Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Methyl 4-hydroxybenzoate (40 g, 260 mmol) was dissolved in DMF (300 ml), K2CO3 (90 g, 650 mmol) was added and heated to 100° C. 4-(2-Chloroethyl)morpholine hydrochloride (53 g, 280 mmol) was added slowly (35 min) to the slurry. After 2 h at 100° C., the solid was removed by filtration and the solution was evaporated in vacuo. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine and dried (Na2SO4) to give the pure product as a white powder in quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:16](O)[CH3:17]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(O)c1

Procedure:
To a solution of 3-hydroxybenzoic acid (10 g, 72.4 mmol) in Ethanol (150 mL) stirred under nitrogen was added H2SO4 (3.86 mL, 72.4 mmol). The reaction mixture was refluxed at 85° overnight. The reaction mixture was concentrated and partitioned between ethyl acetate 100 mL and water 30 mL. The organic layers were combined and dried over Na2SO4, evaporated in vacuo to give the crude product D45 in 11 g. LCMS Retention time=1.45 mins, [M+H]+167 (5 min run)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]([CH:22]=O)[NH:14][C:15]=3C3C=CN=CC=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:22][C:13]2[NH:14][C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[C:2](=[O:1])[CH2:3][CH2:4]4)[N:12]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: O=Cc1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Product: O=C1CCc2cc(-c3nc(CN4CCCCC4)[nH]c3-c3ccccn3)ccc21
Yield: 44 %

Procedure:
The title compound (0.11 g, 44%) was prepared from the product of Step 2 and piperidine as described in Example 6; MS(AP+) m/e 373 [M+H]+.
Reaction SMILES: CS[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1>[Ni]>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]=[CH:4]1
Reactant: CSc1c[nH]c2ccccc12
Agent: [Ni]
Product: c1ccc2[nH]ccc2c1

Procedure:
conversion of the dimethyl acetal from part A to 3-methylthioindole was accomplished by stirring 0.50 g (2.20 mmol) of the dimethylacetal dissolved in 25 ml of ethyl ether for 2 hr. with 10 ml of 0.5 N aqueous hydrogen chloride. The ethereal layer was separated, treated with a saturated sodium bicarbonate solution, dried, filtered and evaporated to yield 0.35 g (2.14 mmol, 97%) of the oily 3-methylthioindole. This 3-methylthioindole was treated with Raney nickel as described to form indole, identified by comparison with an authentic sample.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O[CH2:33][CH2:34][CH2:35]OC1C(C2C=CC=CN=2)(C(N)=O)C1(C1C=CC=CC=1OC)C>C(O)CC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[O:31][CH2:33][CH2:34][CH3:35])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: COc1ccccc1C1(C)C(OCCCO)C1(C(N)=O)c1ccccn1
Solvent: CCCO
Product: CCCOC(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)c1ccccc1OC

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(propoxy)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and propan-1-ol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl(pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4](SC)[N:3]=1.ClC1C=CC=[C:16]([C:20](OO)=O)[CH:15]=1.[NH2:24][CH2:25]C1CC1>ClCCl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([N:24]([CH:20]2[CH2:16][CH2:15]2)[CH3:25])[N:3]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NCC1CC1
Solvent: ClCCl
Product: CN(c1nc(Cl)c(C#N)c(Cl)n1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
A solution of 1.0 g (5.4 mmol) of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (J. Heterocycl. Chem. 1971, 8, 445-453) in 30 ml of dichloromethane was cooled to 0° C. and treated with 1.59 g (70%, 6.4 mmol) of 3-chloro-perbenzoic acid. The reaction mixture was warmed to room temperature and stirring was continued during 3 hours (completion of the reaction was checked by TLC). For the working-up, the reaction mixture was diluted with 70 ml of dichloromethane and washed rapidly with 30 ml of a cold, saturated aqueous solution of sodium hydrogencarbonate. The organic phase was separated and dried over sodium sulfate. Thereupon, without further working-up, the solution was treated with 385 mg (5.4 mmol) of aminomethyl-cyclopropane. After 18 hours at room temperature, the solution was evaporated and the residue obtained was then chromatographed on silica gel using a 10:1 mixture of hexane and ethyl acetate as the eluent giving 450 mg (1.85 mmol, 34% of theory) of the 4,6-dichloro-2-(cyclopropyl-methyl-amino)-pyrimidine-5-carbonitrile as a white powder; MS: [M]+=243.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]4)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:23][CH2:22][CH:21]([O:24][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:20]4)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(=O)c2ccc(Cn3c(-c4ccccc4)nc4ccccc43)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution of 1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ol (0.85 g, 3 mmol) in DCM at 0° C. is treated with and triethylamine (0.91 mL, 6.6 mmol) followed by methylsulfonyl chloride (0.25 mL, 3.3 mmol), stirred at room temperature overnight and concentrated to give methanesulfonic acid 1-[4-(2-phenyl-benzoimidazol-1-ylmethyl)-benzoyl]-pyrrolidin-3-yl ester as a white powder (1.4 g) identified by HPLC and MS [476.3 m/e (M+H)].
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:26][CH:22]4[CH2:23][NH:24][CH2:25][CH:21]4[CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[C:34](#N)C.O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:26][CH:22]4[CH2:23][N:24]([CH3:34])[CH2:25][CH:21]4[CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CNCC2C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 3.9 mmol, 1.0 eq.) and acetonitrile/water 1:1 (5 ml, 5 ml). The reaction mixture was then cooled to 0° C. and 37% solution of formaldehyde in water was added (0.2 g, 7.8 mmol, 2.0 eq). While keeping the temperature at 0° C. Na(OAc)3BH was added (4.4 g, 20.7 mmol, 3.0 eq). After 1 hour the pH was adjusted to 10 and the aqueous was extracted 2×DCM (100 ml). Removal of the DCM resulted in a white solid. The compound was further purified with a biotage system using an eluent EtOAc and 5% MeOH, affording 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydrocyclopenta-[c]pyrrol-5-ylmethoxy)-quinoline (0.9 g, 50% yield).). 1H NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.14 (dd, 1H), 8.12 (dd, 1H), 7.41 (s, 2H), 7.34 (t, 1H), 6.54 (d, 1H), 4.19 (d, 2H), 4.01 (s, 3H), 2.61 (m, 4H), 2.43 (m, 1H), 2.33 (s, 3H), 2.11 (m, 4H), 1.32 (m, 2H); MS (EI) for C25H26FN3O5: 468 (M+H+).
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[C:6]([CH2:8]O)[N:5]([NH2:10])[C:4]=1[CH3:11].S(Cl)([Cl:14])=O>ClCCl>[Cl-:14].[NH2:2][N+:3]1[CH:7]=[C:6]([CH2:8][Cl:1])[N:5]([NH2:10])[C:4]=1[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1n(N)c(CO)c[n+]1N
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1n(N)c(CCl)c[n+]1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.8 g (21.3 mmol) of 1,3-diamino-4-(hydroxymethyl)-2-methylimidazolium chloride are taken up in 200 ml of dichloromethane and treated with 2.56 g (21.3 mmol) of thionyl chloride. The mixture is stirred at room temperature for 3 days, the product is filtered off, washed with dichloromethane and dried at 40° in a high vacuum. There is obtained 1,3-diamino-4-(chloromethyl)-2-methylimidazolium chloride of melting point 163°-165°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:3].[CH2:13]([O:15][C:16](=[O:21])[CH2:17]C([O-])=O)[CH3:14].N1CCCCC1>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[O:21])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CN(C)Cc1ccc(C=O)cc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(CN(C)C)cc1
Reaction time: 5 h

Procedure:
A mixture of 4-dimethylaminomethylbenzaldehyde (32.64 g), monoethylmalonate (29.07 g), pyridine (100 ml) and piperidine (2 ml) were heated under reflux with stirring for 5 hr. The pyridine was evaporated at reduced pressure, and the oily residue was extracted with diethyl ether. The combined ether extracts were washed with water and dried over magnesium sulphate. The ether was evaporated at reduced pressure to yield ethyl 4-(dimethylaminomethyl)cinnamate as a light straw coloured oil (46.57 g).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([CH2:21][CH2:22][CH2:23][C@@H:24]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:30]=3)[C:27](=[O:51])[CH:26]([O:52][C:53](=[O:55])[CH3:54])[CH:25]2OC(=O)C)=[CH:19][CH:20]=1)=[O:15].Cl>CCOCC>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([CH2:21][CH2:22][CH2:23][C@@H:24]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:30]=3)[C:27](=[O:51])[C:26]([O:52][C:53](=[O:55])[CH3:54])=[CH:25]2)=[CH:19][CH:20]=1)=[O:15]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C(OC(C)=O)C(OC(C)=O)[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C(OC(C)=O)=C[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
DBU (15 μL, 0.10 mmol) was added to an ice-cold solution of diacetate 31 (32 mg, 0.048 mmol) in ether (0.5 mL). The solution was stirred at 0° C. for 30 min. and then was allowed to warm to room temperature. After stirring overnight, 1 M HCl was added and the resulting mixture was extracted with ethyl acetate (3×25 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (0%→100% ethyl acetate/hexanes) provided compound 32 (21 mg, 71%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.CC1CCCCC1N>C(O)(=O)C>[CH3:24][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CC1CCCCC1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC1CCCCC1n1cnc2c(-c3ccccc3)csc2c1=O
Yield: 47.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 2-methylcyclohexanamine (0.120 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 65.9 mg (0.20 mmol, 47.2% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CCCCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(F)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(F)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-methylbenzene (10.6 g, 0.056 mol) in anhydrous THF (150 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (22 mL, 0.056 mol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (10 g, 0.037 mol) in anhydrous THF (120 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl (100 mL) solution and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide crude (R)-tert-butyl 3-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate (10.5 g, yield 88%), which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9](F)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:19]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([NH:25][CH2:24][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:26])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
3-fluoro-4-nitro-benzoic acid tert-butyl ester (1 g, 4.14 mmol) and Beta-Alanine ethyl ester hydrochloride 1.037 g, 6.75 mmol) were dissolved in DMF (10 ml). To the solution DIEA 0.872 g, 6.75 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml), extracted with Ethyl acetate 3×, dried over MgSO4, filtered and evaporated to dryness to afford 1.2 g of solid was obtained (86%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([O:21]CC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([CH2:27][CH2:28][NH2:29])[CH3:26]>CCOCC>[OH2:20].[CH3:24][N:25]([CH3:26])[CH2:27][CH2:28][NH:29][C:19](=[O:21])[CH2:18][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1.[CH3:24][N:25]([CH2:27][CH2:28][NH:29][C:19](=[O:21])[CH2:18][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:9]1)[CH3:26]
Reactant: CN(C)CCN
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Solvent: CCOCC
Product: CN(C)CCNC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Product: O
Reaction time: 18 h
Yield: 69.1 %

Procedure:
A mixture of 9 g (0.029 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of Example 1 and 31 mL (0.029 mol) of dimethylaminoethylamine was stirred on a steam bath under nitrogen for 18 hours. The excess dimethylamino ethylamine was stripped in vacuo, the residue dissolved in 300 mL of ether, treated with decolorizing carbon, filtered, and stripped to approximately 10 g of residue. This was triturated in water, filtered, washed and recrystallized from ether to yield 7.16 g of N-[2-(dimethylamino)ethyl]-4,5-diphenyl-1H-pyrazole-1-acetamide hemihydrate, mp 85°-88° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[O:25]=[O:26]>O>[OH:25][OH:26].[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OO

Procedure:
For these enzymes, glucose oxidase catalyzes the reaction of β-D-glucose, water, and oxygen to produce hydrogen peroxide and gluconic acid. Galactose oxidase catalyzes the reaction of D-galactose and oxygen to produce hydrogen peroxide and D-galacto-hexodialdose. Urate oxidase catalyzes the reaction of uric acid, water, and oxygen to produce hydrogen peroxide, allantoin, and carbon dioxide. Choline oxidase catalyzes the reaction of choline and oxygen to produce hydrogen peroxide and betaine aldehyde. D-amino acid oxidase catalyzes the reaction of D-amino acids such as D-proline, D-methionine, D-isoleucine, D-alanine, D-valine, or D-phenylalanine with water and oxygen to produce hydrogen peroxide, ammonia, and the α-keto acid corresponding to the D-amino acid being oxidized. D-glutamate oxidase catalyzes the reaction of D-glutamic acid, water, and oxygen to produce hydrogen peroxide, ammonia, and 2-ketoglutarate. Glycine oxidase catalyzes the reaction of glycine, water, and oxygen to produce hydrogen peroxide, ammonia, and glyoxylic acid. Glycolic acid oxidase (also known as 2-hydroxyacid oxidase) catalyzes the reaction of glycolic acid and oxygen to produce 2-ketoacetic acid and hydrogen peroxide. L-sorbose oxidase catalyzes the reaction of L-sorbose and oxygen to produce 5-dehydro-D-fructose and hydrogen peroxide. Alcohol oxidase catalyzes the reaction of a lower primary alcohol or an unsaturated alcohol and oxygen to produce the corresponding aldehyde and hydrogen peroxide. Amine oxidase catalyzes the reaction of an amine, typically a primary amine, but also, in some cases, a secondary or tertiary amine, water, and oxygen to produce the corresponding aldehyde, ammonia, and hydrogen peroxide. In an illustrative reaction, glucose oxidase catalyzes the reaction of β-D-glucose, water, and oxygen during application to the outer ear to produce hydrogen peroxide and gluconic acid.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:28])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH2:26][OH:27])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:28])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH:26]=[O:27])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cc2nc(CO)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2nc(C=O)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate (180 mg, 0.4 mmol) in DCM/DMSO (0.5 ml/0.5 ml) at 0° C. was added triethylamine (192 μl), followed by SO3-pyridine (222 mg). The mixture was stirred for 1 hour, and was quenched with ice-water. The water phase was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, water and brine, and was dried over sodium sulfate. Concentration gave (S)-2-(5-bromo-2-formyl-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate. ESI+ (m/z): [M+H]+ calc'd for C22H29BrNO4: 450.1; Found: 450.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[NH:17][CH2:18][CH2:19][OH:20])=[CH:12]/[C:13]([O:15]C)=O.C[Si]([N:25]=[C:26]=[S:27])(C)C.O>CC1OCCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:17]([CH2:18][CH2:19][OH:20])[C:26](=[S:27])[NH:25][C:13](=[O:15])[CH:12]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: COC(=O)/C=C(\NCCO)c1ccc(OC)cc1OC
Solvent: CN(C)C=O
Solvent: O
Solvent: CC1CCCO1
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCO)c(OC)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of (Z)-methyl 3-(2,4-dimethoxyphenyl)-3-((2-hydroxyethyl)amino)acrylate (9.50 g, 33.77 mmol) in 2-MeTHF (100 mL) was added (trimethylsilyl)isothiocyanate (23.80 mL, 168.79 mmol), and the reaction mixture was heated at 85° C. After stirring overnight, the reaction mixture was cooled, extracted with an aqueous 1N NaOH solution (1×250 mL, then 1×50 mL), the combined aqueous layers were washed with CH2Cl2 (2×50 mL) and the aqueous phase acidified to pH 4 with concentrated HCl. The resulting solids were filtered, washed with water (2×50 mL) and dried under N2 overnight to give a light yellow powder. The product was dissolved in DMF (70 mL) at 90° C., and then water (80 mL) was added to this hot solution. After allowing to cool to room temperature and stirring overnight, the solids were collected by vacuum filtration, washed with water and dried under high vacuum to provide the title compound (6.7 g, 61%) as an off-white powder.