Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[K].O.O1CCO[CH2:40][CH2:39]1>C(Cl)Cl>[CH2:39]([C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2)[CH3:40]
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: O
Solvent: ClCCl
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1COC1CCCCO1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a suspension of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (200 mg, 0.46 mmol), cesium carbonate (601 mg, 1.8 mmol), potassium ethylrifluoroborate (125 mg, 0.92 mmol) in dioxane (3 mL)/H2O (0.3 mL) Pd(OAc)2 (21 mg, 0.092 mmol) and Ru-Phos (CAS 787618-22-8, 86 mg, 0.18 mmol) were added and then the mixture was stirred at 90° C. for 15 h. The reaction mixture was cooled to room temperature, and diluted with CH2Cl2. The organic phase was separated and washed with H2O, and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue that was purified by SiO2 column chromatography (heptane/EtOAc=1/0 to 3/2) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.75 (d, J=3.79 Hz, 1H), 7.57 (d, J=8.34 Hz, 2H), 7.31 (d, J=8.34 Hz, 2H), 6.95 (s, 1H), 6.91 (d, J=3.79 Hz, 1H), 4.90 (d, J=11.24 Hz, 1H), 4.65 (d, J=11.24 Hz, 1H), 4.61-4.64 (m, 1H), 3.79-3.92 (m, 1H), 3.41-3.54 (m, 1H), 2.71 (q, J=7.58 Hz, 2H), 2.53 (s, 3H), 2.35 (s, 3H), 1.56-1.75 (m, 2H), 1.38-1.56 (m, 4H), 1.16 (t, J=7.58 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.[IH:11]>>[I:11][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12
Reactant: I
Reactant: Clc1ccnc2[nH]cnc12
Product: Ic1ccnc2[nH]cnc12

Procedure:
A mixture of 7-chloro-3H-imidazo[4,5-b]pyridine (1.47 g, 9.64 mmol) and 15 mL of 57% hydriodic acid were reacted at 80° C. for 4 h. After the solid was filtered off it was resubmitted to the reaction with 10 mL of fresh 57% hydriodic acid. The reaction yielded 1.3 g of the product as a black powder, 90% pure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25]3)[C:8]2([NH:15][C@@H](C2C=CC=CC=2)CO)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[NH2:15][C:8]1([C:11]([O:13][CH3:14])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[CH2:28][CH2:29]2
Reactant: COC(=O)C1(N[C@H](CO)c2ccccc2)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 2 h
Yield: 123.1 %

Procedure:
To a solution of methyl 6′-bromo-1′-(((S)-2-hydroxy-1-phenylethyl)amino)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate (0.0180 g, 0.03 mmol) in CH2Cl2 (3 mL) and MeOH (1.5 mL) was added Pb(OAc)4 (0.0500 g, 0.11 mmol) at 0° C. The mixture was stirred for 2 h. After the solvents were evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% MeOH/H2O, 0.1% CF3COOH over 8 min and then 90% MeOH/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0136 g (94%) of methyl 1′-amino-6′-bromo-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate as a TFA salt. LC-MS tR=1.11 min in 3 min chromatography, m/z 368, 370 (MH+), 351, 353, 319, 321; 1H NMR (400 MHz, CD3OD) δ 7.57-7.54 (m, 2H), 7.31 (d, J=8 Hz, 1H), 3.79 (s, 3H), 3.35 (s, 3H), 3.25-3.15 (m, 2H), 3.04 (d, J=16 Hz, 1H), 2.09-2.06 (m, 2H), 1.61-1.29 (m, 6H); 13C NMR (100 MHz, CD3OD) δ 170.36, 143.46, 140.64, 134.50, 128.89, 128.09, 121.70, 79.44, 75.22, 56.11, 54.06, 52.58, 39.97, 31.11, 29.52, 29.44, 28.88.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([NH2:19])[CH3:18]>C1COCC1>[CH2:17]([NH:19][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[CH3:18]
Reactant: CCN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Product: CCNc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and ethylamine in THF. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:34][C:35]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][CH:36]=3)[C:20]([NH:22][C@H:23]([CH2:27][S:28][S:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[NH2:18][C@@H:19]([CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)[C:20]([NH:22][C@H:23]([CH2:27][S:28][S:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])=[O:21]
Reactant: CC(C)(C)SSC[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)SSC[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of ((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Fmoc-Trp-D-Cys(StBu)-OH) (Compound SP642) (1.93 g, 3.12 mmol) in N,N-dimethylformamide (6.3 mL) was mixed with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (706 μL, 4.69 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 1 hour. 1 N hydrochloric acid was added to the reaction solution, and the organic layer was extracted with ethyl acetate, washed with brine and then dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-D-Cys(StBu)-OH) (Compound SP643) (870 mg, 2.20 mmol, 70%).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]1([CH:13]=[C:14]2[C:19](=[O:20])[C:18](=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][S:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O.CO>[C:22]1([CH:21]=[C:18]2[C:19](=[O:20])[C:14](=[CH:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:15][S:16](=[O:2])[CH2:17]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CS(=O)CC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
A solution of 10.4g of sodium periodate in 50ml of water is added to a suspension of 7.0g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one in 300ml of methanol. The mixture is stirred at room temperature for 3 days (a water bath is used for the first hour to moderate a slightly exothermic reaction). Solvent is removed in vacuo and the residue is stirred with chloroform and filtered. The filtrate is concentrated in vacuo and the residue is crystallized from 150ml of methanol, giving 6.4g of the title compound, melting point 155°-160°C. A second crop of 0.5g of the title compound, melting point 154°-157°C is also obtained.
Reaction SMILES: S(Cl)(Cl)(=O)=[O:2].[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]([S:18]([Cl:21])(=[O:20])=[O:19])[CH2:15]2)=[CH:10][CH:9]=1>C(N(CC)CC)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:2][CH2:12][CH2:13][N:14]([S:18]([Cl:21])(=[O:20])=[O:19])[CH2:15][C:16]=2[CH:17]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CCO2

Procedure:
This compound was prepared from 1.4 g of 7-methoxy-2,3,4,5-tetrahydro-benzo[f[1,4]-oxazepine, 0.91 mL of sulfuryl chloride and 4.7 mL of triethylamine using the procedure described for 63f. Yield: 0.23 g (oil), EI-MS: 277 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:26])=[O:25])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:25])=[O:26])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:10][CH2:9]1
Reactant: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(OCC2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Yield: 96 %

Procedure:
2-Chlorobenzenesulfonic acid 3-[[N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]-5-methylphenyl ester (745 mg, 1.5 mmol), as prepared in the preceding step, was treated with 4 N HCl in 1,4-dioxane (20 mL) at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (10% methanol in methylene chloride saturated with NH3) to give the title compound as a colorless syrup (570 mg, 95%). 1H-NMR (300 MHz, CDCl3) δ 1.45 (m, 1 H), 1.94 (m, 3 H), 2.23 (s, 3 H), 2.45 (m, 1 H), 2.71 (dt, 2 H, J=1.2, 12.3 Hz), 3.51 (m, 2H), 3.76 (m, 2 H), 6.46 (t, 1 H, J=2.1 Hz), 6.53 (s, 1 H), 6.58 (s, 1 H), 7.40 (t, 1 H, J=6.5 Hz), 7.62 (m, 2 H), and 7.97 (dd,1 H, J=1.4, 7.9 Hz). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C19H22NO4SCl: 396.1 (M+H), Found: 396.4.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([CH3:10])[CH:3]=1.F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17]2[CH:18]=[N:19][CH:20]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1cc(Cl)ccc1CN
Product: Cc1cc(Cl)ccc1CNc1cnccc1C(=O)O
Yield: 45 %

Procedure:
The title compound was prepared in 45% yield from 4-chloro-2-methylbenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.50 (br s, 1H), 8.10 (s, 1H), 7.85 (d, 1H, J=5.0 Hz), 7.61 (br s, 1H), 7.59 (d, 1H, J=5.0 Hz), 7.31 (s, 1H), 7.19-7.25 (m, 2H), 4.52 (s, 2H), 2.34 (s, 3H). [M+H] calc'd for C14H13ClN2O2, 277, 279. found 277, 279.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@:16]2([CH3:17])[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[CH2:15]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:26][C:20]1[C:19]([CH3:27])=[C:18]([N:14]2[CH2:15][C@:16]3([CH3:17])[C@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[C:13]2=[O:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: Cc1c(N2C[C@]3(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN3C2=O)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(N2C[C@]3(C)[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 11 h
Yield: 89.9 %

Procedure:
To a solution of (7R,7aR)-4-[7-(tert-Butyldimethylsilanyloxy)-7a-methyl-3-oxotetrahydropyrrolo[1,2-c]imidazol-2-yl]-2-chloro-3-methylbenzonitrile (58E) (17 mg, 0.04 mmol) in THF (2 mL) was added acetic acid (100 □L) and a 1 M solution of TBAF in THF (122 □L, 0.12 mmol). After stirring at rt for 11 h, additional TBAF solution was added (100 □L), and after stirring for another 6 h, 200 □L TBAF solution was added. The reaction was stirred overnight, then 100 □L TBAF was added and the reaction stirred an additional 1.5 h. The reaction was then quenched with saturated aqueous NH4Cl and extracted with EtOAC. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting residue was purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 40-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (11 mg). LC/MS m/z 306 [M+H]+.
Reaction SMILES: OS(O)(=O)=O.O[C:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:8]=1[CH2:14][C:15](=[O:17])[CH3:16]>C(Cl)Cl>[CH3:16][C:15]1[O:17][C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:8]=2[CH:14]=1
Reactant: CC(=O)CC1=C(O)CCCC1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cc2c(o1)CCCC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of conc. H2SO4 (300 ml) cooled in an ice-bath was added a solution of 3-hydroxy-2(2-oxopropyl)-2-cyclohexene-1-one (190 g in 300 ml CH2Cl2). Upon completion of addition, the mixture was stirred at ambient temperature for about 1 hour. The mixture was then slowly poured into 3 l ice water, and then about 1 l of CH2Cl2 was added. The layers are separated and the aqueous layer extracted thrice with CH2Cl2 and the combined CH2Cl2 layers again extracted thrice with water. The CH2Cl2 layer washed thrice with dilute aqueous NaHCO3, then once with water and dried (MgSO4). Concentration in vacuo afford an orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[CH:3]1.[Br:24]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:24][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12
Temperature: 70 °C
Yield: 38.9 %

Procedure:
A mixture of 2-(1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)[1,3]thiazolo-[5,4-d]pyrimidine (Intermediate 42) (0.25 g), N-bromosuccinimide (0.26 g) and AIBN (37 mg) in carbon tetrachloride (30 mL) was heated at 70° C. for 18 hours The suspension was filtered and the residue washed well with CCl4. The solvent was evaporated in vacuo to give a yellow solid. Purification by flash chromatography on silica eluting with EtOAC:hexane (1:9) gave the title compound as a white solid (0.12 g, 39%);
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](OB(O)O)=[C:12]([CH3:20])[CH:11]=1>CCOC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[C:12]([CH3:20])[CH:11]=1
Reactant: Cc1cc(Cl)ccc1OB(O)O
Reactant: Nc1cnc(Br)cn1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1cnc(N)cn1

Procedure:
The product was prepared analogously to Example 48.1a from 2.61 g (15.0 mmol) of 5-bromopyrazin-2-ylamine and 2.56 g (15.0 mmol) of 4-chloro-2-methylphenylboric acid. Yield: 1.70 g (52% of theoretical); C11H10ClN3 (M=219.670); calc.: molpeak (M+H)+:220/222 (Cl); found: molpeak (M+H)+:220/222 (Cl); Rf value: 0.35 (silica gel, PE/EtOAc 7:3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:30])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Cc1ccccc1O
Product: Cc1ccccc1OC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Br)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-methylphenol: ESMS m/e: 548.8 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>>[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:30]1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: Clc1ccccc1CC1CCNC1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-(2-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (9.2 mg). Calcd for C22H18ClF3N2O2: 434.1009, found 434.1000.
Reaction SMILES: Cl[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:9])=[O:5].[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][OH:33])[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:9])=[O:5]
Reactant: OCCNCCO
Reactant: CC(CNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl)OC1CCCCO1
Product: CC(CNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N(CCO)CCO)OC1CCCCO1
Yield: 94.6 %

Procedure:
Reaction of 12e (1.45 g, 3.75 mmol) with diethanolamine (1.67 g) as above gave 2-[bis(2-hydroxyethyl)amino]-3,5-dinitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)propyl]benzamide (1.62 g, 95%) as a yellow foam that was used directly;
Reaction SMILES: [Na].[C:2]([NH:5][C:6]1[C:7]([I:21])=[C:8]([C:12]([I:20])=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[C:14]=1[I:15])[C:9]([OH:11])=[O:10])(=[O:4])[CH3:3].Cl[CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[OH:27][CH:24]([CH2:25][OH:26])[CH2:23][O:10][C:9](=[O:11])[C:8]1[C:7]([I:21])=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[C:14]([I:15])=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[C:12]=1[I:20]
Reactant: OCC(O)CCl
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Agent: [Na]
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)OCC(O)CO)c1I

Procedure:
20 g (29 mmol) 3,5-diacetylamino-2,4,6-triiodobenzoic acid-2,3-dihydroxypropyl ester, which can be obtained from the sodium salt of 3,5-diacetylamino-2,4,6-triiodobenzoic acid by reaction with 3-chloropropane-1,2-diol at 105° C. (analogous to Organikum, 12th Edition, Deutscher Verlag der Wissenschaften, Berlin 1973, p.227 et seq.), are dissolved in 80 ml absolute pyridine and cooled to -10° C. To this solution is added dropwise 20 g (130 mmol) of commercially available methacrylic acid anhydride (Fluka) and the mixture is then stirred overnight at room temperature. The resulting clear reaction mixture is mixed with 1 l dilute hydrochloric acid and the white precipitate which forms is filtered off, washed with water to neutral and then reprecipitated from methanol/water. After drying in a fine vacuum (approx. 1 mbar, at room temperature) to a constant weight, 16.1 g (67.1%) colourless powder of amorphous appearance with a DSC melting point of 207° C. is obtained. 1 g of the substance is compressed as described in Example 1 into a tablet and irradiated; there is no discoloration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:34])([F:33])[F:32])([O:26][Si](C)(C)C)[CH:8]([F:35])[CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:32])([F:34])[F:33])([OH:26])[CH:8]([F:35])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(F)C3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)c2[nH]c3cc(Cl)c(Cl)cc3c2CCC1F
Yield: 48.4 %

Procedure:
To 6,7-dichloro-2-fluoro-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.2 g, 0.35 mmol) in THF (10 mL), KOH (98 mg, 1.7 mmol) in H2O (10 mL) was added and the resulting mixture was refluxed for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography [EtOAc-hexane (1:9) as eluant] and the solid obtained was washed with cold pentane to give the title compound (58 mg, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.25 (bs, 1H), 7.62 (s, 1H), 7.5 (s, 1H), 5.25-5.14 (m, 1H), 3.25 (d, J=6.5 Hz, 1H), 2.94-2.89 (m, 1H), 2.80-2.74 (m, 1H), 2.44-2.39 (m, 1H), 2.35-2.29 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].C(N)CN>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]#[N:25])=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)c(CCc2ccccc2)c1
Reactant: N#C[Cu]
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)c(CCc2ccccc2)c1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a stirred solution of the 4-benzyloxy-3-(phenethyl)phenylbromide, (5.5 g, 15 mmol) in DMF (200 ml, dried) was added CuCN (3.32 g, 37 mmol). The reaction was heated to reflux and held at reflux for 20 hours, under argon. The reaction mixture was allowed to cool to ambient temperature, poured into ice water, treated with ethylene diamine (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (2×60 ml), dried (MgSO4) and evaporated. The crude material was purified by chromatography to give 4-benzyloxy-3-phenethylbenzonitrile as a white solid (2.0 g, 43%).
Reaction SMILES: [Br-].[C:2]([CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[OH-].[Na+].[F:26][C:27]1[CH:41]=[CH:40][C:30]([O:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>O.C(Cl)Cl>[F:26][C:27]1[CH:41]=[CH:40][C:30]([O:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=[CH:4][C:2]#[N:3])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#CC=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a solution of (cyanomethyl)triphenylphosphonium bromide (10.61 g, 27.8 mmol) and NaOH (1.387 g, 34.7 mmol) in water (30 mL) and DCM (15 mL) was added 4-(4-fluorophenoxy)benzaldehyde (5 g, 23.13 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. DCM (50 mL) and water (50 mL) was added to the mixture, the organic phase was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Purification via flash chromatography afforded the title compound (5.1 g, 21.09 mmol, 91% yield) as white solid. LCMS: rt=1.60 min, [M+H+]=240
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH:6]=[CH:7][CH:8]=1.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12>>[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([C:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[C:16]([CH3:24])[CH:17]=3)=[O:20])[CH2:30][C:29]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cccc(C2=C(c3ccc(C(=O)O)cc3C)CCCC2)c1
Product: COc1cccc(C2=C(c3ccc(C(=O)N4Cc5cccn5Cc5ccccc54)cc3C)CCCC2)c1
Yield: 62.9 %

Procedure:
4-[2-(3-Methoxy-phenyl)-cyclohex-1-en-1-yl]-3-methyl-benzoic acid of Step B (0.066 g, 0.205 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.041 g, 0.223 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether/diethyl ether afforded the title compound (0.063 g) as white crystals, m.p. 91–94° C.