Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=O)[O:12][C:13]2=[O:18])([O-:8])=[O:7].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]C(O)=O)=[CH:23][C:22]=1[C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:39][CH3:40])[CH2:35][CH2:34]1)=[O:32]>>[F:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[C:11]2\[O:12][C:13](=[O:18])[C:14]3[C:10]\2=[C:9]([N+:6]([O-:8])=[O:7])[CH:17]=[CH:16][CH:15]=3)=[CH:23][C:22]=1[C:31]([N:33]1[CH2:34][CH2:35][CH:36]([O:39][CH3:40])[CH2:37][CH2:38]1)=[O:32]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: COC1CCN(C(=O)c2cc(CC(=O)O)ccc2F)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cccc([N+](=O)[O-])c43)ccc2F)CC1
Temperature: 240 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
Sodium acetate (6.97 mg, 0.08 mmol) was added to 4-nitroisobenzofuran-1,3-dione (558 mg, 2.89 mmol) and 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetic acid (43) (502 mg, 1.70 mmol) under air. The resulting mixture was stirred at 240° C. for 30 minutes. The cooled mixture was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a yellow gum (50 mg, 6.90% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.59-2.00 (4H, m), 3.10-3.26 (1H, m), 3.37 (3H, s), 3.43-3.57 (2H, m), 3.61-3.71 (1H, m), 3.88-4.05 (1H, m), 7.16-7.20 (1H, m), 7.30 (1H, s), 7.70-7.76 (1H, m), 7.86-7.88 (1H, m), 7.97-8.01 (1H, m), 8.27 (1H, d), 8.39 (1H, d); m/z (LC-MS, ESI+), RT=2.29 (M+H 427.3).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl-].[In+3].[Cl-].[Cl-].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:27]2[CH2:29][C:28]2([F:31])[F:30])(O)[CH3:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH2:10]2)([CH:27]2[CH2:29][C:28]2([F:30])[F:31])[CH3:25])=[CH:22][CH:23]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1(F)F
Agent: [Cl-]
Agent: [In+3]
Solvent: Cc1ccccc1
Product: CSCc1cccc2c1NCC2C(C)(c1ccc(Cl)cc1)C1CC1(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
76.2 mg (0.43 mmol) of the compound from Example 8A, dissolved in 1 ml of toluene, were added to 190 mg (0.86 mmol) of indium(III) chloride and 100 mg (0.43 mmol) of the compound from Example 134A in 1 ml of toluene at RT, and the mixture was stirred at 80° C. for 2 h. Then a further 1.90 g (8.60 mmol) of indium(III) chloride were added, and the mixture was stirred at 80° C. for 1 h. It was diluted with toluene and washed with water, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 16.0 mg (10% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [OH2:1].[CH2:2]([CH:5]1[CH2:10][C:9](=[O:11])[O:8][C:6]1=[O:7])[CH:3]=[CH2:4]>>[CH2:2]([CH:5]([CH2:10][C:9]([OH:8])=[O:11])[C:6]([OH:1])=[O:7])[CH:3]=[CH2:4]
Reactant: O
Reactant: C=CCC1CC(=O)OC1=O
Product: C=CCC(CC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 98.6 %

Procedure:
Water (321 g, 321 mL, 1.78 moles) was placed in a 1 L, 3-neck RBF and briefly vacuumed to remove oxygen. Then allyl succinic anhydride (50 g, 42.7 mL, 357 mmoles) was added and the reaction solution heated to 110 C overnight. The reaction solution was then cooled to room temperature and the volatiles removed from a sample to prepare for FTIR analysis. After confirming the anhydride had been converted to carboxylic acid, the volatiles were removed by vacuum transfer while stirring the reaction solution at 30 C. The reaction flask temperature was maintained with a temperature controller while being monitored using a thin wire thermocouple placed between the heating mantle and reaction flask. As the product began to solidify, the solids were broken up to facilitate drying. After the majority of the water had been removed, the flask was connected directly to the Schlenk line to achieve a pressure <20 mtorr overnight. The product is a white solid (55.6 g, 352 mmoles, 98.5% yield). 1H NMR (DMSO-d6, δ): 2.07 to 2.35 and 2.42 to 2.52 (m, 4H, CH2═CHCH2CH(CO2H)CH2CO2H), 2.66 to 2.74 (m, 1H, CH2CH(CO2H)CH2), 5.00 to 5.09 (m, 2H, CH2═CHCH2) 5.6 to 5.78 (m, 1H, CH2═CHCH2CH). IR (cm−1, diamond): 2300 to 3700 (broad CO2H), 3029 w (sp2 C—H), 2978w, 2921w (sp3 C—H), 1689 s (C═O).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2].[F:17][C:18]([F:29])([F:28])C1C=C2C=NNC2=CN=1>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([C:18]([F:29])([F:28])[F:17])[CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: FC(F)(F)c1cc2cn[nH]c2cn1
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Product: NC(=O)c1nn(CC(=O)O)c2cnc(C(F)(F)F)cc12

Procedure:
was prepared by using the same procedure as described for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid and by starting from 5-trifluoromethyl-1H-pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 289 [M+H]+, tR (HPLC conditions c): 2.93 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cn1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.2) (2.0 g, 6.1 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (1.06 g, 6.74 mmol) according to the general procedure IIb. Obtained as a light brown solid (0.94 g, 38%). MS (ISN) 405.2 [(M−H)−]; mp 148.5° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][C:9]#N)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14]>>[F:1][C:2]1[CH:12]=[C:11]2[C:5](=[CH:4][CH:3]=1)[O:6][CH2:7][CH2:8][C:9]2=[O:14]
Reactant: N#CCCOc1ccc(F)cc1
Reactant: O=S(=O)(O)O
Product: O=C1CCOc2ccc(F)cc21

Procedure:
In the former pathway, 3-(4-fluorophenoxy)propionitrile having the formula (I) is stirred in polyphosphoric acid at a temperature of more than 140° C., preferably at about 170° C. for about 15 minutes to form 6-fluoro-4-chromanimine having the formula (V) and then the reaction mixture is poured into ice-water to hydrolyze 6-fluoro-4-chromanimine having the formula (V) into 6-fluoro-4-chromanone having the formula (II). Though this pathway comprises a short and simple step, it accompanies the side reaction with coloration. In the latter pathway, 3-(4-fluorophenoxy)propionitrile having the formula (I) is hydrolyzed with acid such as hydrochloric acid, hydrobromic acid and sulfuric acid into 3-(4-fluorophenoxy)propionic acid having the formula (IV). When hydrobromic acid or sulfuric acid is employed in a high concentration in order to increase the rate of hydrolysis reaction, an unfavourable side reaction such as cleavage of the ether bond and sulfonation of the aromatic ring may occur. On the other hand, when hydrochloric acid is employed, such side reaction as mentioned above does not occur. Concentrated hydrochloric acid is preferably used from the view point of the reaction rate and yield and 3-(4-fluorophenoxy)propionitrile having the formula (I) is refluxed in the concentrated hydrochloric acid for 10 hours to give 3-(4-fluorophenoxy)propionic acid having the formula (IV) in a quantitative yield. Cyclization of 3-(4-fluorophenoxy)propionic acid having the formula (IV) into 6-fluoro-4-chromanone having the formula (II) can be carried out in a good yield by known method where the compound (IV) is stirred in polyphosphoric acid at 100° C. for 10 minutes (U.S. Pat. Nos. 4,117,230 and 4,130,714), or by the method where the compound (IV) is treated in concentrated sulfuric acid. If the condition of acid hydrolysis and ring closure reaction is agreed, 6-fluoro-4-chromanone having the formula (II) can be obtained in an almost quantitative yield from 3-(4-fluorophenoxy)propionitrile having the formula (II). When 3-(4-fluorophenoxy)propionitrile having the formula (I) is stirred in 85 to 95% sulfuric acid at 90° C. for 10 hours, hydrolysis reaction and ring closure reaction occur simultaneously and thus 6-fluoro-4-chromanone having the formula (II) can be obtained directly. In this reaction, however, by-product such as 3-(4-fluorophenoxy)propionic acid is formed and the yield is quite low.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[CH:10][C:8]1=[O:9])[CH3:6]>C(O)(=O)C>[CH2:5]([N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[C:10]([N+:1]([O-:4])=[O:2])[C:8]1=[O:9])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCn1c(=O)cc(O)c2cc(C)ccc21
Solvent: CC(=O)O
Product: CCn1c(=O)c([N+](=O)[O-])c(O)c2cc(C)ccc21

Procedure:
Concentrated nitric acid (2.5 ml; d, 1.42) was added to a suspension of 1-ethyl-4-hydroxy-6-methyl carbostyril. (1.82g; 0.009 mole) in glacial acetic acid (10 ml) and the mixture warmed to 100° C. The solid dissolved and the 3-nitro derivative immediately solidified as a yellow solid. After cooling the solid was filtered, washed well with water and dried in vacuo over P2O5, m.p. 192°-4° C; (Found; C, 58.16; H, 5.02; N, 11.29; C12H12N2O4 requires; C, 58.06; H, 4.87; N, 11.29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[NH2:15][C:16]1[NH:20][N:19]=[CH:18][C:17]=1[C:21]#[N:22].[CH:23]1([N+:28]#[C-:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl(O)(=O)(=O)=O>CO>[CH:23]1([NH:28][C:29]2[N:20]3[N:19]=[CH:18][C:17]([C:21]#[N:22])=[C:16]3[NH:15][C:6]=2[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: N#Cc1cn[nH]c1N
Reactant: [C-]#[N+]C1CCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: COc1cc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.1 %

Procedure:
To a clear light brown solution of 3,4,5-trimethoxybenzaldehyde (600 mg, 3.06 mmol) and 5-amino-1H-pyrazole-4-carbonitrile (331 mg, 3.06 mmol) in methanol (10 mL) in a 20 mL vial were added cyclopentyl isonitrile (294 mg, 342 μL, 3.06 mmol) and perchloric acid (61.4 mg, 54.9 μL, 0.612 mmol) at RT under nitrogen atmosphere. Then, the nitrogen line was disconnected and the resulting brown suspension was stirred for 15 h at RT. The off-white solids were collected by filtration and washed with methanol. After drying in the air, 375 mg (32%) of 3-(cyclopentylamino)-2-(3,4,5-trimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile was isolated as an off-white solid. LC/MS calcd. for C20H23N5O3 (m/e) 381.434, obsd. 382.0 (M+H, ES+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])=[CH:4][C:3]=1[O:21][CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])=[CH:4][C:3]=1[O:21][CH3:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Solvent: c1ccncc1
Product: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.1 g of (E)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 20 ml of pyridine and 2 ml of acetic anhydride was added, followed by stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and the resultant crystals were filtered and washed with ethyl acetate to obtain 7.5 g of the titled compound as colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[C:21]([O:31][CH3:32])=[N:22][C:23]([C:27]([F:30])([F:29])[F:28])=[C:24]([Br:26])[CH:25]=1.[CH:33](OC)=[O:34]>C1COCC1>[Br:19][C:20]1[C:21]([O:31][CH3:32])=[N:22][C:23]([C:27]([F:30])([F:29])[F:28])=[C:24]([Br:26])[C:25]=1[CH:33]=[O:34]
Reactant: COc1nc(C(F)(F)F)c(Br)cc1Br
Reactant: COC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1nc(C(F)(F)F)c(Br)c(C=O)c1Br
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a flame-dried 100 mL round-bottomed flask, was added dry THF (15 mL). The solution was cooled to −78° C. before diisopropylamine (460 μL, 3.28 mmol), 2.5 M n-butyllithium in hexane (1.31 mL, 3.28 mmol), and a solution of 3,5-dibromo-2-methoxy-6-(trifluoromethyl)pyridine (1.00 g, 2.99 mmol) in dry THF (10 mL), were added sequentially. The reaction mixture was stirred at −78° C. for 10 min before methyl formate (276 μL, 4.49 mmol) was slowly added. After the reaction was stirred for another 2 hr, the mixture was warmed and stirred for 30 min at room temperature. Then the mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, washed by water and brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to yield 3,5-dibromo-2-methoxy-6-(trifluoromethyl)isonicotinaldehyde (985 mg, 90.5%). 1H-NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 4.11 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1(/[CH:12]=[CH:13]/[C:14]2[O:15][CH:16]=[C:17]([CH2:19][S:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][OH:30])=[CH:23][CH:22]=3)[N:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.O>O1CCCC1>[CH3:1][S:2]([O:30][CH2:29][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][CH2:19][C:17]2[N:18]=[C:14](/[CH:13]=[CH:12]/[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:15][CH:16]=2)=[CH:26][CH:25]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
Methanesulfonyl chloride (320 mg) was added to a solution of 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propanol (500 mg) and triethylamine (280 mg) in tetrahydrofuran (30 ml) at 0° C. and then stirred for 4 hours at room temperature. To the reaction mixture was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propyl methanesulfonate (540 mg, 90%). Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 97-98° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[Cl:14].ClC1C=C([N+]([O-])=O)C(OC)=CC=1C.ClC1C=C([N+]([O-])=O)C(OC)=CC=1C(Br)Br.[CH2:43]([O:45][P:46]([O:50]CC)[O:47][CH2:48][CH3:49])[CH3:44]>C1(C)C=CC=CC=1>[CH2:43]([O:45][P:46]([CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[Cl:14])(=[O:50])[O:47][CH2:48][CH3:49])[CH3:44]
Reactant: COc1cc(CBr)c(Cl)cc1[N+](=O)[O-]
Reactant: CCOP(OCC)OCC
Agent: COc1cc(C(Br)Br)c(Cl)cc1[N+](=O)[O-]
Agent: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc(OC)c([N+](=O)[O-])cc1Cl)OCC

Procedure:
A mixture of 1-Bromomethyl-2-chloro-5-methoxy-4-nitro-benzene, 1-Chloro-4-methoxy-2-methyl-5-nitro-benzene and 1-chloro-2-dibromomethyl-4-methoxy-5-nitro-benzene (Compound 56G, 24 g, 1:015:0.5) in toluene (100 mL) were treated with triethylphosphite (15.6 g, 94.2 mmol) and heated to reflux for 24 hrs. Toluene and triethylphosphite were distilled off under reduced pressure. The residue was treated with hot diisopropyl ether to give 10 g of the required compound as dark yellow crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C.O>[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCC(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCN1CCC(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Sodium azide was added to a solution of 4-benzyl-1-(3-p-toluenesulfonyloxypropyl)piperidine (0.216 g, 0.56 mmol) in DMF (5 mL). The resulting solution was stirred at 80° C. for 3 h then cooled at 25° C., diluted with water (50 mL) and extracted with diethyl ether (2×50 mL). The collected organic phase was washed with water (2×50 mL), dried and concentrated in vacuum to afford crude title compound as an oil (0.15 g). 1H-NMR (CDCl3): 1.2-1.4 (m, 2H), 1.4-1.6 (m, 1H), 1.628 (dd, J =13.2Hz, 2H), 1.761 (t, J=7.2Hz, 2H), 1.857 (t, J=11.4Hz, 2H), 2.367 (t, J=7.2Hz, 2H), 2.53 (d, J=7.2Hz, 2H), 2.86 (bd, J 11.4, 2H), 3.314 (t, J=6.9Hz, 2H), 7.14 (d, J=7.5Hz, 2H), 7.19 (d, J=6.9, 1H), 7.275 (t, J=7.2Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([Cl:18])[C:12](Cl)=[C:13](Cl)[C:14]=1[Cl:15])[C:8]([OH:10])=[O:9].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([Cl:18])[C:12]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[C:13]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)[C:14]=1[Cl:15])[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(Sc2c(Cl)c(C(=O)O)c(C(O)=NCCO)c(Cl)c2Sc2ccc(C)cc2)cc1

Procedure:
20 g (60.8 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 15.86 g (127.67 millimols) of p-thiocresol, 34.03 g (246.22 millimols) of potassium carbonate and 200 ml of tetrahydrofuran are stirred at 25° C. for 2.5 days. The mixture is acidified and extracted with methylene chloride. After recrystallisation from toluene, 26.42 g (86% of theory) of the title compound are obtained; melting point 211°-2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH:30]=[O:31])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: COCCOCCn1c2ccccc2c2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 2a (1.5 g, 4.3 mmol) in dried THF (45 mL) was added n-BuLi (3.5 mL 5.2 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then added with dried DMF (3 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight before quenched with aqueous ammonia chloride solution. Water was added and extracted with ethyl acetate three times. The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solvent, the residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:2) as eluent to afford 3a (0.76 g) as yellow solid in 60% yield. NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.58 (d, J=0.8 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.98 (dd, J=8.8 Hz, 0.8 Hz, 1H), 7.51 (m, 3H), 7.30 (m, 1H), 4.53 (t, J=6.0 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 3.49 (m, 2H), 3.38 (m, 2H), 3.26 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 191.8, 144.3, 141.1, 128.5, 127.1, 126.6, 123.7, 123.0, 122.9, 120.6, 120.4, 109.4, 109.3, 71.8, 70.8, 69.1, 59.0, 43.4. MS (FAB) m/z Calcd for C18H19NO3 297.1. Found 297.3 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:35]([CH3:37])[CH3:36]>CC(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3=[N:18][CH:19]=[C:20]([F:24])[CH:21]=[C:22]3[N:27]([CH:35]([CH3:37])[CH3:36])[N:26]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Reactant: CC(C)Br
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)n1nc(-c2ccc(OCc3ccccc3)cc2)c2ncc(F)cc21
Temperature: 90 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (100 mg) and hydrazine hydrate (77 mg) in 2-propanol (5 mL) was stirred at room temperature for 30 min and at 90° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in DMF (5 mL), and then Cs2CO3 (150 mg, 0.46 mmol) and 2-bromopropane (50.5 mg) were added successively. The mixture was stirred for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (70.0 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[F:10][C:11]1[C:20]2[NH:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)[C:17]([CH3:34])([CH3:33])[CH2:16][C:15]=2[C:14]([C:35](O)=[O:36])=[CH:13][CH:12]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[C:20]2[NH:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:22]=3)[C:17]([CH3:33])([CH3:34])[CH2:16][C:15]=2[C:14]([C:35]([NH:9][S:6]([CH:3]2[CH2:5][CH2:4]2)(=[O:8])=[O:7])=[O:36])=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2c(C(=O)O)ccc(F)c2NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(C(=O)NS(=O)(=O)C3CC3)ccc(F)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride (200 mg, 5.0 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (630 mg, 5.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (200 mg, 0.52 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-amide (100 mg, 40%) as a white solid: LC/MS m/e calcd for C25H30FN3O4S (M+H)+: 488.60, observed: 488.1.