Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:28]([OH:31])[CH2:29][OH:30].Cl>O>[OH:30][CH2:29][CH2:28][O:31][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: OCCO
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=C1c2ccc(OCCO)cc2C(=O)c2cc3ccccc3cc21
Temperature: 125 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
27.6 g (0.1 mol) of 2-fluoro-5,12-naphthacenequinone, 32.5 g (0.1 mol) of Cs2CO3 and 300 ml of ethylene glycol are introduced into a sulfonating flask under nitrogen. After heating to 125° C., the mixture is stirred for 3 h. The reaction mixture is then poured into 3000 ml of water containing hydrochloric acid and the product which has precipitated is filtered off and washed several times with water. After drying in vacuo at 80° C., 30.3 g (97.1%) of pure product are obtained, melting point 208.8° C. The procedure is analogous in Examples 19-23 (see Table 2).
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>C(Cl)CCl>[C:16]1([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[C:8]([C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:11]([OH:10])=[O:12])=[O:9])=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
Employing a procedure similar to that described in part A of Example 10 above, 7.15 g (0.025 mole) of tetrachlorophthalic anhydride and 3.65 g (0.028 mole) of 2-methylindole were interacted in 100 ml of ethylene dichloride to obtain 2-[(2-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrachlorobenzoic acid (Formula VIII: R°=R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =Y1 =H), an orange solid melting at 200°-201° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CN(C=O)C.C(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(c2)C(=C2C(=O)Nc4ccccc42)OC3)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-(6-amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (1 g, 3.79 mmol) and 2,4-dimethoxybenzaldehyde (0.75 g, 4.54 mmol) in 1% AcOH/DMF (30 ml), was added sodium triacetoxyborohydride (3.2 g, 15.1 mmol). The mixture was stirred at room temperature for 16 hours, diluted with CHCl3 (200 ml), washed with saturated aqueous NaHCO3 solution (200 ml) and water (2×200 ml), dried over anhydrous Na2SO4. Removal of the solvent provided the crude product. Recrystallization of the crude product from MeOH resulted in 3-[6-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a bright yellow solid (1.3 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[C:17](Cl)=[CH:18][C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[N:20][CH:21]=2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]2[O:14][C:17]3[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:20]=[CH:21][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCc3ccccc3)cc2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 3.5 h
Yield: 35.7 %

Procedure:
A suspension of tert-butyl ((2S)-1-((5-((4-(benzyloxy)benzoyl)amino)-4-chloropyridin-2-yl)oxy)propan-2-yl)carbamate (2.50 g), potassium carbonate (1.35 g) and copper(I) iodide (93.9 mg) in DMF (20 mL) was stirred at 160° C. for 3.5 hr. The reaction mixture was subjected to silica gel chromatography (NH, ethyl acetate), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (830 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([OH:17])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([O:17][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:15]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2O)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2OCCCc2ccccc2)cc1
Yield: 18.4 %

Procedure:
A solution of methyl 1-{4-[(ethylamino)carbonyl]phenyl}-5-hydroxy-1H-1,2,3-triazole-4-carboxylate (580 mg, 2 mmol) obtained in Example 1211a), (3-bromopropyl)benzene (438 mg, 2.2 mmol, 1.1 eq.) and potassium carbonate (332 mg, 2.4 mmol, 1.2 eq.) in DMF (5 ml) was stirred at 90° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml), washed with water (10 ml×2) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (150 mg, 18%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](O)=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:33])=O>>[CH2:1]([O:8][C:9]1[C:10]([Cl:33])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C(F)(F)F)ncc1OCc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: FC(F)(F)c1ncc(OCc2ccccc2)c(Cl)n1
Temperature: 100 °C
Yield: 42.6 %

Procedure:
A mixture of XXIII (3.3 g, 12.2 mmol), diethyl aniline (1.94 mL, 12.2 mmol), and phosphorus oxychloride (0.758 mL, 8.13 mmol) was heated in a 100° C. oil bath for 3 hr. The dark reaction mixture was vacuum distilled to give the product as a clear oil (1.0 g, 28.4%).
Reaction SMILES: CN(C)C=O.CC1C=CC(S(O[CH2:17][C@@H:18]2[O:20][CH2:19]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([OH:45])=[C:40]([C:43]#[N:44])[CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:30][C:29]=1[F:48]>C(OCC)(=O)C.O>[NH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:45][CH2:17][C@H:18]4[CH2:19][O:20]4)=[C:40]([C:43]#[N:44])[CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:30][C:29]=1[F:48]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OC[C@H]1CO1
Temperature: 50 °C
Yield: 55.4 %

Procedure:
After adding dimethylformamide (8 ml), (2R)-(−)-glycidyl p-toluenesulfonate (1000 mg) and potassium carbonate (940 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (1000 mg), the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (659 mg) as light yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9](=[O:10])[NH:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 1,1-dimethylethyl(3S)-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate in DCM (100 mL) at RT was added TFA (50 mL). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title compound (2.93 g, 94%) as a light yellow oil: LC-MS (ES) m/e 235 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15]C1CC(C(C)C)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1

Procedure:
The bromination of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][OH:5].[N+:6]([C:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([C:21]=2OC2C=CC=CC=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7].Cl>C1(O)C=CC=CC=1.CCOCC>[ClH:1].[N+:6]([C:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([C:21]=2[NH:2][CH2:3][CH2:4][OH:5])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Oc3ccccc3)c12
Reactant: NCCO
Agent: Cl
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc2nc3ccccc3c(NCCO)c12
Temperature: 80 °C
Yield: 91 %

Procedure:
This compound is synthesized generally using the methods described in EP 38579. Specifically, 2 g of 2-amino-ethanol hydrochloride is added to 6.4 g of 1-nitro-9-phenoxyacridine dissolved in 20 g of freshly distilled phenol. The mixture is heated for 40 minutes at a temperature of 80° C. and then cooled, diluted with ether. It is then poured into a dry ether which was acidified with an ethereal solution of hydrogen chloride. The orange colored precipitate of 1-nitro-9-(2-hydroxyethylamino)-acridine hydrochloride, obtained in this way is filtered and crystallized from dry ethanol. The melting point of the compounds obtained was 170° C., with decomposition. Yield 91%. Elementary analysis for the formula: C15H14N3O3Cl: calculated: 56.47% C, 4.42% H, 13.17% N; determined: 56.44% C, 4.40% H, 13.03% N
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:27])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].C1C(=O)N([Br:35])C(=O)C1.O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:27])[C:8]([Br:35])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)cn1C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)c(Br)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 3-(4-benzyloxy-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester. (184.73 g, 0.512 mol, prepared in example E-6a or E-6b) in anhydrous THF (2,000 mL) is treated with NBS (109.47 g, 0.615 mol). The resulting reaction mixture is allowed to stir at room temperature overnight. The reaction mixture is poured into water (2,000 mL). The resulting solution is divided into 2 equal parts, and each is extracted with EtOAc (3×800 mL each). The combined organics are dried over anhydrous MgSO4, filtered, then concentrated in vacuo to afford a yellow solid. The yellow solid is purified by column chromatography (silica gel, EtOAc/Hexanes 1/3) to afford the title compound (133.99 g, ˜60% yield) as a white solid: 1H NMR (500 MHz; CDCl3) δ 7.46-7.44 (m, 2H), 7.41-7.38 (m, 2H), 7.36-7.32 (m, 1H), 7.29-7.26 (m, 2H), 7.01-6.99 (m, 2H), 5.10 (s, 2H), 4.11 (q, 2H), 3.98 (s, 3H), 1.02 (t, 31); MS(ES): m/z 438.9.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[C:9](I)[CH:10]=[C:11]([CH3:13])[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C2C=CC=CC=2O)C=CC=CC=1.CCCCCCCCCCCC>[Cu]I>[CH2:1]([O:5][C:9]1[CH:10]=[C:11]([CH3:13])[CH:12]=[C:7]([CH3:6])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)cc(I)c1
Reactant: CCCCO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1-c1ccccc1
Solvent: CCCCCCCCCCCC
Product: CCCCOc1cc(C)cc(C)c1
Temperature: 90 °C

Procedure:
A screw cap test tube was charged with n-butanol (573 μL, 6.26 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (19.0 mg, 0.100 mmol), Cs2CO3 (977 mg, 3.00 mmol), 2-phenylphenol (85.1 mg, 0.500 mmol) and the solvent (1 mL). The test tube was sealed with a screw cap. The reaction mixture was stirred magnetically and heated at 90° C. for 36 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. The yield of the desired product was determined using GC analysis; the results are tabulated below.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=Cc1ccccc1
Product: Oc1cccc2ccc(C=Cc3ccccc3)nc12
Temperature: 25 °C

Procedure:
A mixture of 8-hydroxyquinaldine (10.02 g) and benzaldehyde (16.8 mL) is heated at reflux overnight. The reaction is cooled to room temperature and vacuum distilled. After the excess benzaldehyde has distilled off, the residue remaining in the flask is dissolved in hot 95% EtOH. Any undissolved material is filtered off. The EtOH filtrate is cooled slowly to give the product as light yellow crystals (5.17 g).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[CH2:19]([NH2:21])[CH3:20]>>[N+:1]([CH:4]=[C:5]([NH:21][CH2:19][CH3:20])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: CCN
Product: CCNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-immidazolyl)-methylthio)ethylamino]ethylene with ethylamine according to the process of Example 2(ii) yielded the title compound, m.p. 171°-172°.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[I-:33].[Na+].O>CC(C)=O>[CH2:26]([O:25][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:14][CH2:13][CH2:12][I:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC(COc2ccc(F)cc2)OCc2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Fc1ccc(OCC(CCCI)OCc2ccccc2)cc1
Yield: 79.7 %

Procedure:
A solution of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentanol tosylate (3.78 g., 8.24 mmoles) and sodium iodide (3.71 g., 25 mmoles) in acetone (70 ml.) is stirred at room temperature overnight (ca. 17 hours) and then heated on the steam bath for 15 minutes. The mixture is poured into cold water and extracted with ether three times. The combined extracts are washed with aqueous sodium thiosulfate and dried over anhydrous magnesium sulfate. The solvent is removed on a rotary evaportor to leave an oil residue which is further purified by chromatography on a silica gel (70 g.) column. Elution with chloroform gives the pure title compound (2.72 g., 6.57 mmoles, 79%). ir (neat) 3.28, 3.40, 6.20, 6.62, 6.87, 8.00, 8.23, 9.10, 12.07, 13.16, 13.58, 14.37μ; pmr (CCl4) δ 1.4-2.2 (4H, m), 3.08 (2H, t, J=6Hz), 3.5-4.1 (3H, m), 4.47 (1H, d, J=12 Hz), 4.69 (1H, d, J=12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [NH2:1][C:2]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[CH:20][C:19]([F:31])=[CH:18][C:3]=1[O:4][C:5]1[C:6]([CH3:17])=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1>[CH2:15]([S:12]([NH:11][C:7]1[C:6]([CH3:17])=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[CH:18]=[C:19]([F:31])[CH:20]=[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])[C:2]=1[NH:1][S:35]([CH:32]1[CH2:34][CH2:33]1)(=[O:37])=[O:36])(=[O:13])=[O:14])[CH3:16]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1C
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
185 mg N-(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-2-methylphenyl)ethanesulfonamide (0.33 mmol, 1 eq.) were dissolved in 3 mL pyridine, and treated with 49 mg cyclopropyl sulfonyl chloride (0.33 mmol, 1 eq.) and stirred at it for 16 h. Further 15 mg cyclopropyl sulfonyl chloride were added and stirring was continued for 4 h. Additional 15 mg cyclopropyl sulfonyl chloride were added and stirring was continued overnight. The reaction mixture was quenched with water, diluted with toluene and concentrated in vacuo. The residue was portioned between water and ethyl acetate, the aqueous layer reextracted with ethyl acetate, the combined organic layers dried, filtered and concentrated in vacuo. Flash column chromatography provided 150 mg of the target compound (64% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:19][C:20]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:21]=1[CH2:22][N:23]([CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:26][CH2:25][CH2:24][N:23]([CH2:22][C:21]3[CH:42]=[CH:43][CH:44]=[C:45]([C:46]([F:47])([F:48])[F:49])[C:20]=3[Cl:19])[CH2:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCN(c2cccc(O)c2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirring solution of 1-(3-hydroxyphenyl)-piperidine-4-carboxylic acid ethyl ester (0.19 g, 0.77 mmol) in 10 mL of anhydrous toluene was added 3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-ol (0.41 g, 0.92 mmol). Polymer bound triphenyphosphine (0.41 g, 1,23 mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture was reacted for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (0.2 g, 0.96 mmol) was added in a dropwise fashion. After stirring at RT overnight, the crude reaction mixture was filtered and the solid was washed with EtOAc. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 10% EtOAc: hexane as eluent to afford 0.32 g (62%) of the title compound as an oil: MS(ESI) 679.0 (M+H+).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[CH2:29][C:28]([CH3:32])([CH3:31])[CH2:27][CH2:26][C:25]=5[N:24]([CH3:33])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[CH2:29][C:28]([CH3:31])([CH3:32])[CH2:27][CH2:26][C:25]=5[N:24]([CH3:33])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12)C(=O)N1CC(C#N)C1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
In a round-bottomed flask, 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (112 mg, 0.19 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.6 ml, 7.5 mmol) was added. The yellow solution was stirred at room temperature for 2.5 h then concentrated. The residue was redissolved in dichloromethane (0.9 ml) and ethylenediamine (0.8 ml, 11.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 47 mg (51%) of 2-(1,5,5-Trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white powder. MS: (M+H)+=461; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.61 (br. s., 1H), 8.94 (s, 1H), 8.27-8.41 (m, 2H), 4.43-4.80 (m, 3H), 3.94-4.24 (m, 2H), 3.80 (s, 3H), 3.72-3.91 (m, 1H), 2.89 (d, J=15.9 Hz, 1H), 2.59-2.71 (m, 3H), 1.59 (t, J=6.2 Hz, 2H), 1.40 (dd, J=6.8, 3.0 Hz, 3H), 1.00 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11x, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.98 (d, 1H), 8.69 (m, 1H), 8.62 (m, 1H), 8.50 (d, 1H), 7.99 (m, 1H), 7.86 (m, 3H), 7.48 (m, 1H), 7.26 (m, 2H), 7.11 (m, 1H), 7.01 (d, 1H), 6.94 (d, 1H), 6.89 (s, 1H), 4.56 (s, 2H), 4.48 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 503 (M+1).