Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C:5]2[CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[CH:20][C:4]=2[NH:3]1.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:9][C@H:8]1[CH2:7][CH2:6][C:5]2[CH:17]=[C:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:20][C:4]=2[NH:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(-c3ccccc3)ccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCc2cc(-c3ccccc3)ccc2NC1=O
Reaction time: 4 h

Procedure:
5.63 g of 13a (15.97 mmol) are taken up in a 250 ml round-bottomed flask and 140 ml of a solution of hydrochloric acid in dioxane (4M) are added. The medium is stirred for 4 h at AT under argon. A precipitate forms and is filter-dried and washed with 5 ml of dioxane and then 5 ml of isopropyl ether. After drying, 5.7 g of amine 14a in hydrochloride form are obtained.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:6][C@H:7]([CH3:29])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][O:24][CH2:25][CH3:26])[C:18](Br)=[N:17][C:16]=2[N:15]([CH3:28])[C:13]1=[O:14])(=[O:5])[CH3:4].O>CS(C)=O>[C:3]([O:6][C@H:7]([CH3:29])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][O:24][CH2:25][CH3:26])[C:18]([NH:2][CH3:1])=[N:17][C:16]=2[N:15]([CH3:28])[C:13]1=[O:14])(=[O:5])[CH3:4]
Reactant: CN
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Solvent: O
Solvent: CS(C)=O
Product: CCOCn1c(NC)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 70 °C

Procedure:
A 40% aqueous solution of methylamine (10 ml) was added to a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (0.450 g) in dimethylsulfoxide (20 ml). After heating at 70° C. for 6 hours, the mixture was treated with water (50 ml) and extracted with ethyl acetate (3x 50 ml). The combined extracts were washed with water (2x 30 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-3-methyl-8-methylaminoxanthine (0.32 g).
Reaction SMILES: I[Si](C)(C)C.C[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17]C)[CH:13]([CH3:19])[CH2:12][CH2:11]2.O>C(#N)C>[CH3:19][CH:13]1[C:14]2[C:10](=[CH:9][C:8]([OH:7])=[C:16]([OH:17])[CH:15]=2)[CH2:11][CH2:12]1
Reactant: COc1cc2c(cc1OC)C(C)CC2
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Product: CC1CCc2cc(O)c(O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
Over 90 min at room temperature, 27.5 ml (202 mmol) of iodotrimethylsilane were added dropwise with stirring to a solution of 19.4 g (101 mmol) of 5,6-dimethoxy-1-methylindane in 150 ml of acetonitrile. The mixture was stirred for a further 2.5 d at room temperature, in the course of which, after 48 h, again 10 ml (73.5 mmol) of iodotrimethylsilane were added. The reaction mixture was then poured into 500 ml of water and the product was extracted twice, each time with 200 ml of ether. The combined extracts were washed with 100 ml of 40% sodium hydrogen sulfite solution, 100 ml of water and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. After flash chromatography (pentane/ether, 2:1, Rf=0.28) on silica gel, 15.5 g (93%) of 1-methylindane-5,6-diol were obtained.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][C:15]=1[CH3:28].CCN(C(C)C)C(C)C>C(#N)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([C@@H:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:24][CH2:23]2)=[O:21])=[CH:16][C:15]=1[CH3:28]
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1C
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1C
Temperature: 85 °C
Yield: 67.4 %

Procedure:
In a 1 L round bottom flask was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (prepared according to procedure in Eur. Pat. Appl., 257602, 2 Mar. 1988) (18.75 mmol, 3.36 g) and (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone (18.75 mmol, 4.37 g) in DIEA (75 mmol, 13.1 mL) and acetonitrile (100 mL). The reaction mixture was heated at 85° C. for 4 hours. The reaction was evaporated under a vacuum and silica gel flash column chromatography was performed on the remaining residue eluting with ethyl acetate to 20% MeOH/ethyl acetate to provide the title compound as a white solid (4 g, 67.4% yield). Calculated for C18H24N2O3 MS=316.4036. found MS (ESI) m/e 317.1863 (M+H+); 1H NMR (400 MHz, MeOD) δ ppm 1.69-1.89 (m, 4H) 2.08-2.21 (m, 1H) 2.24-2.30 (m, 1H) 2.44-2.56 (m, 1H) 2.73-2.84 (m, 1H) 2.84-2.92 (m, 1H) 3.08-3.17 (m, 1H) 3.30-3.42 (m, 6H) 3.45-3.54 (m, 1H) 3.90 (s, 3H) 6.95-7.04 (m, 1H) 7.72-7.81 (m, 1H) 7.83-7.90 (m, 1H); analytical RP-HPLC retention time=4.67 min.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([NH:15][C:16](=[O:23])[C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19]O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:15]4[CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[C:16]4=[O:23])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)(CCO)C(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)C1=O
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 4-bromo-7-(4-hydroxy-2,2-dimethylbutanamido)-9H-carbazole-1-carboxamide (Intermediate 58-1, 89 mg, 0.213 mmol), diethyl azodicarboxylate (0.051 mL, 0.319 mmol) and triphenylphosphine (84 mg, 0.319 mmol) in THF (1 mL) was stirred at rt for 1 h. More diethyl azodicarboxylate (0.051 mL, 0.319 mmol) and triphenylphosphine (84 mg, 0.319 mmol) were added, and these additions repeated again after 1 h more. The mixture was diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide), then by preparative HPLC. The appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated to provide 4-bromo-7-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide as a yellow solid (44 mg, 52%). 1H NMR (400 MHz, methanol-d4) δ 8.66 (1H, d, J=8.58 Hz), 7.94 (1H, d, J=1.54 Hz), 7.73 (1H, d, J=8.36 Hz), 7.55 (1H, dd, J=8.80, 1.98 Hz), 7.39 (1H, d, J=8.14 Hz), 3.97 (2H, t, J=6.93 Hz), 2.11 (2H, t, J=6.93 Hz), 1.28 (6H, s). Mass spectrum m/z 400, 402 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.O.CN([CH:22]=[O:23])C>>[OH:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Oc1cc2ccccc2cc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c(O)c(O)cc2ccccc12
Reaction time: 4 h

Procedure:
Phosphorous oxychloride (1.9 ml) was added to a solution of 2,3-dihydroxynaphthalene (3.2 g) in DMF (26 ml) at 0° C. The reaction mixture was kept for four hours at 100° C. Water (50 ml) was added to the cooled mixture and the resulting oily suspension refluxed for 20 min. The cool reaction mixture was poured into ice, filtered, washed with water and recrystallized from 2-propanol-water. Yield: 0.1 g, melting point 129-134° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1.B.C1COCC1.C(O)(=O)C>C1COCC1.[Fe]>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)n1
Agent: [Fe]
Agent: B
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1cc(Br)nc(CO)c1
Yield: 33.9 %

Procedure:
A solution of 6-bromo-4-nitro-pyridine-2-carboxylic acid (6.60 g, 29.1 mmol) in THF (150 ml) was treated with borane/THF (87 ml of a 1M solution). The mixture was refluxed for 6 hr, then powdered iron (16.3 g, 291 mmol) was added, followed by acetic acid ( 150 ml). Reflux was maintained for 6 hr, the mixture was filtered, evaporated and partitioned (AcOEt/aqueous NaHCO3-solution). The organic phase was dried (Na2SO4), concentrated and chromatographed (SiO2 with CH2Cl/MeOH=93/7) to provide 2.0 g (34%) of the title compound as a white solid material. Mp. 144-145° C. (AcOEt), MS: m/e=202 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:17]3[N:16]([C:17]4[CH2:18][CH2:19][CH2:20][N:16]=4)[CH2:20][CH2:19][CH:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: Clc1cccc2c1Sc1ccccc1N2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Clc1cccc2c1Sc1ccccc1N2C1=CCCN1C1=NCCC1
Yield: 17.1 %

Procedure:
A solution of 4-chlorophenothiazine (32.3 g., 0.134 mole) and 2-pyrrolidinone (23 g., 0.27 mole) in 125 ml. of 1,2-dichloroethane is added dropwise to a solution of phosphorus oxychloride (20.5 g., 0.134 mole) in 50 ml. of 1,2-dichloroethane in about 35 min. Isolation of the product from the reaction mixture according to the procedure of Example 1 provides 7.5 g., (17.1% yield) of 4-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE free base, m.p. 195°-197° C. Analytically pure 4-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE HYDROCHLORIDE obtained by crystallization from ethanol-ether has a melting point of 232°-234° C. (corr.).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:23])(=[O:22])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH3:21].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)#[N:25]>ClCCl.CN(C)C1C=CN=CC=1>[C:16]([O:23][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)=[CH:37][CH:36]=1)(=[O:22])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH3:21]
Reactant: C/C=C/C=C/C(=O)O
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/C=C/C(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N,N'-dicyclohexylcarbodiimide (0.87 g, 0.0042 mol) in dichloromethane (10 CM3) was added to a solution of (E,E)-hexa-2,4-dienoic acid (0.47 g, 0.0042 mol), 4-cyano-4'-hydroxybiphenyl (0.67 g, 0.0035 mol), 4-(dimethylamino)pyridine (0.05 g) in dichoromethane (25 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, filtered to remove precipitated material and the filtrate was evaporated down under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane as eluent, followed by recrystallisation from a 1:1 ethanol/ethyl acetate mixture to yield 0.76 g (76%). K 160° C., N-I 227° C.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22]([OH:24])=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].CO.[C:31]([O-])(O)=O.[Na+]>OS(O)(=O)=O.CCOC(C)=O>[CH3:31][O:23][C:22]([C:17]12[CH2:20][CH2:21][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:19][CH2:18]1)[CH2:15][CH2:16]2)=[O:24]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Yield: 97 %

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (Example 13) (1.50 g, 3.86 mmol) was combined with 60 ml of MeOH, and 10 drops of conc'd H2SO4. The reaction solution was brought to reflux until consumption of starting material ceased. Sat'd NaHCO3 was then added until neutral pH and the reaction mixture was conc'd in vacuo. The residue was taken up in EtOAc and washed with sat'd NaHCO3, brine, and dried over Na2SO4. The EtOAc solution was conc'd in vacuo to give 1.51 g (97% yield) of a white solid. (MH+=403.13)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9]Br)=[CH:6][CH:5]=1)[CH3:2].[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:9][C:8]([C:7]1[CH:12]=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)=[O:11])(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: CCOc1ccc(C(=O)CBr)cc1
Product: CCOc1ccc(C(=O)COC(C)=O)cc1

Procedure:
Following the procedure of Example 1, 5 grams of 4-ethoxyphenacyl bromide are reacted with 5 grams of acetic acid to obtain 4-ethoxyphenacyl acetate, m.p. 81°-82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([C:19]1[C:20]([N:26]=[CH:27][N:28]([CH3:30])C)=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1)#N>C(O)(=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:2]([NH:1][C:30]2[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[N:21][C:20]=3[N:26]=[CH:27][N:28]=2)[CH:7]=1
Reactant: Nc1cc(Br)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc(Br)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 130 °C
Yield: 35.4 %

Procedure:
A mixture of the product from Example 238B (0.158 g, 0.533 mmol) and the product from Example 10B (0.100 g, 0.533 mmol) in glacial acetic acid (2 mL) was heated in a 130° C. oil bath for 30 min. An additional amount of the product from Example 10B (0.060 g, 0.319 mmol) was added and the reaction mixture was heated for an additional 30 min at 130° C. The reaction mixture was then cooled to room temperature and the solvent evaporated under reduced pressure. The residue was triturated with 2-propanol, and the resulting solid isolated by vacuum filtration and dried to provide the title compound (0.083 g, 36% yield) as a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=O)[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][C:53]1[S:54][CH:55]=[C:56]([C:58]2[CH:69]=[CH:68][C:61]([C:62]([NH:64][CH:65]3[CH2:67][CH2:66]3)=[O:63])=[CH:60][CH:59]=2)[N:57]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:18])[NH:52][C:53]2[S:54][CH:55]=[C:56]([C:58]3[CH:59]=[CH:60][C:61]([C:62](=[O:63])[NH:64][CH:65]4[CH2:67][CH2:66]4)=[CH:68][CH:69]=3)[N:57]=2)[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reactant: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CSCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-Thiazolidine-3,4-dicarboxylic acid 3-benzyl ester (52.5 mg, 0.20 mmol) was dissolved in DMF (2 mL). DIEA (68.5 μL, 0.39 mmol) was added followed by HATU (74.8 mg, 0.20 mmol). The reaction was stirred at ambient temperature for 15 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide (51.1 mg, 0.20 mmol) was added, and the reaction was stirred at ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product. Yield 18.5 mg. MS: 509.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.54-0.75 (m, 4H), 2.78-2.90 (m, 1H), 4.51-4.59 (m, 1H), 4.62-4.70 (m, 1H), 4.83-5.18 (m, 3H), 7.07-7.43 (m, 5H), 7.77-7.99 (m, 5H), 8.39-8.47 (m, 1H), 12.55-12.64 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:29][Si:30]([C:33]#[C:34][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1)([CH3:32])[CH3:31]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-pyridinecarbonitrile [Cesko-Slovenska Farmacie 25(5),181(1976)] (0.73 g, 4.0 mmol) was dissolved in 18 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (31 mg, 0.12 mmol) and bis(triphenylphosphine)palladium(II) chloride (141 mg, 0.20 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I) iodide (23 mg, 0.12 mmol) and trimethylsilyl-acetylene (590 mg, 6.0 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with 100 ml of ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/methylene chloride 1:2). The desired product was obtained as a yellow oil (329 mg, 41%), MS: m/e=201.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH4+:22].[OH-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:22])=[O:8]
Reactant: O=C(Cl)c1sc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)c1sc2ccc(OCc3ccccc3)cc2c1Cl
Yield: 84 %

Procedure:
To a warm solution of 3-chloro-5-(phenylmethoxy)benzo[b]thiophene-2-carbonyl chloride (2.0 g, 6 mmol) [Connor D. T., et al., J. Med. Chem, 35, 935, (1992)] in 20 mL of toluene is added dropwise 10 mL of aqueous NH4OH. The resulting precipitate is collected by filtration washing with ethyl alcohol to provide 3-chloro-5-(phenylmethoxy)benzo[b]thiophene-2-carboxamide in 84% yield; mp=205.5°-206° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].[Al+3].Cl.C(OCC)C>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(=O)CCc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(O)cc1)CCc1ccc(O)cc1
Temperature: 80 °C
Yield: 105.7 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)-3-pentanone (2.1 g, 7 mmol), prepared as in step 1, and aluminum tribromide (10.64 g, 40 mmol) in toluene (60 mL) was refluxed at 80° C. for 30 minutes and then cooled to room temperature. The reaction mixture was slowly added to a mixture of aqueous 1N HCl (150 mL) and ethyl ether (150 mL). The ether layer was separated, washed with aqueous 1N HCl, water, and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 1,5-bis-(4-hydroxyphenyl)-3-pentanone (2 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43]1>C(#N)C>[S:42]1[CH:46]=[CH:45][C:44]([S:47]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:49])=[O:48])=[CH:43]1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccsc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 63.6 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0951 g, 0.206 mmol) was dissolved in acetonitrile (4.0 mL), and the solution was treated with triethylamine (0.0860 mL, 0.618 mmol) and 3-thiophenesulfonyl chloride (0.0754 g, 0.412 mmol) to obtain 4-(3-thiophenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0796 g, yield 64%).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[C:19]([CH2:23]O)[CH:20]=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1>ClCCl>[Cl:3][CH2:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)[CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(-c2cccc(Cl)c2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cncc(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
271 mg (0.165 ml, 2.28 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 250 mg (1.14 mmol) [5-(3-Chloro-phenyl)-pyridin-3-yl]-methanol in 20 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase was extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (248 mg, 84%) used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[NH:12]2)=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:28]([CH:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[N:12]2[C:38](=[O:39])[NH:37][CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH3:29])=[O:10])=[CH:19][CH:20]=1
Reactant: CCC(N=C=O)c1ccccc1
Reactant: C=CC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H]1C(=O)N(C(=O)NC(CC)c2ccccc2)[C@@H]1C(=O)OCc1ccc(OC)cc1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A mixture of compound 59 (41 mg, 0.15 mmol), triethylamine (83 uL, 0.60 mmol), α-ethyl-benzyl isocyanate (29 mg, 0.18 mmol) in methylene chloride (1.2 mL) was stirred overnight. TLC analysis indicated the completion the reaction. Removal of solvents gave the crude material, which was purified by preparative TLC plate (15% EtOAc in hexanes), yielding 38.2 mg of compound 60 (59%): LC-MS purity: 98.1%; 1HNMR (300 MHz, CDCl3): 0.95 (t, 3H), 1.92 (m, 2H), 2.69 (m, 2H), 3.30 (m, 1H), 3.83 (s, 3H), 4.22 (d, 1H), 4.85 (q, 1H), 5.18 (m, 4H), 5.80 (m, 1H), 6.85 (br, d, 1H), 7.45 (m, 9H). Anal. C25H28N2O5, Mol. Wt.: 436.5. Found: ESI-MS: 437.1 (M+H)+.