Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][I:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])(=O)=O>C(Cl)Cl>[I:10][CH2:9][CH2:8][C@H:2]([O:1][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)[C@@H](O)CCI
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)[C@H](CCI)O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 392 (15.5 g, 60.1 mmol), 2,6-lutidine (21.0 ml, 180 mmol) and DCM (125 mL) cooled to 0° C. and maintained under N2 was added dropwise triethylsilyl trifluoromethanesulfonate (17.5 g, 66.1 mmol). The reaction was stirred at 0° C. for 1 h then warmed to RT and stirred for 18 h. The reaction was quenched by adding satd. aq. NH4Cl and extracted with DCM. The organic extract was washed organic with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography (SNAP 100) eluting with EtOAc/hexane (9:1) to afford 18.9 g (76%) of (S)-ethyl 4-iodo-2-(triethylsilyloxy)butanoate (396) as a yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:32])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[OH:32][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:7][CH2:6][N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]4[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=4[C:15]=3[C:14]=2[CH:13]=1
Reactant: CS(=O)(=O)OCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Reactant: c1c[nH]cn1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCn1ccnc1
Yield: 50 %

Procedure:
Mesylate (205) (70 mg, 0.16 mmol) prepared as described in example 174 was reacted with imidazole according to the procedure described in example 179 to give amine (213) (34 mg, 50%) as a yellow powder, mp>345° C. 1H NMR δ [(CD3)2SO] 11.05 (br s, 1H), 9.34 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.59 (m, 2H), 7.45 (m, 5H), 7.27 (s, 1H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 7.02 (s, 1H), 6.75 (s, 1H), 4.80 (t, J=5.7 Hz, 2H), 4.41 (t, J=5.7 Hz, 2H). Found: C, 70.36; H, 4.38; N, 12.68. C25H18N4O3.1/4H2O requires: C, 70.33; H, 4.37; N, 13.12.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH:7]1[C@@H:11]2[CH2:12][N:13]([C:15]3[N:20]=[C:19]([C:21]4[O:25][C:24]([C:26]5[CH:31]=[CH:30][C:29]([CH2:32][N:33](C)[C:34](=O)OC(C)(C)C)=[CH:28][CH:27]=5)=[N:23][N:22]=4)[C:18]([N:42](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:17][CH:16]=3)[CH2:14][C@@H:10]2[CH2:9][CH2:8]1)(=[O:5])=[O:4])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][C:18]1[N:17]=[CH:16][C:15]([N:13]2[CH2:14][C@@H:10]3[CH2:9][CH2:8][CH:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[C@@H:11]3[CH2:12]2)=[N:20][C:19]=1[C:21]1[O:25][C:24]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][NH:33][CH3:34])=[CH:30][CH:31]=2)=[N:23][N:22]=1
Reactant: CCS(=O)(=O)NC1CC[C@H]2CN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CC[C@H]2CN(c3cnc(N)c(-c4nnc(-c5ccc(CNC)cc5)o4)n3)C[C@@H]12
Reaction time: 1 h

Procedure:
A solution of tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-(ethylsulfonylamino)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (110 mg, 0.14 mmol) in DCM (1 mL) was treated with TFA (1.0 g, 676 μL, 8.8 mmol). The reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was purified via reverse phase HPLC using 10 to 99% ACN in water (5 mM HCl modifier) to obtain N-[(3aR,6aS)-2-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-6-yl]ethanesulfonamide. LC/MS m/z 499.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[O:6].Cl.[NH2:26][OH:27]>>[OH:27][NH:26][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:2]([CH3:1])[CH:3]=1)=[O:14]
Reactant: Cc1cc(C(=O)NCCCCCC(=O)O)ccc1-c1ccccc1
Reactant: NO
Agent: Cl
Product: Cc1cc(C(=O)NCCCCCC(=O)NO)ccc1-c1ccccc1
Yield: 51.9 %

Procedure:
The procedure of the step 3 in Example 80 was repeated except that 6-(3-methyl-4-phenyl-benzamido)hexanoic acid (70 mg (0.215 mmol)) instead of 6-(3-bromo-2-methylbenzamido)hexanoic acid, and 30 mg of hydroxylamine hydrochloride (0.43 mmol) instead of 1,2-phenylenediamine were used and purified by a preparative HPLC (C18, 20% H2O/CH3CN, 20 ml/min) to obtain the title compound (38 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[CH3:7][C:4]1[C:3]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([S:17]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[C:2]([NH2:1])[NH:6][N:5]=1
Reactant: CN1CCNCC1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2s1
Yield: 19.6 %

Procedure:
the title compound (30 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (128 mg, 0.39 mmol), 4-methylpiperazine (39 mg, 0.43 mmol) and triethylamine (0.1 mL). MS (m/z, ES+): 393.1 (M+1, 100%). Yield=20%.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2.Cl>O1CCCC1>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)([OH:22])[CH2:17][CH2:16]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: C1CSCSC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(C2SCCCS2)CCc2cc(Br)ccc21
Temperature: -15 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 1,3-dithiane (11.96 g, 99 mmol) in anhydrous tetrahydrofuran (100 mL) at −30° C. was treated dropwise over 10 min with n-butyllithium (2.5M in hexanes, 38.4 mL, 96 mmol) followed by stirring at −15° C. for 2 h. The solution was then treated with a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (15 g, 71.1 mmol) in anhydrous tetrahydrofuran (250 mL) over 1 h, maintaining the temperature between −9° C. and 2° C. The mixture was then allowed to set in the refrigerator at 2-8° C. for 18 h. The solution was concentrated in vacuo to afford a maroon oil, which was treated with 1 N hydrochloric acid solution and extracted with ether. The ether layer was extracted with saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo to afford an amber oil (23.55 g).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1>>[F:17][C:18]1[CH:19]=[C:20]([F:24])[CH:21]=[CH:22][C:23]=1[C:8]([CH:7]1[CH2:11][CH2:12][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1)=[O:9]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
N-Acetyl isonipecotoyl chloride (70.0 g, 0.369 mol) was added over a 20 minute period to a vigorously stirred suspension of AlCl3 (98 g, 0.735 mol) in 1,3-difluorobenzene (125 ml, 1.27 mol, Aldrich Chem. Co.) at 25° C. The mixture was then refluxed, under N2 for 4.5 hours, cooled to 25° C., and poured over 300 ml of ice/water. The layers were separated, the aqueous layer was extracted (2×100 ml CH2Cl2) and combined with the organic layer and dried with MgSO4. Concentration in vacuo gave 4-(2,4-difluorobenzoyl)-1-acetyl-piperidine (II) as a white solid (81 g, 82%), m.p. 94°-96° C.
Reaction SMILES: O.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][OH:10])O[CH:5]=[C:4]1[O:11][CH2:12][C:13]([O:15]CC)=[O:14].[NH3:18]>>[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:18][CH:5]=[C:4]1[O:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: N
Reactant: CCOC(=O)COc1coc(CO)cc1=O
Solvent: O
Product: O=C(O)COc1c[nH]c(CO)cc1=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(4-oxo-6-hydroxymethyl-4H-pyran-3-yloxy)acetate monohydrate (10 g) in conc. ammonia was heated at 120° C. for 10 hours in a sealed vessel and the reaction mixture was concentrated. To the residue was added water and the resultant solution was adjusted to pH 1 to 2 with 10% hydrochloric acid. The resultant precipitates were washed with water and dried to give crystals (6 g) of 2-(4-oxo-6-hydroxymethyl-1,4-dihydropyridin-3-yloxy)acetic acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1.C(O)(=O)C.[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=O.C([BH3-])#N.[Na+]>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1)[CH2:42][C:38]1[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2n1CCC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The compound (64.0 mg) obtained in Example 4-1 was dissolved in methanol (1.3 ml) and added with acetic acid (0.065 ml) and 1-methyl-2-imidazole carboxaldehyde (16.6 mg) and the whole was cooled to 0° C. Then, the solution was added with sodium cyanoborohydride (14.2 mg) and stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After washing with a 1 mol/l sodium hydroxide aqueous solution, the solution was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate.
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]=[O:9])[CH2:4][CH2:5][CH3:6].C=O.C[CH2:17][O:18]CC>CO.O>[CH2:3]([C:7]([CH2:17][OH:18])([CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C=O)CCCC
Reactant: CCOCC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(C=O)(CO)CCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of 1 N sodium hydroxide (150 mL) was added dropwise to a solution of 209 g of dibutylacetaldehyde (supplied from Aldrich) and 127 g of an aqueous solution of 35% formalin (supplied from Wako Pure Chemical Industries) in 1500 mL of methanol under ice cooling, and stirred at room temperature overnight. Then 2 L of ether and 2 L of water were added to the reaction solution, and the mixture was separated into two liquid phases. The organic layer was dried on sodium sulfate anhydrate and concentrated, to yield 248 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.[CH3:12][O:13]C(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: COC(Cl)Cl
Reactant: Fc1ccc2c(c1)CCCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cc(F)cc2c1OCCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.8 %

Procedure:
13.74 g (90.28 mmol) of 6-fluorochroman are dissolved in 250 ml of methylene chloride. The whole is cooled to 0° C. and 20.15 ml (0.18 mol) of TiCl4 are added dropwise. The solution becomes brown and is stirred for 10 minutes at room temperature. 8.78 ml (99.3 mmol) of α,α-dichloromethyl ether are then introduced. The whole is stirred overnight at room temperature, poured into ice-cold water and decanted. The organic phase is dried and evaporated to yield 17.7 g of a residue which is purified by chromatography on silica (eluant CH2Cl2 /cyclohexane: 50/50). 6.3 g of the expected product are obtained. Yield: 38.7%.
Reaction SMILES: [C:1]([CH2:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=O)#[N:2].[CH3:18][NH:19][NH2:20]>CCO>[NH2:2][C:1]1[N:19]([CH3:18])[N:20]=[C:4]([C@@H:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1
Reactant: CNN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)CC#N
Solvent: CCO
Product: Cn1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)cc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
tert-Butyl (2S)-2-(2-cyanoacetyl)pyrrolidine-1-carboxylate (5.8 g, 24.3 mmol), was dissolved in EtOH (100 mL). Methylhydrazine (1.8 mL, 35 mmol) was added and the resulting mixture was heated, for about 12 h, at about 80° C. After cooling to rt, the mixture was concentrated in vacuo. The residue was taken up in toluene (50 mL) and stirred overnight. The precipitated solid was collected by filtration and washed with toluene (2 mL) and diethyl ether to afford tert-butyl (2S)-2-(5-amino-1-methyl-pyrazol-3-yl)pyrrolidine-1-carboxylate (4.43 g, 16.3 mmol, 68%), as white solid: 1H-NMR (CDCl3, Bruker 400 MHz, rotamers) δ 1.35 and 1.45 (9 H, br. s), 1.70-2.24 (4 H, m), 3.36-3.53 (4 H, m), 3.60 (3 H, br s), 4.70-4.78 and 4.83-4.90 (1 H, m), 5.35 and 5.41 (1H, br s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Yield: 71.6 %

Procedure:
tert-Butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (230 mg, 0.609 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (123 mg, 0.534 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (199 mg, 71%) as a colorless oil: ESI MS m/z 521 [M+H]+.
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[S:12][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:20]1[CH:19]=[CH:18][C:11]2[S:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]=2[CH:21]=1
Reactant: BrBr
Reactant: COC(=O)c1sc2ccccc2c1-c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Add 29.3 g. bromine (10 ml; 0.37 mole) to 8.0 g. (0.03 mole) of methyl 3-phenylbenzo [b]thiophene-2-carboxylate in 100 ml. of acetic acid and stir the mixture overnight at room temperature. Add a saturated solution of sodium bisulfite. Decant the supernatant and wash the oil with water. Triturate with methanol. Recrystallize from methanol to yield the title compound; m.p. 125°-126°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)[CH:6]=[CH:5][N:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])[CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccnc(OC)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccnc(OC)c3)c2)=C(C)C1=O
Yield: 54.8 %

Procedure:
N-(2-Methoxypyridin-4-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.100 g, 0.208 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.114 mmol, 55%).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([C:1]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:6])[CH2:2][CH2:3][CH2:4][OH:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCO1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4-Butyrolactone (11.93 mL, 0.155 mol) was dissolved in anhydrous THF and cooled to 0° C. Phenylmagnesium bromide (3 M in ether, 112 mL) was added dropwise over 30 minutes to the reaction under N2. After the addition, the reaction was warmed to room temperature overnight. Additional phenylmagnesium bromide (3 M in ether, 103 mL) was added, and the reaction stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl (150 mL). Ether (200 mL) and 10% HCl (100 mL) were added. The organic layer was separated and washed with 10% HCl (100 mL), brine (100 mL), and then dried over MgSO4. The solution was filtered, concentrated, and the crude material chromatographed on silica gel eluting with 50% EtOAc/Hexanes to give 26.94 g (72%) of desired product as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc(OC)c1
Yield: 98 %

Procedure:
Prepared from VII and 3,5-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 98%; yellow solid; mp 248° C.; IR (KBr) νmax/cm−1 3242, 2940, 2837, 2223, 1711, 1647, 1578, 1455, 1419, 1383, 1357, 1306, 1265, 1205, 1144, 1058, 1046, 968, 943, 917, 833, 806; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.06 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 6.31 (m, 3H), 3.74 (s, 6H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0856.
Reaction SMILES: C(OC(=O)[N:10]([CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([C:35](=[O:45])[N:36]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])([CH3:34])[CH3:33])[CH:30]=2)[NH:25][C:24]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)C1C=CC=CC=1.CCO>[Pd].CCOC(C)=O>[CH3:53][C:48]1[CH:47]=[C:46]([C:24]2[NH:25][C:26]3[C:31]([C:23]=2[CH2:22][CH2:21][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:30][C:29]([C:32]([CH3:33])([CH3:34])[C:35]([N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:45])=[CH:28][CH:27]=3)[CH:51]=[C:50]([CH3:52])[CH:49]=1
Reactant: CCCCN(CCCC)C(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3cccnc3)C(=O)OCc3ccccc3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3cccnc3)c2c1
Reaction time: 6 h

Procedure:
A mixture of 76.5 mg (0.105 mmol) of [2-[5-(1-dibutylcarbamoyl-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-[4-(pyridin-3-yl)butyl]carbamic acid benzyl ester, 40 mg of 10% palladium on carbon, 4 ml of absolute EtOH, and 4 ml of EtOAc was shaken with H2 (approx. 47 psig) in a pressure vessel for 6 hours. The catalyst was removed by filtration through Celite under N2, and the filtrate was concentrated in vacuo at room temperature. The residue was purified by preparative TLC on 4 Analtech tapered silica gel plates (20×20 cm), which were developed in 92.5:7.5:0.75 CH2Cl2 -MeOH-concentrated NH4OH. The product band from each plate was isolated, combined, and extracted with 92.5:7.5:0.75 CH2Cl2 -MeOH-concentrated NH4OH. Concentration of the extracts in vacuo yielded 51.4 mg (82%) of a pale yellow, stiff gum; homogeneous by TLC in 92.5:7.5:0.75 CH2Cl2 -MeOH-concentrated NH40H. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e 595.6 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9](C(=O)C)[N:8]=1>>[CH3:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=2)[NH:9][N:8]=1
Reactant: CC(=O)n1nc(C)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: Cc1n[nH]c2ccc(S(=O)(=O)Cl)cc12
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To chlorosulfonic acid (0.38 ml, 5.7 mmol) under a blanket of argon in an ice bath was added 1-(3-methyl-indazol-1-yl)-ethanone (200 mg, 1.1 mmol). The reaction was allowed to warm to RT and then was heated at 70° C. for 45 min. The reaction was cooled to rt, slowly quenched over ice and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated in vacuo to a tan solid (160 mg, 0.7 mmol, 61% yield).
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH:20]([C:22]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2C(OC(C)(C)C)=O)=O.CO>C1COCC1>[CH3:32][O:31][C:30]1[C:22]([CH2:20][C:17]#[N:18])=[C:23]2[C:27](=[C:28]([CH3:33])[CH:29]=1)[NH:26][CH:25]=[CH:24]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]ccc2c1CC#N
Reaction time: 0.25 h

Procedure:
To a suspension of KOtBu (6.98 g, 62.2 mmol) in THF (50.0 mL) at −78° C. was added TOSMIC (8.10 g, 41.5 mmol) in THF (50.0 mL). The mixture was stirred at −78° for 15 minutes. To the mixture at −78° C. was then added a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (6 g, 20.74 mmol) in THF (50 mL). The reaction was stirred at −78° C. for 1.5 hours. MeOH (10 ml) was then added and the reaction was removed from the dry ice bath. After 30 minutes the reaction was placed in a 40° C. water bath for 30 minutes. At this point, the reaction was cooled in an ice bath and was quenched with a saturated solution of ammonium chloride and then diluted with water and EtOAc. The layers were separated and the organics layer was dried, concentrated and absorbed onto silica to purify via FCC (0-50% EtOAc:heptanes) to afford the title compound. MS (ESI+) m/z 201.2 (M+H).