Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=1)[CH3:2].[OH-].[Li+]>C(#N)C.O>[CH2:1]([N:3]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=1)[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 93.9 %

Procedure:
Methyl 2-({2-[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-ethyl}thio)benzoate (0.085 g, 0.160 mmol) was dissolved in a mixture of acetonitrile/water (1/1, 4 ml), then lithium hydroxide (0.008 g, 0.320 mmol) was added. The reaction was performed in an single node microwave oven (5 min, 150 deg). Work-up by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water phase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation and gave 0.07773 g of 2-({2-[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethyl}thio)benzoic acid (yield 93.0%).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].CN(C=O)C>CO>[Si:21]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:2]1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-deoxycytidine dC (2.85 g, 12.54 mmol), imidiazole (6.49 g, 95.31 mmol), and TBSCl (7.18 g, 47.65 mmol) were added to anhydrous DMF (27 mL) and stirred at room temperature overnight under a N2 atmosphere. Methanol (20 mL) was added, and the mixture was stirred for 30 minutes and then concentrated in vacuo. Ethyl acetate (60 mL) and water (60 mL) were then added. The organic layer was separated and washed twice with water (20 mL), and the combined aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to give 3′,5′-O-bis-tert-butyldimethylsilyl-2′-deoxycytidine dC.01 (4.79 g, 84%) as a white foam.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](Cl)(=[O:17])[CH3:16].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[C:9]([O:13][CH3:14])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Cl
Reactant: COc1cccc(C2CCCCC2)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(C2CCCCC2)ccc1C(C)=O

Procedure:
20 g of 3-cyclohexyl anisole are dissolved in 200 cc of benzene, 8.15 g of acetyl chloride are added, and 27.4 g of tin(IV) chloride are subsequently added dropwise at 5° - 10° while stirring. After stirring at 23° for 16 hours, the reaction mixture is poured on ice and extracted thrice with benzene. The organic phase is successively washed with 2 N hydrochloric acid, a 2 N caustic soda solution and water, is dried over anhydrous sodium sulphate and concentrated. The residue is recrystallized from acetone/petroleum ether. The resulting title compound has a M.P. of 99°-100°.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:18])C(=O)C1.O>C(Cl)Cl>[Br:18][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Solvent: O
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.91 g, 38 mmol) in DCM (250 mL) was added NBS (7.93 g, 44 mmol). The suspension was stirred at room temperature for 3 hours. Water (200 mL) was added to the reaction mixture. The mixture was sonicated for 5 min. The solid was collected by filtration and washed with water, then taken into 100 mL of MeOH. The suspension was sonicated for 3 min. The solid was collected by filtration as the desired product (6.47 g, 72%). LCMS[M+1]: 232.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]([C:51]([O:53]C(C)(C)C)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@@H:42]([C:51]([OH:53])=[O:52])[CH2:43][C:44]3[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=3)=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccc(O)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@H](Cc3ccc(O)cc3)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-D-Tyr-OtBu (47 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.78-13.25 (br.s, 1 H), 8.95 (s, 1 H), 8.64-9.80 (br.s, 1 H), 8.03 (d, 1 H), 7.26 (m, 6 H), 7.19 (m, 1 H), 7.12 (d, 2 H), 7.00 (m, 5 H), 6.88 (m, 4 H), 6.64 (d, 2 H), 4.35 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 2.94 (d, 1 H), 2.91 (s, 3 H), 2.72 (dd, 1 H), 2.44 (t, 2 H), 2.39 (s, 3 H), 2.06 (m, 2 H), 1.69 (m, 2 H); MS (APCI+) m/z 723 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(=O)([O-])[O-].[K+].[K+].C(OP([CH2:27][C:28]#[N:29])(=O)OCC)C.O>O1CCCC1>[C:28]([CH:27]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:29]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(C=CC#N)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-formylbenzoate (2.00 g, 12.2 mmol) in tetrahydrofuran (20 mL) were added potassium carbonate (2.02 g, 14.6 mmol), diethyl(cyanomethyl)phosphonate (2.29 mL, 14.6 mmol) and water (0.4 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 3-(2-cyanoethenyl)benzoate as a white solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[CH:10][N:11]=2)=C.O=O.[O:15]=[O+][O-]>CO>[N:11]1[CH:10]=[CH:9][N:8]=[C:7]2[N:12]=[C:3]([CH:1]=[O:15])[CH:4]=[CH:5][C:6]=12
Reactant: C=Cc1ccc2nccnc2n1
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CO
Product: O=Cc1ccc2nccnc2n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
6-vinylpyrido[2,3-b]pyrazine (Intermediate 4.3) (1 g, 6.37 mmol, 1 eq.) was dissolved in methanol (20 mL) and cooled down to −70° C. A gentle flux of a mixture of oxygen/ozone was then bubbled through for 20 minutes. The reaction was monitored by TLC using cyclohexane/ethyl acetate (8/2). When the reaction was finished, dimethylsulfide (0.1 mL) was added and reaction was left at rt for 30 minutes. Methanol was evaporated under vacuum and 600 mg of pyrido[2,3-b]pyrazine-6-carbaldehyde was recovered. Crude material was analyzed without further purification (Intermediate 4.4). Amount: 0.60 g; Yield: 60%; Formula: C8H5N3O; HPLC Purity: 90%; HPLC H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=0.90 min; 90%; 1H NMR (DMSO-d6) δ 10.1 (1, 1H), 9.05 (s, 1H), 8.95 (s, 1H), 8.70 (d, 1H, J=8 Hz), 8.20 (d, 1H, J=8 Hz); LC-MS: M/Z ESI: Rt (min) 0.76 min, 158.13 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][CH2:10][CH2:11][P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.BrCCBr.[OH-:35].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[P:7]([CH2:8][CH2:9][CH2:10][CH2:11][P:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:35])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: BrCCBr
Product: O=P(CCCCP(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of palladium acetate (10 mg; 4.45×10-2 mmol), dppb (4.00 g; 9.4 mmol), 1,2-dibromoethane (3.6 g; 19.15 mmol), and dichloromethane (10 mL) was stirred for 30 minutes. To this suspension, aqueous NaOH (20% by weight; 10 mL) was added and the mixture was vigorously stirred at room temperature for 3 days. Dichloromethane (30 mL) was added, the organic phase was filtered through a silica plug which was then washed with 80 mL of CH2Cl2 /AcOEt (5:3 by volume). The combined organic solutions were evaporated to dryness. The solid residue was dissolved in boiling CH2Cl2 (ca. 30 mL) and the solution was treated with ether (100 mL; portionwise) and left at room temperature for 2 hours. Well-shaped, colorless crystals were separated, washed with ether, and dried under vacuum. The yield was 3.33 g (80%). 1H NMR (CDCl3, 20° C.), δ: 1.5 (m, 2H, CH2); 1.7 (m, 2H, CH2); 2.0 (m, 2H, CH2); 2.2 (m, 2H, CH2); 7.2-7.8 (m, 20H, Ph). 31P NMR (CDCl3, 20° C.), δ: -15.5 (s, 1P, PPh2); 32.2 (s, 1P, P(O)Ph2).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][C:12](=C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:24]>>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][C:12](=[O:24])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=C1C[C@H](COCc2ccccc2)[C@H](c2cccc(F)c2)C1
Product: O=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(S)-(benzyloxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane (0.77 g, 2.75 mmol) from Step A in methanol (30 mL) was cooled to −70° C. and ozone was bubbled through the solution until a blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethyl sulfide (5 mL) was added and the reaction was allowed to warm to rt over 16 h. Several drops of 2N HCl were added and the solution was stirred for 15 min to convert any methyl ketal to the desired ketone. The methanol was removed in vacuo and the was residue diluted with water, aq. sodium bicarbonate and ether.). The layers were separated and the aqueous was extracted with ether. The organic layers were washed with water, then brine, dried over sodium sulfate and concentrated. The residue was purified by FC using 10% ethyl acetate in hexanes to afford the title compound (0.88 g).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[C:15]([O-])(=[S:17])[CH3:16].[K+]>C1COCC1>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3][CH:2]2[C:15](=[S:17])[CH3:16]
Reactant: CC1(C)CCC(Br)c2cc(Br)ccc21
Reactant: CC([O-])=S
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=S)C1CCC(C)(C)c2ccc(Br)cc21

Procedure:
Employing the above-described procedure for the conversion of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-naphthalene (Compound F) to the dibromonaphthalene derivative (Compound I), 3.5 g (14.6 mmol) of (Compound F), 2.86 g (16.1 mmol) of N-bromosuccinimide and 150 mg (0.62 mmol) of benzoylperoxide gave crude 4,6-dibromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I). To a solution of this crude dibromonaphthalene derivative (Compound I) in 50 ml of THF was added 5.38 g (47.1 mmol) of potassium thioacetate. The mixture was refluxed for 6 hours under argon atmosphere, filtered through celite and concentrated in vacuo. Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as red oil.
Reaction SMILES: CCO.O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[NH:15][CH:16]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>CCO>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Yield: 97.3 %

Procedure:
A 95:5 EtOH/H2O solution (5.0 mL) containing methyl 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (120 mg, 0.51 mmol) and NaOH (1.53 mol) was refluxed for 2 h whereupon the EtOH was removed in vacuum. After removal of traces of EtOH by azotroping twice with water, acidification to pH 3 with 1 M HCl generated a white precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuum to give 110 mg (98%) of the title compound as a white solid. MS (ESI) 222 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.CN(C=O)C.CCN(CC)CC>[OH:9][C:3]1([C:1]#[C:2][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:14](=[O:20])[NH:15]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C#CC1(O)CCCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclohexanol (60 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclohexyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 94 mg, 65%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)O)=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:42]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClC(Cl)C>[N:22]1([CH2:21][CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:11][C:10]3[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH2:1])=[CH:42][C:7]=4[S:8][C:9]=3[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][CH2:40][CH2:41]4)=[CH:30][CH:29]=3)=[CH:14][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: CC[SiH](CC)CC
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.32 g (2.3 mmol) of 6-(aminomethyl)-α-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene-3-methanol in 40 mL of anhydrous dichloroethane at 0° C. was added 1.84 g (15.8 mmol) of triethylsilane and 2.62 g (23.0 mmol) of trifluoroacetic acid, respectively, under a nitrogen atmosphere. After one hour at 0° C., the reaction was warmed to room temperature and stirred for 24 h. The reaction was quenched with 10 mL of saturated aqueous sodium bicarbonate and poured into 30 mL of water. The aqueous layer was saturated with sodium chloride, separated from the dichloroethane layer, and extracted with three 50 mL portions of THF. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated at reduced pressure to give 786 mg (60% crude yield) of a brown foam. This material was carried on to the salt in Part D.
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>>[CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[C:30]([F:29])([F:39])[F:40])[C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Reactant: FC(F)(F)c1ccccc1CBr
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(Cc2ccccc2C(F)(F)F)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.147 g, 34%) from {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using 2-trifluoromethyl benzyl bromide and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.72 (t, J=7.8 Hz, 3H), 1.08-1.29 (m, 4H), 1.51-1.67 (m, 2H), 2.71 (t, J=8.6 Hz, 2H), 5.29 (s, 2H), 5.47 (s, 2H), 6.37 (d, J=8.6 Hz, 1H), 7.08-7.21 (m, 2H), 7.23-7.32 (m, 2H), 7.35-7.45 (m, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.63-7.75 (m, 2H), 7.83-7.92 (m, 3H); mass spectrum [(+) ESI], m/z 527 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:5]2=[O:20].CO.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:14])[N:6]([CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[C:5]2=[O:20]
Reactant: Cc1c(N)c([N+](=O)[O-])cc2c1C(=O)N(CCN(C)C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(N)c(N)cc2c1C(=O)N(CCN(C)C)C2=O

Procedure:
To a solution of 5-amino-2-(2-(dimethylamino)ethyl)-4-methyl-6-nitroisoindoline-1,3-dione (0.40 g, 1.37 mmol) in the mixture of methanol (8 mL) and acetic acid (0.4 mL) was added Pd/C (20 mg), and the resulting reaction mixture was hydrogenated for 2-3 h at 20-25 psi of hydrogen at rt. The reaction mixture was filtered through a pad of Celite and washed with methanol. The combined solvents were concentrated under vacuum to dryness. The crude product was used for the next step reaction without further purification. Mass (ESI, positive) m/z 263.0 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][C:8]([CH2:10][CH3:11])=O.C(O)C>O.[Pd]>[CH:8]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([CH2:10][CH3:11])[CH3:7]
Reactant: C[C@H](N)C(=O)O
Reactant: CCC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCC(C)N[C@@H](C)C(=O)O

Procedure:
356 g of alanine (4 mols) is dissolved in 1.5 liters of deionized water and put into a 1-gallon autoclave. 25 g of 10% Pd on carbon, wet with water, 423 g of methylethylketone (5.85 mols) and 250 ml of ethanol are added. The autoclave is closed and hydrogenation is carried out at 90°-105° C. and 63.3-77.3 kg/cm2. A pressure drop corresponding to 83.3 kg/cm2 is observed in the course of 4 hours. The autoclave is allowed to cool overnight.
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20][C:19]([CH3:28])=[C:18]2[C:29]([O:31][CH3:32])=[O:30])[CH:14]=[CH:15][CH:16]=1)C.[CH3:33][N:34]([CH:36]=O)[CH3:35]>>[CH:33]1([N:34]2[CH2:36][CH2:35][N:34]([CH2:36][CH2:4][CH2:5][NH:10][C:4]3[C:7](=[O:8])[C:6](=[O:9])[C:5]=3[NH:10][C:11]3[CH:12]=[C:13]([CH:17]4[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20][C:19]([CH3:28])=[C:18]4[C:29]([O:31][CH3:32])=[O:30])[CH:14]=[CH:15][CH:16]=3)[CH2:33][CH2:35]2)[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]1
Reactant: CN(C)C=O
Reactant: CCOc1c(Nc2cccc(C3C(C(=O)OC)=C(C)NC(C)=C3C(=O)OC)c2)c(=O)c1=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Nc2c(NCCCN3CCN(C4CCCCC4)CC3)c(=O)c2=O)c1

Procedure:
The compound of Example 1 (160 mg, 0.364 mmol) and 4-cyclohexyl-1-piperazine-1-propanamine (81.4 mg, 0.362 mmol) were stirred in 2 mL DMF at room temperature for 64 hours. The crude reaction mixture was evaporated to dryness under high vacuum (0.1 mmHg) at 50-55° C. The resulting gum was triturated with methylene chloride followed by the addition of hexanes. The titled compound precipitated out as fine creamy white crystalline solid (165 mg, 73.6%): mp 210-212° C.; 1H NMR (DMSO-d6) δ 9.52 (br. s, 1H), 8.91 (br. s, 1H), 7.54 (br. 1H), 7.27 (d, 1H, J=7.3 Hz), 7.16 (m, 2H), 6.80 (d, 1H, J=7.5 Hz), 4.88 (s, 1H), 3.61 (m, 2H), 3.55 (s, 6H), 2.45 (m, 5H), 2.30 (m, 4H), 2.26 (s, 6H), 1.69 (m, 7H), 1.53 (br. d, 1H, J=11.0 Hz), 1.11 (m, 6H); 13C NMR (DMSO-d6) δ 207.50, 207.28, 206.89, 203.73, 199.89, 194.77, 193.47, 192.12, 169.21, 167.38, 163.58, 153.67, 149.15, 145.92, 138.90, 128.87, 121.51, 116.60, 115.86, 101.11, 62.50, 54.94, 53.29, 50.57, 49.90, 48.28, 42.22, 28.32, 27.73, 26.26, 23.50, 18.29, 17.37. Anal Calcd. for C34H45N5O6•0.13 H2O: C, 65.64; H, 7.33; N, 11.26. Found: C, 65.65; H, 7.25; N, 11.09.