for 18 hours. The mixture was cooled, diluted with dichloromethane, and washed with sat. aq. NaHSO4. The aqueous phase was back extracted with dichloromethane (3×), and the organics were combined, washed with brine, dried over MgSO4, and concentrated to give the title compound in quantitative yield. MS (ES+) [M+H]+=318.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=[O:46])/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[Cl:45])[CH:24]=[CH:25][C:26]=1[CH2:27][CH2:28][CH2:29]O.[Br:47]C(Br)(Br)Br>ClCCl>[Br:47][CH2:29][CH2:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([NH:31][C:32](=[O:46])/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[Cl:45])=[CH:22][C:21]=1[Cl:20]
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCCO)c(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.577 g (2.200 mmol) triphenylphosphine was added batchwise to a suspension of 0.836 g (2.000 mmol) (E)-N-[3-chloro-4-(3-hydroxy-propyl)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide and 0.730 g (2.200 mmol) tetrabromomethane in 10 mL dichloromethane and the mixture was stirred for 48 h at RT. The reaction mixture was purified by column chromatography (silica gel, dichloromethane) and the residue was triturated with petroleum ether.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([CH3:16])=[CH2:15])=O)(C)(C)C.O1CCOCC1.[ClH:23]>C(Cl)Cl>[ClH:23].[NH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)c1sccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=C(C)c1sccc1N
Temperature: 0 °C

Procedure:
A solution containing 0.3 g of 3-(t-butoxycarbonylamino)-2-isopropenylthiophene in 7 ml of methylene chloride was cooled to 0° C., and 3 ml of a 4N-hydrogen chloride dioxane solution was added. The mixture obtained was used as intact for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Cu]I.[Cu].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([O:21][C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[Cl:13])=[CH:8][C:7]([CH3:11])=[N:6][CH:5]=1
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: COC(=O)c1cnc(C)cc1Cl
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(C)cc1Oc1cc(Cl)ccc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a solution of 0.53 g (2.855 mmol) 4-chloro-6-methyl-nicotinic acid methyl ester (commercially available, CAS RN 886372-05-0) in 7.5 mL dry N,N-dimethylformamide was added 489 mg (2.998 mmol) 2,5-dichlorophenol, 789 mg (5.711 mmol) potassium carbonate, 54 mg (0.286 mmol) copper(I) iodide and 54 mg (0.857 mmol) copper nanopowder (avg. particle size 100 nm). The reaction mixture was stirred at 120° C. for 3 hours and then poured on 30 mL 1M aqueous hydrochloric acid and 30 mL ethyl acetate. The layers were separated and the aqueous layer was extracted with 30 mL ethyl acetate. The combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100), to give 432 mg (48%) of the compound as a light yellow solid. MS (ESI): m/z=312.019 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[S:8](=[O:21])(=[O:20])[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:11](=O)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](#[N:26])[CH2:23][C:24]#[N:25]>N1CCCCC1>[C:24]([C:23]([C:22]#[N:26])=[C:11]1[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:8](=[O:21])(=[O:20])[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10]1)#[N:25]
Reactant: O=C1C=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Product: N#CC(C#N)=C1C=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1
Temperature: 25 °C

Procedure:
A mixture of 8 gm (0.0464 mol) of 2,6-diphenyl-4H-thiopyran-4-one-1,1-dioxide of Example 1, 3.1 gm (0.047 mol) of malononitrile, 50 ml of alcohol and 20 drops of piperidine was refluxed for 1 hour. The reaction mixture was cooled to room temperature and the title compound was collected and recrystallized from 100 ml of toluene (mp 216°-217° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@@H:12]1[CH2:18][O:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:24]=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=2)[C:13](=[O:17])[C@@H:12]1[CH2:18][O:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@H]1C(=O)NCCN1C(=O)OCc1ccccc1
Reactant: CSc1ncc(CBr)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC[C@H]1C(=O)N(Cc2cnc(SC)nc2)CCN1C(=O)OCc1ccccc1
Yield: 32.4 %

Procedure:
4-Benzyloxycarbonyl-3-(S)-methoxymethyl-piperazine-2-one (0.1 g 0.37 mmol), 5-bromomethyl-2-methylthiopyrimidine (0.08 g, 0.37 mmol) and tetra-n-butylammonium bromide (0.06 g, 0.19 mmol) are placed in dichloromethane (1 mL) and 50% aqueous NaOH (0.03 mL) and stirred for 4 h. The mixture is diluted with water and is extracted with dichloromethane (2×20 mL). The combined organic extracts are dried (MgSO4) and are evaporated. The residue is purified by flash chromatography (silica gel, 98:2 dichloromethane/methanol) to provide the intermediate title compound as a colorless oil (0.05 g, 33%).