Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[C:12]#[N:13])[S:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].[OH2:26]>S(=O)(=O)(O)O>[C:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=3)[C:12]([NH2:13])=[O:26])[S:10][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O
Reactant: N#CC(=C1Nc2ccc(C(=O)O)cc2S1)c1nccc(C(F)(F)F)n1
Agent: O=S(=O)(O)O
Product: NC(=O)C(=C1Nc2ccc(C(=O)O)cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 2-[6-carboxybenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)-acetonitrile (620 mg, 1.70 mmol) in concentrated sulfuric acid (5 mL), was heated to 50° C. for 10 hr. The mixture was cooled to room temperature and added dropwise to rapidly stirred room-temperature water (100 mL). The precipitate that formed was collected by filtration, washed with water and hexanes, and dried under vacuum to give 2-[6-carboxybenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (587 mg, 90% yield) as a brown solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10](=[O:16])[CH2:9][CH2:8]2.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>C1COCC1>[CH2:19]([O:18][C:17]([CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][CH3:3])[CH:6]=2)[C:10]1=[O:16])=[O:21])[CH3:20]
Reactant: CCOC(=O)OCC
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2cc(OC)c(OC)cc2C1=O
Yield: 98 %

Procedure:
This compound is prepared according to the procedure disclosed in EP 534859. To a suspension of sodium hydride (50% dispersion in oil, 20 g) in 240 mL of THF, diethyl carbonate was added and the mixture was stirred and refluxed for 90 min. A solution of 5,6-Dimethoxyindan-1-one (40 g) in THF (440 mL) was added, the mixture was heated under reflux for 3 h, then cooled and concentrated. Ethyl acetate (200 mL) was added, the organic layer was washed with water. The organic layer was dried over MgSO4, filtered and the ethyl acetate was removed under reduced pressure. The title product was obtained in 98% yield.
Reaction SMILES: C(O[C@H](C1N(C2C=CC=CC=2)N=CC=1)[C@H](C1C=CC(Cl)=C(Cl)C=1)CC=O)(=O)C.C([O:32][C@H:33]([C:46]1[N:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:49]=[CH:48][CH:47]=1)[C@H:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:35][CH:36]=[CH2:37])(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.C(OCC)C.O.[Os](=O)(=O)(=O)=O>[Cl:45][C:40]1[CH:39]=[C:38]([C@H:34]([CH2:35][CH:36]=[CH2:37])[C@@H:33]([C:46]2[N:50]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:49]=[CH:48][CH:47]=2)[OH:32])[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H](OC(C)=O)c1ccnn1-c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)O[C@H](c1ccnn1-c1ccccc1)[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H](O)c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110 %

Procedure:
5-[(1S,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazole.A solution of 5-[(1S,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenylpyrazole (90 mg) in tetrahydrofuran (1 mL), diethyl ether (2 mL) and water (2 mL) was treated with osmium tetraoxide (0.07 mL of a 0.2M solution in water) and sodium periodate (100 mg). The resulting biphasic mixture was stirred vigorously at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed (brine), dried, and evaporated to afford the title compound as a pale amber foam (89 mg). This material was used immediately; NMR: 9.57 (s,1), 7.62 (d,1), 7.45-7.21 (m,6), 6.99 (d,1), 6.72 (dd,1), 6.31 (d,1), 6.15 (d,1), 3.63 (m,1), 2.77 (m,2), 2.03 (s,3); MS: m/z=419((M+1), 37Cl), 417((M+1), 35Cl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+](C1C=C(S(O[CH2:36][C@@H:37]2[CH2:39][O:38]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][C:5]([O:12][CH2:36][C@@H:37]2[CH2:39][O:38]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1OC[C@@H]1CO1
Yield: 74 %

Procedure:
A solution of methyl 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (0.37 g, 1.16 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.30 g, 1.16 mmol) and caesium carbonate (0.45 g, 1.4 mmol) in dimethylformamide (15 mL) was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by flash chromatoghrphy on silica gel (eluent:ethyl acetate/n-heptane), yielding the titled compound (0.33, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14](=O)(=O)[CH2:15][CH2:16][C:12]=3[N:11](C(OC(C)(C)C)=O)[C:10]3[CH2:26][O:27][CH2:28][C:29](=[O:30])[C:9]2=3)=[CH:4][C:3]=1[Sn](C)(C)C.ClN1C(=O)CCC1=O.[I-:43].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14][CH2:15][CH2:16][C:12]=3[NH:11][C:10]3[CH2:26][O:27][CH2:28][C:29](=[O:30])[C:9]2=3)=[CH:4][C:3]=1[I:43]
Reactant: CC(C)(C)OC(=O)N1C2=C(C(=O)COC2)C(c2ccc(F)c([Sn](C)(C)C)c2)C2=C1CCS2(=O)=O
Reactant: [I-]
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C1COCC2=C1C(c1ccc(F)c(I)c1)C1=C(CCS1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
A mixture of the product from Example 37B (0.023 g, 0.038 mmol) in 1% acetic acid in methanol (25 mL) was treated with N-chlorosuccinimide (0.010 g, 0.077 mmol), then treated with sodium iodide (0.011 g, 0.077 mmol), stirred for 10 minutes, treated with pulverized sodium thiosulfate pentahydrate (0.020 g, 0.080 mmol), stirred for 10 minutes and concentrated to dryness. The residue was treated with trifluoroacetic acid (3 mL), stirred at ambient temperature for 15 minutes and concentrated to dryness. The residue was treated with trifluoroacetic acid (3 mL), heated gently on a steam bath for 1 minute, cooled to ambient temperature and concentrated to dryness. The residue was purified by chromatography on silica gel (2% methanol and then 5% methanol in methylene chloride) to provide the title compound (0.0156 g).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]=1)=[NH:5])C.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C[O-].[Na+]>CO>[CH3:26][O:25][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:9]3[C:13]4[C:12](=[CH:8][CH:7]=[C:6]([C:4]5[N:5]=[C:29]([CH2:30][N:31]6[CH2:35][CH2:34][CH2:33][CH2:32]6)[NH:28][N:27]=5)[CH:14]=4)[NH:11][N:10]=3)[CH:16]=2)[CH:21]=1
Reactant: NNC(=O)CN1CCCC1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc4cc(OC)ccc4c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(-c3n[nH]c4ccc(-c5n[nH]c(CN6CCCC6)n5)cc34)ccc2c1
Temperature: 95 °C
Yield: 10.5 %

Procedure:
The title compound was prepared using the same procedure as for Example 423. To a suspension of ethoxy[3-(6-methoxy(2-naphthyl))(1H-indazol-5-yl)]methanimine (0.386 g, 1.01 mmol) in methanol (5 mL) was added N-amino-2-pyrrolidinylacetamide (0.433 g, 3.03 mmol) and 4.3 M sodium methoxide (0.518 mL, 2.23 mmol). The mixture was heated in a sealed tube at 95° C. for 16 h. The solvent was removed using a rotary evaporator which gave a solid residue. Purification of the residue by preparative HPLC (30–100%, acetonitrile/water) gave the title compound (0.045 g, 10% yield): 1H NMR (DMSO-d6) δ 13.41 (br s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.09 (t, 2H), 8.00 (t, 2H), 7.68 (d, 1H), 7.39 (d, 1H), 7.23 (dd, 1H), 3.91 (s, 3H), 3.75 (s, 2H), 2.53 (m, 4H), 2.49 (m, 4H); ES-MS (m/z) 425 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[C:14]1[C:15]2[CH:24]=[CH:23][NH:22][C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.ClC(N(C)C)=C(C)C.[N:38]1[CH:43]=[CH:42][CH:41]=[N:40][C:39]=1[NH2:44]>O1CCCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:44][C:39]2[N:40]=[CH:41][CH:42]=[CH:43][N:38]=2)=[O:10])=[CH:7][C:6]=1[C:14]1[C:15]2[CH:24]=[CH:23][NH:22][C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1
Reactant: Cn1cc(-c2cc(C(=O)O)ccc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Reactant: Nc1ncccn1
Agent: CC(C)=C(Cl)N(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(C(=O)Nc3ncccn3)ccc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of Example 50b (24 mg, 0.06 mmol) in a 4 mL vial was dissolved in anhydrous tetrahydrofuran (1.0 mL), followed by the addition of 1-chloro-N,N,2-trimethyl-1-propenylamine (65 μL, 0.48 mmol). This was capped and placed to shake for 2 hours at ambient temperature. Then, a solution of pyrimidin-2-amine (9 mg, 0.09 mmol) in anhydrous tetrahydrofuran (0.3 mL) was added, followed by a solution of 4-(dimethylamino)pyridine (37 mg, 0.3 mmol) in anhydrous tetrahydrofuran (0.5 mL). The mixture was stirred at 60° C. for 16 hours, cooled, and concentrated to dryness. The residues were dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (10-80% acetonitrile in 0.1% TFA water). 1H NMR (500 MHz, DMSO-d6/D2O, Temp=25° C.) δ ppm 8.73 (d, J=4.88 Hz, 2H) 8.09 (d, J=2.44 Hz, 1H) 7.95 (dd, J=8.70, 2.29 Hz, 1H) 7.42-7.48 (m, 1H) 7.41 (s, 1H) 7.32-7.38 (m, 2H) 7.27 (t, J=4.88 Hz, 1H) 7.11-7.17 (m, 1H) 6.90 (d, J=8.85 Hz, 1H) 6.32 (d, J=2.75 Hz, 1H) 3.60 (s, 3H); (ESI) m/z 474 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[C:17]=[S:18])[N:5]=1.[CH3:19]I.O>O1CCCC1>[CH3:3][C:4]1[N:5]=[C:6]2[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:17]([S:18][CH3:19])[N:7]2[N:8]=1
Reactant: CI
Reactant: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC1=Nc2ccccc2Cc2nc(C)nn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.91 g of sodium hydride in 27 ml of tetrahydrofuran is added dropwise a solution of 8.74 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 60 ml of tetrahydrofuran over a period of 20 minutes. The mixture is stirred at room temperature for 2 hours. To the resulting suspension is added a solution of 5.4 g of methyl iodide in 35 ml of tetrahydrofuran dropwise at 0° over a period of 15 minutes. The mixture is stirred at room temperature for 1 hour, poured into water and extracted three times with methylene chloride. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to give 2-methyl-5-methylthio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][C:3]1=[O:4].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12].C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[C:10]([O:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][C:3]1=[O:4])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(C)CC(O)C(=O)O1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of 100 mmole of the above-prepared 2-hydroxy4,4-dimethyl-γ-butyrolactone, 150 mmole of methacrylic chloride, 150 mmole of triethylamine, and 300 ml of toluene was stirred at 25° C. for 4 hours. Water was added to the reaction mixture, the organic layer was then concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield 2-methacryloyloxy-4,4-dimethyl-γ-butyrolactone in a yield of 85%.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:23])=[C:11]([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][N:16]=2)[N:12]=1.O1CCCC1.C(O)C>O>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:23])=[C:11]([CH2:13][O:14][C:15]2[N:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=2)[N:12]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Sodium borohydride (410 mg) was added to a mixture of 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]nicotinaldehyde (3.10 g), tetrahydrofuran (50 ml) and ethanol (50 mL) at room temperature, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethanol (2.86 g, yield 92%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 120–121° C.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10](Cl)=[O:11])[CH:8]=[CH:9][C:2]=12.[N:13]1[C:18]2[NH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[NH:22][CH2:23][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:22]3[CH2:23][C:17]4[CH:16]=[CH:15][CH:14]=[N:13][C:18]=4[NH:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]3=4)=[O:11])[CH:8]=[CH:9][C:2]=12
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2nonc2c1)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
Under a nitrogen atmosphere, an equimolar mixture of benzofurazan-5-carbonyl chloride (0.5 g, 2.75 mmol), 6,1 1-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (0.54 g, 2.75 mmol) and potassium carbonate in N,N-dimethylformamide (10 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, and dried over sodium sulfate. The solution was filtered through a thin pad of silica gel Merck-60, and the filtrate evaporated in vacuo. The residual oil was crystallized from diethyl ether to provide the pure title compound as a yellow solid (0.495 g), m.p. 193-194° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C@H:25]([CH3:35])[CH2:26][NH:27]C(=O)OC(C)(C)C.[ClH:36]>CCOCC>[ClH:36].[NH2:27][CH2:26][C@H:25]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])=[CH:7][C:2]=1[F:1])[CH3:35]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN)c(F)c1
Yield: 98 %

Procedure:
Following General Procedure D1, (S)-tert-butyl 2-(2-fluoro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (100 mg, 0.20 mmol) was reacted with HCl in ether (10 mL) to afford the desired product (80 mg, 98%) as an off-white solid: ESI MS m/z 397 [C22H21FN2O2S+H]+.
Reaction SMILES: FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[Tl+3].[C:23]([O:26][CH2:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:25])[CH3:24].[I:36]I.O>FC(F)(F)C(O)=O.C(OCC)C>[C:23]([O:26][CH2:27][C:28]1[C:29]([F:35])=[CH:30][CH:31]=[C:32]([I:36])[C:33]=1[F:34])(=[O:25])[CH3:24]
Reactant: II
Reactant: CC(=O)OCc1c(F)cccc1F
Agent: O=C([O-])C(F)(F)F
Agent: [Tl+3]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(=O)OCc1c(F)ccc(I)c1F
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Thallium tris(trifluoroacetate) (24.5 g, 0.045 mole) was added to a stirred solution of 16.8 g (0.090 mole) of (2,6-difluorophenyl)methyl acetate in 60 ml of trifluoroacetic acid. The reaction mixture was heated at 40°-50° C. for 15 minutes then 12.7 g (0.05 mole) of iodine was added. Upon complete addition the reaction mixture was heated under reflux for an additional 2 hours. The solvent was removed under reduced pressure and replaced with an equal volume of methylene chloride. The methylene chloride was removed under reduced pressure to give an oily residue. The residue was poured onto ice, using water and diethyl ether to rinse. The mixture was stirred for 30 minutes as 10 g of sodium metabisulfite and then 40 ml of a 5% aqueous solution of sodium hydroxide were added. The aqueous phase was separated and the organic phase was washed with two portions of water, one portion of a 5% aqueous solution of sodium thiosulfate, two portions of water, and finally one portion of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was distilled under reduced pressure to give 10.5 g of (2,6-difluoro-3-iodophenyl)methyl acetate, b.p. 70°-80° C./2.2 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])[CH:3]=1.[ClH:30]>ClCCl.CO>[ClH:30].[ClH:30].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOc1nc(C(=O)NCC2CCNCC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The compound prepared in Example 225 (0.603 g) was suspended in dichloromethane (30 mL) and methanol (10 mL). Hydrogen chloride solution (4 mol/L in 1,4-dioxane) (10.0 mL) was added and the reaction mixture stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (0.547 g), which was used without further purification, possessing the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:11]([OH:14])(=[O:13])=O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:11]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:13])=[O:14])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc(Br)cc(S(=O)(=O)O)c1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 3-bromo-5-nitrobenzenesulfonic acid (1.86 g, 6.59 mmol) in toluene (37 mL) and phosphorus pentachloride (2.75 g, 13.2 mmol) were heated at 100° C. overnight. The reaction mixture was cooled to 0° C. and treated with tert-butylamine (1.03 mL, 9.89 mmol) and N,N-diisopropylethylamine (5.74 mL, 33.0 mmol). After stirring at 25° C. for 30 min, the reaction mixture was diluted with 1 N HCl and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (2.2 g, 98%). 1H NMR (400 MHz, (400 MHz, DMSO-d6): δ 8.62 (m, 1H), 8.56 (m, 1H), 8.37 (m, 1H), 8.03 (s, 1H), 1.32 (s, 9H).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)#[N:2]
Reactant: [C-]#N
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: N#CCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 67.5 %

Procedure:
Potassium cyanide (2.6g) was added to a stirred, two-phase mixture of 4-(chloromethyl)biphenyl (2.02g) and tetrabutyl ammonium hydrogen sulphate (200 mg) in dichloromethane (50 ml). The reaction mixture was stirred at ambient temperature for 36 hours. The organic layer was separated and washed with water (10 ml), dried (MgS04) and evaporated to give a solid residue which was crystallised from n-hexane to give 4-(cyanomethyl)biphenyl (1.3g) as a solid, m.p. 95° C.; microanalysis, found: C, 86.3; H, 5.7; N, 7.2%; C14H11N .O.1H2O requires C, 86.2; H, 5.7; N, 7.18%.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([N:24]2[CH2:29][CH2:28][N:27](C3C4C(C)=CNC=4N=CN=3)[CH2:26][C@@H:25]2[CH3:40])=[N:21][C:22]#[N:23])[CH:16]=[CH:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]4[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:26][C@@H:25]2[CH3:40])=[N:21][C:22]#[N:23])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc2c(Cl)ncnc2[nH]1
Reactant: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Product: Cc1cc2c(N3CCN(C(=NC#N)Nc4cccc(Br)c4)[C@@H](C)C3)ncnc2[nH]1

Procedure:
Using the pyrrolopyrimidine from step A, the title compound was prepared in the same manner as (S)—N-(3-bromophenyl)-N′-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide from Example 5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.[CH3:56][C@H:57]1[O:62][C@@H:61]([CH3:63])[CH2:60][NH:59][CH2:58]1>O1CCOCC1.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:59]3[CH2:58][C@H:57]([CH3:56])[O:62][C@H:61]([CH3:63])[CH2:60]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH:14]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)C[C@H](C)O1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g (3.96 mmol), rac-2,2′-bis diphenylphosphino)-1,1′-binaphthyl 0.12 g (0.198 mmol), cis-2,6-dimethylmorpholine 0.37 g (3.3 mmol) and Pd (dba)3 60 mg (0.066 mmol) in 6 ml dioxane, followed by work up and HPLC purification: LC-MSD, m/z for C24H24ClN3O4S [M+H]+: 486.0