Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([S:19][CH3:20])[CH:16]=[C:15]([CH3:21])[C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].[Cl:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:22][CH2:20][S:19][C:17]1[CH:18]=[C:2]([CH3:1])[C:3]([O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:6]([CH3:7])[CH3:8])[CH:9]([CH3:10])[CH3:11])=[C:15]([CH3:21])[CH:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(SCCl)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a stirring solution of (2,6-dimethyl-4-methylsulfanyl-phenoxy)triisopropylsilane (2.18 g, 6.72 mmol) in CCl4 (25 mL) at room temperature was added N-chlorosuccinimide (0.99 g, 7.39 mmol). The reaction mixture was stirred at room temperature for 16 hrs and filtered through a Celite plug. The solvent was removed under reduced pressure to afford crude (4-chloromethylsulfanyl-2,6-dimethylphenoxy)triisopropylsilane as an oil (2.4 g, 100%). This crude oil was dissolved into phosphorous acid triethyl ester (1.5 mL). It was heated at 180° C. for 30 min by microwave. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford diethyl (3,5-dimethyl-4-triisopropylsilanyloxy-phenylsulfanyl)methylphosphonate as a yellow oil (1.6 g, 52%): 1H NMR (200 MHz, DMSO-d6): δ 7.09 (s, 2 H), 4.98 (m, 4 H), 3.31 (d, J=13.8 Hz, 2 H), 2.17 (s, 6 H), 1.25 (m, 9 H), 1.09 (d, J=7.0 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate/Hexanes (2:3); Rf=0.45.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:19]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=O.[NH3:31]>CO>[N:25]1([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]3[CH:15]=[N:14][C:9]4[NH:10][C:11]5[CH:12]=[N:13][C:5]([C:3]([NH2:31])=[O:2])=[CH:6][C:7]=5[C:8]=4[CH:17]=3)=[CH:19][CH:20]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Yield: 16 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (67.3 mg, 0.168 mmol) in 7M ammonia in methanol (8.0 mL) was heated to 70° C. for 24 h in a sealed tube. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in DMSO and purified by preparative HPLC (2-60% MeCN/water modified with 0.1% ammonium hydroxide) to afford a light-yellow fluffy solid (10.3 mg, 16%). 1H NMR (DMSO-D6, 500 MHz): 12.56 (s, 1H), 9.18 (d, J=2.2 Hz, 1H), 9.00 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.90 (s, 1H), 8.10 (s, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.53 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 3.49 (s, 2H), 2.36 (m, 4H), 1.56-1.47 (m, 4H), 1.40 (m, 2H). LCMS (Method D): RT=5.88 min, M+H+=386.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].C(I)CCCCC>>[CH2:12]([C:9]1[N:10]([CH3:11])[C:6]([C:4](=[O:5])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[CH3:1])=[C:7]([CH3:18])[CH:8]=1)[CH3:13].[CH2:9]([CH2:12][C:13]([O-:15])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:4][CH3:3]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2C)n1C
Solvent: CCCCCCI
Product: CCCCCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccccc2C)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 92), using an equivalent quantity of n-hexyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH:13]O.Cl>[OH-].[Na+]>[NH2:9][C:10]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:13]
Reactant: OO
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(F)cccc1C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 7-fluoro-1H-indol-2,3-dione (13.0 g, 78.7 mmol) in 10N sodium hydroxide (125 mL) was heated and stirred at 70° C. for 1 hour. 30% Hydrogen peroxide (25 mL) was added dropwise over 20 minutes at the same temperature, and the mixture was heated and stirred at the same temperature further for 1 hour. The solution was ice cooled, and conc. hydrochloric acid was added to the solution carefully until the pH of the solution became 4. Organic matter was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crystals thus obtained were collected by filtration to give the title compound (7.15 g, 59% yield).
Reaction SMILES: Cl[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].[NH3:24].C(OCC)(=O)C.O>O1CCCC1>[NH2:24][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12]
Reactant: N
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C2CCC(C2)C1=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(N)C2CCC(C2)C1=O
Reaction time: 0.5 h
Yield: 86 %

Procedure:
1.0 g (0.0029 mol) of 4-chloro-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one are dissolved in 10 ml of tetrahydrofuran and, at 25° C., treated with 2.0 ml of aqueous ammonia (30%). After 0.5 hours at 25° C., the reaction mixture is added to ethyl acetate and water, the organic phase is washed twice with water, dried with sodium sulfate and evaporated and the residue is triturated with a little ethyl acetate. Filtration gives 0.81 g (86% of theory) of 4-amino-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]oct-3en-2-one in the form of white crystals (m.p. 262-263° C). 1H NMR (CDCl3, ppm): 10.62 br s 1H; 8.223 br s 1H; 7.41, d, J=8.1 Hz, 1H; 7.35, d, J=8.1 Hz, 1H; 3.03, br t, J=4.8 Hz, 1H; 2.70, br t, J=4.8 Hz, 1H; 2.41, s, 3H; 1.97-2.14, m, 3H; 1.77-1.812, m, 1H; 1.47-1.70, m, 2H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=1.[Br:32]N1C(=O)CCC1=O>CN(C=O)C>[Br:32][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a solution of tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (29 mg, 0.055 mmol) in DMF (1 mL) was added N-bromosuccinimide (12 mg, 0.066 mmol) and the reaction was stirred at room temperature for 1 h and heated at 50° C. for 2 h. The reaction mixture was concentrated and the residue was purified by preparatory TLC (silica, methanol/methylene chloride gradient) to afford the desired product (10 mg, 35%): ESI MS m/z 516 [C24H23BrN2O4S+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH2:17][O:18][CH2:19][O:20][CH3:21])([CH2:12][O:13][CH2:14][O:15][CH3:16])C(O)=O)[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([N:31](CC)CC)C.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:31])([CH2:17][O:18][CH2:19][O:20][CH3:21])[CH2:12][O:13][CH2:14][O:15][CH3:16])[CH:5]=[CH:4][CH:3]=1
Reactant: COCOCC(COCOC)(C(=O)O)c1cccc(Br)n1
Reactant: CCN(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCOCC(N)(COCOC)c1cccc(Br)n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a suspension of 2-(6-bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionic acid (18.0 g) in toluene (150 ml)diphenyl phosphoryl azide (4.08 g, 148.27 mmol) and triethylamine (14.97 g [20.6 ml], 148.27 mmol) were added at rt and stirred at 100° C. for 15 h. Reaction mixture was cooled to rt and concentrated under reduced pressure. The residue obtained was dissolved in THF (600 ml) and 20% NaOH solution was added at rt and stirred for 1 h. Solvent was removed under reduced pressure and the product formed was extracted with ethyl acetate. Organic layer was washed with brine, followed by dried over MgSO4. The organic portion was concentrated under reduced pressure and column chromatographic purification of the crude product using 35% ethyl acetate in hexane furnished title compound as a brown liquid. Yield=15.0 g (88% [2 steps]). TLC (70% ethyl acetate in hexane) Rf=0.51; LCMS: RtH7=0.28, [M+1]=335.0 and 337.0.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][S:11][C:12](=[O:14])[CH3:13])[C:2]1C=CC=CC=1.C([O-:18])(=S)C.[K+].C(=O)(O)[O-].[Na+].[CH3:25][CH2:26][O:27][CH2:28][CH3:29]>CN(C=O)C>[C:12]([S:11][CH2:10][C:9]1([C:8]([O:1][CH3:2])=[O:18])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:14])[CH3:13]
Reactant: CCOCC
Reactant: CC([O-])=S
Reactant: CC(=O)SCCCOc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(CSC(C)=O)CCOCC1

Procedure:
A solution of Intermediate 4 (3.05 g) in DMF (20 ml) was treated with potassium thioacetate (1.47 g) at room temperature for 18 h, then the brown solution was added to 5% sodium bicarbonate solution and extacted with ether (3×200 ml). The solvent was washed with water (200 ml) and brine, dried over MgSO4 and evaporated to give the title compound (2.42 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.[NH3:15].[H][H]>[Ni].CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:15])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1
Reactant: N
Reactant: COc1ccc(C=O)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1ccc(CN)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 67.5 %

Procedure:
To a mixture of 4-(methyloxy)-2-(trifluoromethyl)benzaldehyde (14 g, 65 mmol, 1.0 equiv), aqueous NH3 (25-28%, 370 mL, 5.20 mol, 80 equiv), and MeOH (300 mL) was added Raney-Ni (3.8 g, 65 mmol, 1.0 equiv). The flask was fitted with a hydrogen balloon, and the mixture was stirred for 7 days at room temperature. The reaction mixture was filtered through a celite cake, and the filtrate was concentrated. The residue was purified by HPLC to afford 9 g (64%) of the title compound as the trifluoroacetate salt. MS (ES+): m/e 206 [M+H]+. 1H NMR (400 MHz, DMSO-D6) 7.6 (d, 1H), 7.3 (d, 1H), 7.2 (s, 1H), 4.1 (s, 2H), 3.8 (s, 3H)
Reaction SMILES: C([O-])(O)=O.[Na+].[ClH:6].[CH:7]([N:20]1[CH2:23][C:22]([CH:25]2[CH2:27][CH2:26]2)(O)[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COCCN(S(F)(F)[F:38])CCOC>C(OCC)(=O)C>[ClH:6].[CH:7]([N:20]1[CH2:23][C:22]([CH:25]2[CH2:27][CH2:26]2)([F:38])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: FC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 60.5 %

Procedure:
Saturated NaHCO3 (100 ml) was added to a suspension of 1-Benzhydryl-3-cyclopropylazetidin-3-ol hydrochloride (7.78 g, 24.50 mmol) in ethyl acetate (100 ml). The mixture was transferred to a separating funnel and shaken vigorously until all of the solid had dissolved. The organic layer was separated and the aqueous extracted further with ethyl acetate (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated an oil. The oil was dissolved in dichloromethane (100 ml) and cooled to −78° C. [bis(2-methoxyethyl)amino]sulfur trifluoride (5.98 g, 27.05 mmol, 5.0 ml) was added dropwise and the solution stirred for 30 mins at −78° C. and then warmed to 0° C. and stirred for a further 1 hr. Reaction was quenched with Saturated NaHCO3 (50 ml) and brine (50 ml) and the aqueous layer extracted with dichloromethane (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a yellow oil. The crude was purified on silica gel, eluting with 5% ethyl acetate/petrol. The resulting alcohol was dissolved in ether (100 ml) and the solution cooled to 0° C. A solution of HCl in ether (2M, 25 ml) was then added dropwise over 5 minutes. The HCl salt precipitated from solution. The resulting slurry was stirred at 0° C. for an additional 10 minutes then filtered. The filter cake washed with ether (20 ml) and the solid dried under vacuum. This furnished the product as a white solid (4.71 g, 61%). 1H NMR d4-MeOH δ 0.30-0.52 (4H, m), 1.22 (1H, brs), 4.01-4.23 (4H, m), 5.50-5.60 (1H, brs), 7.13-7.46 (10H, m); ES+ 282.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=C[N:15](C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.N[CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[CH2:35]2.Cl>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:36]2[CH2:35][C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][C:6]4[CH:5]=[C:4]([S:3][CH2:1][CH3:2])[CH:12]=[CH:11][C:7]=4[C:8]([NH2:15])=[O:10])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCSc1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CCSc1ccc(C(N)=O)c(Cc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 4-(ethylthio)benzoic acid (0.26 g, 1.4 mmol) and CDI (0.24 g, 1.5 mmol) in DMF (30 ml) was stirred at 40° C. for 4 hours. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) was added and the mixture was stirred at 40° C. for 2 h. 4% Aqueous HCl (30 mL) was added and the resulting precipitate was filtered, washed with water (30 mL) and dried in vacuo providing N-([2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethylsulfanyl-benzamide as a white solid, (0.39 g, 66% yield); mp 217-219° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 35/65 CH3CN/0.1% H3PO4, 5.75 (99.03%); 1H NMR (DMSO-d6) δ 1.26 (t, 3H, J=7.2 Hz), 1.97-2.01 (m, 1H), 2.03-2.45 (m, 1H), 2.57-2.62 (m, 1H), 2.85-2.97 (m, 1H), 3.05 (q, 2H, J=7.2 Hz), 4.30 (d, 1H, J=17.4 Hz), 4.44 (d, 1H, J=17.4 Hz), 4.58 (d, 1H, J=7.8 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 7.37 (d, 2H, J=8.4 Hz), 7.46 (d, 1H, J=7.8 Hz), 7.53 (s, 1H), 7.69 (d, 1H, J=7.8 Hz), 7.85 (d, 2H, J=8.7 Hz), 9.12 (t, 1H, J=5.7 Hz), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 13.9, 22.5, 25.2, 31.2, 42.7, 47.1, 51.5, 122.0, 122.9, 126.3, 127.0, 127.8, 130.3, 130.6, 140.9, 142.3, 143.9, 165.7, 167.9, 170.9, 172.8; LCMS: MH=438; Anal. Calcd for C23H23N3O4S: C, 62.37; H, 5.37; N, 9.49. Found: C, 62.30; H, 5.29; N, 9.60.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15](O)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].[C:25]1([CH:33]=[C:31]([OH:32])[CH:30]=[C:28]([OH:29])[CH:27]=1)O>CS(O)(=O)=O>[OH:32][C:31]1[C:33]2[C:15](=[O:23])[C:16]3[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:18][C:25]=2[CH:27]=[C:28]([OH:29])[CH:30]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: O=C(O)c1ccccc1S
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2sc2cc(O)cc(O)c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of phosphorous pentoxide (3.71 g, 26.15 mmol) and methane sulfonic acid (27.05 mL, 0.42 mmol) was stirred at 90° C. for about one hour until a clear solution was obtained. To the reaction solution were added thiosalicylic acid (1.04 g, 6.76 mmol) and phloroglucinol (1.02 g, 8.11 mmol), followed by stirring at 70° C. for 10 minutes. After the reaction was completed, the reaction mixture was poured in 1 L of ice water. The resulting precipitate was allowed to stand at 4° C. overnight, combined, washed with water, and then dried under reduced pressure to give an orange solid compound. This compound was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1 (v/v)) to give a yellow solid compound (1.14 g, 51.1%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCN(c2nc3ccc(C(=O)O)cc3s2)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3ccc(C(=O)N4CCOCC4)cc3s2)CC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxylic acid (800 mg, 2.1 mmol) in THF (14 mL) was added HOBt (342 mg, 2.5 mmol), EDAC (807 mg, 4.2 mmol), triethylamine (1.7 g, 17 mmol) and morpholine (735 mg, 8.4 mmol) at room temperature. The reaction mixture was stirred at 40-50° C. for 12 h under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel with a gradient of CH2Cl2/MeOH (100:1->50:1) as eluent to give the crude product, which was further purified by preparative HPLC to give 224 mg (28%) of [2-(4-isopropyl-piperazin-1-yl)benzothiazol-6-yl]morpholin-4-ylmethanone as a trifluoroacetate salt.
Reaction SMILES: [CH:1]([NH2:3])=[CH2:2].[CH:4]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH2:5].C(=O)([O-])[O-].[K+].[K+].[N+:25]([C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1F)([O-:27])=[O:26]>CN(C)C=O>[CH:1]([NH:3][C:29]1[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=1[N+:25]([O-:27])=[O:26])=[CH2:2].[CH:4]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH2:5]
Reactant: C=CN
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: C=Cn1c2ccccc2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
1 gram of a copolymer comprising vinylamine/N-vinylcarbazole (25/75 mole percent) is dissolved in 50 milliliters of anhydrous dimethylformamide (DMF). 0.184 grams potassium carbonate is then suspended in this polymer solution and thereafter 1 milliliter of 2,4-dinitrofluorobenzene (Sanger's reagent) added by dropwise addition. Immediately after the addition of Sanger's reagent a yellow color develops within the solution and becomes more intense as the reaction proceeds. The flask containing the solution is then heated over a steam bath for about 11/2 hours at which time the polymer precipitated from the DMF by the addition of water. The precipitate is separated from the solution by filtration and purified by washing with warm dilute aqueous potassium hydroxide solution. This washing procedure is repeated several times until the filtrate is colorless. The polymer is then dried in a vacuum oven at about 70°C. The number average molecular weight of the product is in the range of about 100,000.
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.ClS([N:18]=[C:19]=O)(=O)=O.CN(C)C=O.O>C(COC)OC>[Br:1][C:2]1[NH:3][C:4]([C:19]#[N:18])=[CH:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: Clc1ccc(-c2cc[nH]c2Br)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(Br)[nH]1
Reaction time: 8 h
Yield: 33151.5 %

Procedure:
A freshly prepared sample of 2-bromo-3-(p-chlorophenyl)pyrrole (4.0 g., 0.015 mmol) is dissolved in dry dimethoxyethane (25 mL). Then while holding the temperature below 25° C., chlorosulfonyl isocyanate (3.08 g., 0.022 mmol) is added. After stirring overnight, the solution is treated with dimethylformamide (6 mL) and stirred for 3 hours. Finally, the solution is poured into water precipitating a brown solid (3.8 g, 90%). Dry column chromatography (80/20 hexane/ethyl acetate) yields 1.4 g (33%) of white solid with m.p. 202°-204° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: COc1ccc(NC(=O)NCCCOc2cccc(CN3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.3 %

Procedure:
To the mixture of 3-(3-piperidinomethylphenoxy)propylamine (3.1 g) in ethanol (31 ml) was added 4-methoxyphenylisocyanate (1.9 g) dropwise slowly under cooling on an ice-water bath. The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (50 ml), washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the crude product (3.3 g) was obtained (yield 66.0 %). This crude product was recrystallized from ethanol to give the title compound (2.1 g), mp 111°-112° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9](CNC)=[CH:8]1.[CH2:19]([N:21](CC)[CH2:22]C)C>C(Cl)Cl>[CH3:19][N:21]([CH2:22][C:8]1[N:7]([CH3:6])[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)[C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: CNCc1cn(C)c2ncccc12
Reactant: C=CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cc2cccnc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of acryloyl chloride (0.43 g, 5.58 mmole) in CH2Cl2 (10 mL) was added dropwise with stirring to a solution of 1-methyl-3-(methylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (0.93 g, 5.28 mmole) and triethylamine (0.8 mL, 5.8 mmole) in CH2Cl2 (40 mL) at 0° C. under N2. The reaction was allowed to warm to RT and stir for 1 hr, then was concentrated in vacuo. The residue was dissolved in 10% NaOH and extracted with CH2Cl2 (3×20 mL). The extracts were dried (MgSO4), filtered, and concentrated. The residual oil was flash chromatographed on silica gel (5% MeOH/CH2Cl2) to give the title compound (1.0 g, 80%) as a colorless oil: MS (ES) m/e 216 (M+H)+.