Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][CH2:23][C:22]=4[CH:21]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][CH2:23][C:22]2[CH:21]=[C:20]([C:16]3[N:15]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:19]=[CH:18][CH:17]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)CCCC4(C)C)n2)CC1
Agent: Cl
Product: CC1(C)CCCc2cc(-c3cccc(N4CCNCC4)n3)ccc21

Procedure:
The above compound is prepared analogously to FS201 starting from 4-[6-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester. Product is the hydrochloride.
Reaction SMILES: N1C=CC=CC=1.[C:7]([NH2:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=O)=[CH:21][CH:20]=1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:7](=[O:15])[N:16]=2)=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccccc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2nc(=O)c3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.5 ml pyridine is added to a suspension of 0.25 mol salicylamide in 50 ml xylene. While boiling under reflux (water separator) 0.26 mol 4-methoxybenzoyl chloride is added within 3 hours and it is heated to boiling for a further 3 hours under reflux. A further 2.5 ml pyridine is added and it is heated for a further 8 hours. After cooling to room temperature it is poured onto 400 ml isopropanol and suction filtered. The residue is recrystallized from ethylene glycol monomethyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:36])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCSCCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCS(=O)CCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1
Yield: 55.1 %

Procedure:
A solution of (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(9-pentylthiononyl)thiochroman (178 mg, 0.355 mmol) and sodium periodate (83 mg, 0.390 mmol) in methanol (20 ml) and water (5 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was quenched with water and then diluted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated. The concentrate was purified with preparative chromatography on silica gel plate (hexane:ethyl acetate=1:1) to obtain 101 mg (yield: 55%) of the title compound as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]=[C:8]([CH3:27])[CH2:9][CH2:10][CH:11]([C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH2:12][C:13]([O:15]C)=[O:14].Cl>C(O)(C)(C)C.O>[O:7]=[C:8]1[CH2:9][CH2:10][CH:11]([CH2:12][C:13]([OH:15])=[O:14])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:27]1
Reactant: COC(=O)CC(CCC(C)=O)C(=O)c1ccccc1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccccc1C1=CC(=O)CCC1CC(=O)O

Procedure:
A solution of potassium t-butoxide (0.507 g.) in t-butanol (5 ml.) was added gradually to a stirred solution of (A) (1.2 g.) in t-butanol (10 ml.) maintained under an argon atmosphere and with external cooling to 20°-25° C. The resultant mixture was stirred for 15 minutes and then evaporated to give a sticky solid. This solid was dissolved in water. The resultant solution was acidified (1M HCl) to pH2 and extracted with ether. The extracts were shaken with 10% w/v sodium carbonate solution (3×20 ml.). The combined carbonate extracts were acidified (1M HCl) to give (4-keto- 2-o-methoxyphenyl-cyclohex-2-enyl)acetic acid (B) as a solid precipitate (0.806 g.), m.p. 183°-184° C. NMR: 2.2 (7H,m), 3.5 (1H,m), 3.8 (3H,s), 6.05 (1H,d), 7.05 (4H,m) ppm.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([S:27][CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].Cl>C(OCC)(OCC)OCC.C(OCC)(=O)C>[CH3:26][C:23]([C:20]1[CH:19]=[C:18]([S:27][CH2:28][CH2:29][C:30]2[O:31][CH:1]=[N:33][N:32]=2)[CH:17]=[C:16]([C:13]([CH3:12])([CH3:14])[CH3:15])[C:21]=1[OH:22])([CH3:24])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: CC(C)(C)c1cc(SCCc2nnco2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 679.6 %

Procedure:
A catalytic amount of p-toluenesulfonic acid (25 mg) is added to a stirred solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (0.50 g, 1.54 mmol) in triethyl orthoformate (10 mL). After 30 minutes, 10 mL of 1N hydrochloric acid is added and stirring is continued for 30 minutes. The reaction mixture is diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate, twice with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a crude product which is chromatographed on a column of silica with ethyl acetate/hexane (1/9 then 1/4) to afford 0.33 g (64%) of 2,6-bis(1,1-dimethylethyl)-4-[[2-(1,3,4-oxadiazol-2-yl)ethyl]thio]phenol, mp 87.5°-89.0° C.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].CCN(CC)CC.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH3:15][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Yield: 105 %

Procedure:
A solution of 2.82 g (10.3 mmol) of 2-Bromo-N-methyl-N-(4-nitrophenyl)-acetamide and 2.08 g (20.6 mmol) of Et3N in 30 mL of CH2Cl2 at 0° C. under N2 is treated with 0.875 g (10.3 mmol) of piperidine for 5 min at 0° C. and refluxed for 1.25 h. The cooled reaction mixture is washed with H2O, treated with Darco, dried (MgSO4) and evaporated to give 3.00 g (100%) of brown oil. 1H NMR (DMSO-d6) δ 8.25 (d, 2H, J=6.9 Hz), 7.63 (d, 2H, J=6.9 Hz), 3.30 (s, 3H), 3.09 (s, 2H), 2.25 (s, 4H), 1.31 (m, 6H); MS (ESI) m/z 278.0 (M+H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:19][CH:20]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])(=[O:18])[CH3:17]>>[C:16]([O:19][CH:20]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:32])(=[O:18])[CH3:17]
Reactant: CCCCCCC(C/C=C\CCCCCCCC(=O)Cl)OC(C)=O
Reactant: O=C(OCCOCCO)c1ccccc1
Product: CCCCCCC(C/C=C\CCCCCCCC(=O)OCCOCCOC(=O)c1ccccc1)OC(C)=O

Procedure:
2-Benzoyloxyethoxyethyl 12-acetoxyoleate was prepared by the procedure of Example 1 from 21 gms (0.1 mole) of diethylene glycol monobenzoate and 36 gms (0.1 mole) of 12-acetoxyoleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[CH:22]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:24]3)[CH:15]1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:23]2
Reactant: CC(C)(C)OC(=O)N1CCC(NC2C3CC4CC(C3)CC2C4)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CC(NC2C3CC4CC(C3)CC2C4)CCN1
Yield: 93.8 %

Procedure:
Ammonium formate (300 mg, 4.8 mmol) was added to a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol) in methanolic ammonia (2.5 mL) followed by 10% Pd/C (50 mg) and stirring was continued at room temperature overnight. The above mixture was filtered through celite, filtrate was collected, and concentrated under reduced pressure to furnish a crude residue. The residue was treated with 2N aqueous NaOH solution, extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure to afford 200 mg (83% yield) of (4-amino-piperidine-1-carboxylic acid tert-butyl ester. Titanium isopropoxide (756 mg, 2.66 mmol) was added to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (293 mg, 1.46 mmol) and adamantan-2-one (200 mg, 1.33 mmol) in EtOH (5 mL) and stirring was continued at room temperature overnight. NaBH4 (100 mg, 2.64 mmol) was added in portionwise and the resulting mixture was stirred at room temperature for 10 hrs. The reaction mixture was quenched with 2N aqueous NH3 solution and filtered. The filtrate was extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure The residue was purified by column chromatography (using neutral alumina and 20% EtOAc in hexane as eluent) to afford 420 mg (94.4% Yield) of 4-(adamantan-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3): δ 4.0 (s, 2H), 2.9-2.4 (m, 4H), 2.0-1.6 (m, 9H), 1.7 (s, 4H), 1.6-1.5 (d, 4H), 1.45 (s, 9H), 1.35-1.2 (m, 3H). A mixture of 4-(adamantan-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (420 mg, 1.25 mmol) in dioxane.HCl (20 mL) was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to get the residue, which was washed with ether to afford 363 mg (93.8% Yield) of 4-(adamantan-2-ylamino)-piperidine dihydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 9.2 (s, 1H), 9.0 (s, 3H), 3.8 (s, 4H), 3.5-3.3 (m, 4H), 3.0-2.8 (m, 2H), 2.4 (d, 2H), 2.3 (d, 3H), 2.0 (t, 2H), 1.9-1.8 (m, 5H), 1.7 (s, 2H), 1.6-1.5 (d, 2H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[C:13]1[C:12]1[C:7](=[C:8]([CH3:21])[C:9]([O:19][CH3:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[Br:32]Br>C(Cl)Cl.O>[Br:32][C:14]1[C:15](=[O:18])[CH2:16][CH2:17][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=1[C:12]1[C:7](=[C:8]([CH3:21])[C:9]([O:19][CH3:20])=[CH:10][CH:11]=1)[CH2:6]2
Reactant: BrBr
Reactant: CCCCC12CCC(=O)C=C1c1ccc(OC)c(C)c1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)c(C)c1C2
Reaction time: 0.08 h
Yield: 89 %

Procedure:
A mixture of 9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (133 mg, 0.468 mmol), CCl4 (0.94 mL), and NaHCO3 (196 mg, 2.333 mmol) was cooled in an ice bath and stirred. Bromine (0.024 mL, 0.467 mmol) was added while stirring and swirling the reaction mixture by hand. A gummy, red precipitate formed during the addition. The mixture was swirled by hand for 5 minutes in order to break up the gum, which gradually changed to a stirrable orange solid. The mixture was stirred and swirled a total of 35 minutes at 0° C. The mixture was diluted with CH2Cl2 and water and shaken. The organic phase was separated, washed with water containing Na2S2O4, washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to a yellow gum (241 mg). The crude product was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates, developing with 4:1 hexanes-EtOAc. The major UV visible band at Rf 0.39-0.50 was eluted with EtOAc and evaporated under vacuum to give 4-bromo-9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (151 mg) as a white solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20])(=[O:13])=[O:12])([O-:4])=[O:3].[CH2:21]([O:28][C:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH2:41][C:42](O)=[O:43])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH2:41][C:42]([N:17]1[CH2:18][CH2:19][N:14]([S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N+:2]([O-:4])=[O:3])(=[O:12])=[O:13])[C:15](=[O:20])[CH2:16]1)=[O:43])=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Reactant: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C(=O)C1)OCc1ccccc1
Yield: 61.5 %

Procedure:
The title compound (731 mg, 61%) was synthesized by reaction of 1-(2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (644 mg, 2.0 mmol) with [6-N-(benzyloxycarbonyl)-adenin-9-yl]-acetic acid (655 mg, 2.0 mmol) as per the procedure of example 77. 1H NMR (DMSO-d6) δ 10.69 (s, 1H), 9.00 (m, 1H), 8.71 (m, 1H), 8.63˜8.58 (m, 2H), 8.31 (s, 0.6H), 8.29 (s, 0.4H), 7.47˜7.33 (m, 5H), 5.39 (s, 1.2H), 5.29 (s, 0.8H), 5.21 (s, 2H), 4.57 (s, 0.8H), 4.29 (s, 1.2H), 4.15˜4.09 (m, 2.4H), 3.93˜3.86 (m, 1.6H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[OH-].[Na+].[C:15]([CH2:18][S:19][C:20](=S)[S:21]CC(O)=O)(O)=[O:16]>O>[O:16]=[C:15]1[CH2:18][S:19][C:20](=[S:21])[N:3]1[NH:2][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)CSC(=S)SCC(=O)O
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a water (20 mL) solution of 2-hydrazino-benzoic acid hydrochloride (2.508 g, 13.30 mmol) was added water solution of sodium hydroxide (1.029 N, d=1.040, 26.81 g, 26.60 mmol) followed by bis(carboxymethyl)trithiocarbonate (3.006 g, 13.28 mmol). The mixture was stirred at reflux temperature for 10 h, cooled to room temperature and stirred for 50 h. The solid product was filtered off and washed on funnel successively with water (2×10 ml), ether (5 mL) and hexane (20 mL). The material was dried in a vacuum oven at 80° C. for 5 h to afford 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (2.93 g, 82%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (1H, bs), 6.66 (1H, m), 6.90 (1H, m), 7.40 (1H, m), 7.89 (1H, m), 13.37 (1H, bs). ESI-MS: 267.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]([OH:12])[CH2:10][CH2:9][C:4]2(OCC[O:5]2)[CH2:3]1.Cl.C(OCC)(=O)C>CO>[OH:12][CH:11]1[CH2:10][CH2:9][C:4](=[O:5])[CH2:3][C:2]1([CH3:13])[CH3:1]
Reactant: CC1(C)CC2(CCC1O)OCCO2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)CCC1O
Yield: 88 %

Procedure:
A solution of 7,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol (1.0 equiv.) in 2.0 N hydrochloric acid aqueous solution (3.7 equiv.) and MeOH (0.9 M) was stirred at room temperature overnight. TLC (petroleum ether:ethyl acetate=3:1) showed that the reaction was completed. The solvent was removed under reduced pressure, the resulting residue was basified with saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give 4-hydroxy-3,3-dimethylcyclohexanone (88% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.69-3.71 (m, 1H), 2.42-2.45 (m, 2H), 2.09-2.25 (m, 1H), 2.04-2.08 (m, 4H), 1.91-1.95 (m, 1H), 0.98 (s, 6H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:30]=[CH:29][N:28](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[OH-].[K+].CC(O)=O>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:30]=[CH:29][NH:28][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cn1ncc2cc(Nc3nc(Nc4ccc(C(N)=O)cc4)nc4[nH]ccc34)ccc21
Temperature: 70 °C
Reaction time: 20 h
Yield: 24.4 %

Procedure:
To a solution of 4-(4-(1-methyl-1H-indazol-5-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (40 mg, 0.072 mmol) in dioxane (2 mL), aq. 1N KOH (1.8 mL, 1.80 mmol) was added. The mixture was stirred at 70° C. for 20 h. HOAc (1.0 mL) was added. The mixture was purified by HPLC to give the titled compound (7 mg). MS 399.2 (M+H) (Compound 25-1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:14]=[CH:15]/[Si](C)(C)C.[Cl:20]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:14]=[CH:15]/[Cl:20]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1/C=C/[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)c(F)c(N)c1/C=C/Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To a solution of (E)-methyl 4-amino-6-chloro-5-fluoro-3-(2-(trimethylsilyl)vinyl)picolinate (176 mg, 0.581 mmol) in DMF (2.3 mL) was added N-chlorosuccinimide (116 mg, 0.872 mmol). The reaction mixture was stirred at 60° C. After 4 h, the observed conversion was ˜50%. At this point, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (SiO2, hexane/EtOAc gradient) to afford the title compound (75 mg, 0.283 mmol, 48.7% yield) as an orange solid: mp 128-130° C.; 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=14.1 Hz, 1H), 6.45 (d, J=14.1 Hz, 1H), 4.73 (s, 2H), 3.93 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −138.17; ESIMS m/z 265 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCNCC1)c1cccc(Cl)c1
Yield: 54.9 %

Procedure:
A solution of 0.500 g (1.66 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide and 0.71 g (8.3 mmol) of piperazine in acetonitrile (5 mL) are heated to 175° C. for 30 minutes in a microwave reactor. The mixture is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography to provide 0.320 g (54.9%) of 3-chloro-N-(5-chloro-2-piperazin-1-yl-pyridin-3-yl)-benzamide as a colorless solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Cl[C:21]1[C:22]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:23]=2[S:24][C:25]=1[C:26]#[N:27]>CN(C=O)C>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:22]2[C:21]([O:19][C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[C:25]([C:26]#[N:27])[S:24][C:23]=2[CH:28]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)c1ccc2c(Cl)c(C#N)sc2c1
Reactant: COc1ccc(O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C#N)sc3cc(S(C)(=O)=O)ccc23)cc1
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of KHMDS (0.18 g, 0.90 mmol) in DMF (7 mL) was treated by sequential addition of 4-methoxyphenol (0.12 g, 0.99 mmol) then 3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carbonitrile 8 (0.20 g, 0.75 mmol). After 2 h, the mixture was partitioned between EtOAc and brine. The organic layer was washed with brine (2×), dried (Na2SO4), filtered, and evaporated. Chromatography, followed by recrystallization (EtOAc/hexane) gave 0.20 g (74%) of 6-methanesulfonyl-3-(4-methoxy-phenoxy)-benzo[b]thiophene-2-carbonitrile 15 as white needles; (m+H)+ 360.
Reaction SMILES: [CH:1]([C:4]([CH3:14])([N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13])[C:5]#[N:6])([CH3:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][C:9]1[C:8](=[O:13])[N:7]([C:4]([CH:1]([CH3:3])[CH3:2])([CH3:14])[C:5]#[N:6])[C:11](=[O:12])[CH:10]=1
Reactant: BrBr
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Solvent: CC(=O)O
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Br)C1=O
Temperature: 5 °C

Procedure:
To a solution of α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (50 g, 0.25 mol) in acetic acid (500 ml) heated at 75° C. is added bromine (40.76 g, 0.255 mol) in acetic acid (80 ml) dropwise with stirring. The reaction is maintained at 85° overnight and evaporated to a syrup, which is dissolved in methylene chloride (300 ml), is cooled to 5° C. to which triethylamine (34.78 ml) is added. After stirring for 2 hours the brown methylene chloride solution is diluted with ether and a white precipitate is formed. This is extracted with water (400 ml) and the organic layer is dried over anhydrous magnesium sulfate, then passed through a 2 inch bed of silica gel with methylene chloride to elute. The eluate is obtained as a dark brown oil. Anal. calcd. for C10H10N2O2Br: C, 44.29; H, 4.09; N, 10.33. Found: C, 43.37; H, 4.05; N, 10.07.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][NH2:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][NH:27][CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CNCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: CNCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-methylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.03-8.0 (m, 3 H), 7.87-7.84 (d, J=8.8 Hz, 1 H), 7.71-7.70 (d, J=1.2 Hz, 1 H), 7.57-7.53 (m, 2 H), 6.07 (s, 1 H), 5.40 (s, 2 H), 4.56 (s, 2 H), 3.96-3.93 (dd, J=6.0, 6.4 Hz, 2 H), 3.75-3.73 (q, J=4.4 Hz, 2 H), 3.43-3.40 (q, J=6 Hz, 2 H), 2.80 (s, 3 H), 2.46 (s, 3 H).