Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([NH:15][C:16]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]1=[S:1])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN=C=O
Reactant: Sc1nc2ccccc2[nH]1
Product: CCCCNC(=O)n1c(=S)[nH]c2ccccc21
Temperature: 25 °C
Yield: 89.4 %

Procedure:
The mixture of 2-mercaptobenzimidazole (29.30 g, 0.195 mole) and butyl isocyanate (48.3 mL, 0.33 mole) in a 500 ml of round-bottom flask equipped with a condenser was heated to 130°-140° C. in an oil bath for 45 min. After the reaction mixture was cooled to room temperature, the solid was filtered, washed with hexane, and dried under vacuum to give 43.48 g (89%) of 1-(butylcarbamoyl)-1,3-dihydrobenzimidazole-2-thione as white crystals: mp 179°-180° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.C[O-].[Na+].Cl[C:15]1[C:16]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:17][C:18]2[C:23]([N:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2.CS(C)=O>ClCCl.O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:16]2[C:15]([N:7]3[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][O:3][CH3:2])[CH2:6]3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=3)[N:17]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: COCC1CCCNC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCC1CCCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL sealed tube, was placed a solution of 3-(methoxymethyl)piperidine hydrochloride (170 mg, 1.03 mmol, 2.00 equiv) in dichloromethane (7 mL), and sodium methoxide (128 mg, 2.37 mmol, 5.00 equiv). The resulting solution was stirred for 3 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum and was added into a 8-mL sealed tube with methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv) and DMSO (4 mL). The mixture was stirred overnight at 100° C. Water was added to quench the reaction and the resulting solids were collected by filtration. The residue was purified by silica gel column chromatography with PE/EA (50:1). This resulted in 179.9 mg (88%) of methyl 2-(4-fluorophenyl)-3-(3-(methoxymethyl)piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[CH3:12].S(=O)=[O:14].[S:16](=[O:19])(=[O:18])=[O:17]>>[S:16](=[O:14])(=[O:19])([OH:18])[OH:17].[Cl:1][C:2]1[C:3]([CH2:12][OH:14])=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=S=O
Reactant: O=S(=O)=O
Product: O=S(=O)(O)O
Product: OCc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reaction time: 0.17 h

Procedure:
Liquid sulfur trioxide, (200 ml, 385 g) was added to 26.4 g. (0.1 mole) of pure 2,3,4,5,6-pentachlorotoluene (mp 224°-225° C.) placed in a 500 ml 3-neck tared flask provided with stirrer, thermometer and reflux condenser the end of which was attached to a bubble counter so that the rate of gas evolution during the reaction can be visually estimated. External heat was applied to the flask to bring the sulfur trioxide to reflux. Soon a light blue color developed, which turned gradually deeper to a vivid royal blue. The color change was accompanied by gas evolution which was identified as sulfur dioxide. The steady gas evolution, which began after 10 minutes of reflux, lasted for 2-3 hours, after which it became gradually slower and the reaction mixture gradually acquired a dark green-gray color. The weight of the reaction mixture at this time indicated a loss of 6.9 g, as compared to the theoretical loss of 6.4 g, corresponding to one mole of sulfur dioxide evolved. The excess of sulfur trioxide, which acted also as a solvent during the reaction was distilled off first at atmospheric pressure, then under aspirator vacuum at a temperature not exceeding 70° C. The weight (45.2 g) of the product, a greenish-grey solid, indicated as C7H3Cl5O7S2 composition and this was confirmed by its hydrolysis which yielded 0.2 moles of sulfuric acid and 0.1 mole of pentachlorobenzyl alcohol, identified by elemental analysis, infrared spectroscopy, melting point and nuclear magnetic resonance spectroscopy (see Example 23). The evolvement of the reaction was also followed by nuclear magnetic resonance (nmr) spectroscopy which indicated that even in the early stages of the reaction the characteristic proton resonance of pentachlorotoluene at 2.52 ppm downfield from tetramethylsilane (TMS) completely disappeared. Instead, a new peak at 4.55 ppm appeared, which is assignable to the radical cation formed from pentachlorotoluene by the loss of one electron. During the refluxing and sulfur dioxide eveolution period two additional peaks developed in increasing intensities and in approximately in a 2:1 ratio at 6.29 and 9.21-9.60 ppm (the later is somewhat variable during the reaction). The former corresponds to the two benzylic hydrogens adjacent to the oxonium moiety and the latter corresponds to the acidic proton of the sulfuric acid moiety. The intensity of the peak corresponding to the radical cation, which accounts for the intense blue color, diminishes to a few percent after 2 hours of reflux and the intensities of the protons of oxonium compound become constant after this period.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(=[O:5])[CH3:4].[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl>CN(C=O)C>[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])(=[O:5])[CH3:4]
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1O
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To the suspension of 0.26 g of the sodium hydride in anhydrous DMF, the solution of 1.36 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in 5 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 0.61 g of 3-dimethylaminopropyl chloride in 10 ml of anhydrous DMF is added. The reaction mixture is stirred for 2 hours at 80° C., and washed with n-hexane after cooling and poured into ice-water. The separated oil is extracted with ethyl acetate. The organic layer is washed with N--NaOH solution, water and saturated sodium chloride solution in the order named and dried over anhydrous magnesium sulfate. Ethy acetate is removed off in vacuo to give 1.0 g (56%) of the titled compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].ClC1C([O:15][C:16](=O)[CH2:17][N:18]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:20][C:19]2=[O:30])=C(Cl)C(Cl)=C(Cl)C=1Cl>CN(C)C=O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH:21]2[CH2:22][N:18]([CH2:17][C:16]([N:4]3[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]3)=[O:15])[C:19](=[O:30])[CH2:20]2)=[CH:28][CH:27]=1
Reactant: O=C1CNCCN1
Reactant: O=C(CN1CC(c2ccc(Cl)cc2)CC1=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)CN2CC(c3ccc(Cl)cc3)CC2=O)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4.46 g (44.6 mmol) of piperazin-2-one (ketopiperazine) and 300 ml of dimethylformamide are added to 22.4 g (44.6 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid pentachlorophenyl ester and the whole is stirred for 5 hours at room temperature. The whole is concentrated to dryness by evaporation under reduced pressure at 70°, stirred with 150 ml of ethyl acetate for 1 hour and then 150 ml of diethyl ether are added; the whole is filtered with suction, washed with 50 ml of diethyl ether and allowed to dry. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 205°-207° is obtained and can be purified further by recrystallisation from 300 ml of butanol, washing with 50 ml of diethyl ether and drying, and then melts at 208°-210°.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2.[N-:16]=[N+:17]=[N-:18].[Na+].[CH3:20]N(C)C=O>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:20][CH2:1][C:2]21[CH2:14][CH2:13][CH:12]([N:16]=[N+:17]=[N-:18])[CH2:11][CH2:10]2
Reactant: O=C1CCC2(CC1)Cc1ccccc1C2
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Agent: [Na+]
Product: [N-]=[N+]=NC1CCC2(CCc3ccccc3C2)CC1

Procedure:
A 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol lower alkyl sulfonate prepared in step (11) and sodium azide in a solvent such as dimethylformamide on heating (at from about 65° to about 100° C. for from about 4 to about 20 hours); yields a corresponding 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylazide, which on reaction with lithium aluminum hydride in a solvent such as tetrahydrofuran at moderate (room) temperature for from about 3 to about 10 hours, yields a corresponding 3',4'-dihydrospiro(cyclohexan-1,2'(1'H)-naphthalen)-4-ylamine [ I(c)] in its free base form. On treating an ether extract of a thus produced compound with an ethereal solution of a suitable (pharmacologically acceptable) acid, its acid addition salt form is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]([NH:15][C:4]2[CH:3]=[C:2]([N:25]3[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]3)[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[N:5]=2)[CH3:17])=[CH:19][CH:20]=1
Reactant: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CC(=O)N[C@H]1CCNC1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H]1CCN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)c2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
100 mg of (S)-4-chloro-N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine (Reference Example 2), 112 mg of (S)—N-(pyrrolidin-3-yl)acetamide, 69 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 92 mg of sodium t-butoxide and 30 mg of tris (dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 115 mg of N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidin-3-yl}acetamide as pale brown powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 67 mg of the objective compound as brown powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(F)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(F)cc1)OCC

Procedure:
A solution of 5.0 g of ethyl 2-(4-fluorophenyl)-3-nitropropyl-(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 40 g of an 8% solution of ammonia in ethanol. To this are added 7 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-fluorophenyl)propyl-(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.4 ppm (CDCl3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1[CH2:19]OC[CH2:16]1.[CH2:20]([Mg]Br)[CH:21]=[CH2:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:14])[CH2:19][CH:15]=[CH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:14])[CH2:22][CH:21]=[CH2:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[Mg]Br
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Product: C=CC[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Product: C=CC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (1.5 g, 7.5 mmol) was dissolved in THF (15.0 mL, 186 mmol). The reaction mixture and cooled at −78° C., before adding allylmagnesium bromide (1.0M in ether; 11.3 mL, 11.3 mmol) dropwise. The resulting mixture was allowed to warm to room temperature slowly overnight. The reaction was quenched with saturated aqueous NH4Cl (30 mL), added dropwise. The resulting mixture was extracted with EtOAc (2×30 mL), then the combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL), then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield the crude product, which was then purified by preparative HPLC (10-50% MeCN:H2O; 0.05% TFA; over 80 minutes). Each diastereomer dissolved in EtOAc and free based by adding saturated aqueous NH4CO3. The organics were separated, dried over Na2SO4, and the solvent removed to yield (S)-3-((S)-1-hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (105 mg; 1st eluting peak) and (S)-3-((R)-1-hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (90 mg; 2nd eluting peak).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Cl)[CH:9]=1)[C:5]#[N:6].[CH3:11][O-:12].[Na+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Cl)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C#N)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
To a 250 mL round bottom flask charged with 3,5-dichlorobenzonitrile (130a, 7.31 g; 34.90 mmol) and maintained under an argon atmosphere was added DMF (70 mL). The flask was cooled to 0° C. and powdered sodium methoxide (1.88 g; 34.90 mmol) was added in two portions 15 m apart. The homogeneous mixture was allowed to warm to room temperature and stirred for 24 h. The solution was cooled to 0° C. and aqueous 10% HCl (20 mL) was added dropwise via an addition funnel after which the reaction was warmed to RT. The mixture was extracted with EtOAc and the combined extracts washed sequentially with water and brine. The organic phase was dried (Na2SO4), filtered, and volatile solvents were removed in vacuo. The resulting solid was recrystallized from hexanes to afford 3-chloro-5-methoxybenzonitrile (130b, 4.2 g; 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[O:19]1[CH2:24][CH2:23][CH:22](OS(C)(=O)=O)[CH2:21][CH2:20]1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[O:12][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 52.6 %

Procedure:
Step B To a solution of 3-methoxy-4-nitrophenol (0.5 g, 3 mmol) prepared in Example 132 Step A in anhydrous DMF (13 mL) were added Cs2CO3 (2.9 g, 8.9 mmol) and methanesulfonic acid tetrahydropyran-4-yl ester (0.64 g, 3.6 mmol) sequentially. The reaction mixture was heated at 120° C. for 3 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (40-60% EtOAc in hexanes) to give 4-(3-methoxy-4-nitrophenoxy)tetrahydro-2H-pyran as a yellow oil (0.4 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN1CCCC1=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:28][CH3:29])[C:13]([CH3:20])([CH3:19])[CH2:12]2)[CH:3]=1
Reactant: CC1(C)CC(Nc2cc(Cl)ccc2C#N)CC(C)(C)N1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCN1C(C)(C)CC(Nc2cc(Cl)ccc2C#N)CC1(C)C
Temperature: 90 °C

Procedure:
4-Chloro-2-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]benzonitrile was dissolved in N-methyl-2-pyrrolidinone, potassium carbonate and iodoethane were added, followed by stirring at 90° C. By post-treating the reaction liquid, 4-chloro-2-[(1-ethyl-2,2,6,6-tetramethylpiperidin-4-yl)amino]benzonitrile was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].ClC1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]
Reactant: CSc1ccc(NC(C)=O)cc1F
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
The product from Example 39c (1.00 g, 5.0 mmol) and t-BuSNa (1.88 g, 15.1 mmol) in anhydrous DMF (10 mL) was heated at 160° C. for 4 hours under N2 flow, and then cooled to room temperature. To the reaction mixture was added 1-chloro-4-methyl-2-nitrobenzene (2.36 mL, 17.6 mmol) at room temperature and then the mixture was heated at 80° C. for 4 hours under N2 flow. The mixture was diluted with H2O and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by silica gel column chromatography eluting with 2:1 EtOAc/hexane to give the title compound as yellow crystals (1.04 g, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:35]([O:42][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1

Procedure:
A suspension of 2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, 0.05 equiv), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium hydroxide (1.1 g, 2.4 equiv) in toluene (30 mL) were heated at reflux for 3 h in an apparatus fitted with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in water, and extracted into methylene chloride. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85%) which was used without purification. Mass spec.: 264.25 (MH)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[O:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:21][CH2:20][N:19]([CH:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)[CH2:24][CH2:23]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (750 μL), 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride (2.1 g), potassium carbonate (3.2 g), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. To the reactant was added water, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 1-(4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (1.83 g).
Reaction SMILES: CS(=[N:7][C:8]#[N:9])C(=S)OC.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][NH:17][CH2:18][CH2:19][SH:20])=[CH:14][CH:13]=1.[CH3:23]S>C(O)C>[C:8]([N:7]=[C:23]1[N:17]([CH2:16][C:15]2[CH:21]=[CH:22][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH2:18][CH2:19][S:20]1)#[N:9]
Reactant: CS
Reactant: COc1ccc(CNCCS)cc1
Reactant: COC(=S)S(C)=NC#N
Solvent: CCO
Product: COc1ccc(CN2CCSC2=NC#N)cc1
Yield: 92 %

Procedure:
3.65 g (23.5 moles) of cyanimino-dithiocarbonic acid dimethylester (purity: 94%) and 5.91 (30 moles) of N-(4-methoxybenzyl)-cysteamine are boiled in 30 ml of ethanol until the evolution of methyl mercaptan terminates. The reaction mixture is evaporated and the crystalline residue is recrystallized from 15 ml of isopropanol. 5.35 g (92%) of 2-cyanimino-3-(4-methoxybenzyl)-thiazolidine are obtained, melting at 99° to 102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9]C)=O)[C:5]([OH:12])=[CH:4][CH:3]=1.O1CC[CH2:15][CH2:14]1.[CH:18]([Mg]Cl)=[CH2:19].[Cl-].[NH4+]>CCOCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([C:7]([CH:18]=[CH2:19])([CH:14]=[CH2:15])[OH:9])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: C=C[Mg]Cl
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: C=CC(O)(C=C)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 5-chlorosalicylate in 200 ml of anhydrous ether was added dropwise with stirring at 10° C. to a mixture of 250 ml of a tetrahydrofuran solution titrating 2.6 M/liter of ethenyl magnesium chloride and 300 ml of anhydrous ether and the mixture was allowed to return to room temperature and was then stirred overnight at room temperature. The mixture was poured into a liter of iced water containing 10% of ammonium chloride and the decanted aqueous phase was extracted twice with 150 ml of ether. The organic extracts were washed 3 times with 100 ml of water, dried over magnesium sulfate, treated with activated carbon and was filtered. The filtrate was evaporated to dryness under reduced pressure and the 39 g of oil residue was chromatographed under pressure over silica gel H. Fractional elution with methylene chloride and evaporation of the solvent yielded 13.9 g of 5-chloro-α,α-bis-ethenyl-2-hydroxybenzene-methanol.