Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ccc(Cn3cc([N+](=O)[O-])cn3)s2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-4-nitro-1H-pyrazole (390 mg, 1.32 mmol), iron powder (223 mg, 3.96 mmol) and NH4Cl (357 mg, 6.60 mmol) in a mixture of EtOH (7.0 mL) and water (3.5 mL) was stirred at 75° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (40 mL) was added followed by 1M NaOH (40 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a deep red oil. LC-MS-conditions 02: tR=0.63 min; [M+H]+=266.34.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClC(Cl)Cl>[CH3:25][S:26]([O:13][CH:10]1[CH2:11][CH2:12][CH:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][C:4]=2[N+:16]([O-:18])=[O:17])[CH2:8][CH2:9]1)(=[O:28])=[O:27]
Reactant: O=[N+]([O-])c1cc(F)ccc1OC1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC1CCC(Oc2ccc(F)cc2[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 18.3 parts of 4-(4-fluoro-2-nitrophenoxy)cyclohexanol, 6.23 parts of pyridine and 135 parts of trichloromethane were added dropwise, during a 10 minutes period, 9 parts of methanesulfonyl chloride. Upon completion, stirring was continued overnight at room temperature. The whole was further stirred and refluxed for 2 hours. The reaction mixture was evaporated and the residue was stirred in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 8.5 parts of 4-(4-fluoro-2-nitrophenoxy)cyclohexanol methanesulfonate (ester); mp. 111.7° C. (intermediate 102).
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[CH:17]2[CH:12]([CH2:13][C:14](=[O:23])[CH2:15][CH:16]2[CH:20]([CH3:22])[CH3:21])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:26]I.[H-].[Na+]>>[CH2:1]([N:8]1[C:18](=[O:19])[CH:17]2[C:12](=[CH:13][CH:14]([O:23][CH3:26])[CH2:15][CH:16]2[CH:20]([CH3:21])[CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1CC(=O)CC2C1C(=O)N(Cc1ccccc1)S2(=O)=O
Reactant: CI
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Product: COC1C=C2C(C(=O)N(Cc3ccccc3)S2(=O)=O)C(C(C)C)C1

Procedure:
2-Benzyl-4-isopropyl-6-oxo-tetrahydrosaccharin of preparation 21 is reduced with sodium borohydride and methylated with methyl iodide in the presence of sodium hydride to provide 2-benzyl-4-isopropyl-6-methoxy-tetrahydrosaccharin. This is debenzylated and chloromethylated as in preparation 21 to provide 2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrosaccharin.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)([CH3:11])[CH2:9][OH:10])[C:5](O)=[C:4]([CH3:22])[C:3]=1[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]([CH3:22])[C:5]2[O:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)([CH3:11])[C:6]=2[CH:7]=1
Reactant: Cc1c(Br)cc(C(C)(CO)c2ccc(C(C)C)cc2)c(O)c1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Br)cc2c(c1C)OCC2(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-2,3-dimethylphenol obtained in Reference Example 22 (830 mg, 2.21 mmol) and triphenylphosphine (638 mg, 2.43 mmol) in THF (60 mL) was added diethyl azodicarboxylate (a 40% toluene solution, 1.06 g, 2.43 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain oily 5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran 660 mg. To a solution of said compound (660 mg, 1.84 mmol) and benzylamine (0.24 mL, 2.21 mmol) in toluene (10 mL) were added palladium acetate (4 mg, 0.02 mmol) and BINAP (34 mg, 0.6 mmol) at room temperature, and the mixture was stirred under argon stream for 15 minutes.
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[C:9]([O:28]CC)=[CH:10][C:11]2[N:17]([CH2:18][CH3:19])[C:16](=[O:20])[CH2:15][N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[CH:27]=1)C>C(Cl)Cl>[CH2:18]([N:17]1[C:11]2[CH:10]=[C:9]([OH:28])[C:8]([OH:7])=[CH:27][C:12]=2[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:14][CH2:15][C:16]1=[O:20])[CH3:19]
Reactant: CCOc1cc2c(cc1OCC)N(CC)C(=O)CN=C2c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN1C(=O)CN=C(c2ccccc2)c2cc(O)c(O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.3 %

Procedure:
Add dropwise at 0° C. under an inert atmosphere, 0.68 ml of a 1 M solution of BBr3 (0.68 mmol) in CH2Cl2 on 200 mg (0.62 mmol) of 7,8-diethoxy-1-ethyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbg) in 5 ml of dichloromethane. Stir at room temperature for 12 hours. Quench at 0° C. with methanol. Evaporate to dryness. Triturate again and evaporate. Purify by chromatography (AcOEt). Recrystallize in EtO2/pentane. One obtains 30 mg of the abovenamed product as a yellow powder. Yield: 16%. M: 230–231° C. 1H-NMR (DMSO, 200 MHz): d 0.96 (t, 3H, CH3), 3.80 (AB system, ? d=0.54, JAB=13.7, 2H, —NCH2), 4.05 (AB system, ? d=0.72, JAB=10.0, 2H, CH2), 6.52 (s, 1H Ar), 6.91 (s, 1H Ar), 7.42–7.55 (m, 5H Ar), 9–10.5 (hump, 2H, 2×—OH).
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:22][CH3:23])[CH2:12][O:11][CH:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[O:9][CH2:8]1)(=O)=O.[C:24]([NH2:35])(=[O:34])[C:25]1[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:27](N)=[O:28].[K]>CS(C)=O.CCOC(C)=O.O>[CH2:22]([C:7]1([CH2:6][N:35]2[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]2=[O:28])[CH2:12][O:11][CH:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[O:9][CH2:8]1)[CH3:23]
Reactant: CCC1(COS(C)(=O)=O)COC(c2c([N+](=O)[O-])cnn2C)OC1
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: [K]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1(CN2C(=O)c3ccccc3C2=O)COC(c2c([N+](=O)[O-])cnn2C)OC1
Temperature: 180 °C
Yield: 35.2 %

Procedure:
To a solution of (5-ethyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl methanesulfonate (816 mg, 2.25 mmol, intermediate 74) in dry DMSO (10 mL) was added potassium phthalamide (2.1 g, 11.3 mmol) in a single portion. The reaction mixture was heated at 180° C. for 5 hr, cooled to room temperature and diluted with EtOAc (50 mL) and water (30 mL). The organic layer was washed with water (3×30 mL), 2 N NaOH (2×20 mL) and water (20 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-((5-ethyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)isoindoline-1,3-dione as a colourless solid (317 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.93-7.88 (m, 2H), 7.82-7.76 (m, 2H), 6.31 (s, 1H), 4.14 (s, 3H), 4.06 (d, J=11.8 Hz, 2H), 3.85 (d, J=11.8 Hz, 2H), 3.51 (s, 2H), 1.92 (q, J=7.6 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:7]2=[N:6][C:5]1=[O:17])([CH3:3])[CH3:2].[CH2:19]([SH:22])[CH:20]=[CH2:21].C(N(CC)CC)C.C(O)=O>O1CCCC1>[CH2:19]([S:22][C:7]12[NH:6][C:5](=[O:17])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:18])[N:8]1[C:9](=[O:16])[C:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:20]=[CH2:21]
Reactant: C=CCS
Reactant: CC(C)C1(C)C(=O)N=C2c3ncccc3C(=O)N21
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCSC12NC(=O)C(C)(C(C)C)N1C(=O)c1cccnc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, 7.8 g of 3-isopropyl-3-methyl-3H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5-dione in 50 ml of tetrahydrofuran are stirred together with 3.5 ml of allylmercaptan and 4.9 ml of triethylamine. The mixture is stirred further for 15 hours at room temperature. In order to work up the reaction mixture, 1.2 ml of formic acid are added and most of the solvent is evaporated off. The residue is chromatographed through a column of silica gel eluted with a 1:1 mixture of ethyl acetate and hexane. The eluant is evaporated off off, leaving a residue which crystallises. Yield: 3.2 g of the title product; m.p.: 126°-138° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.ClCCl.O>C(#N)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
Trichlorinated derivative, 2-chloro-1-(2,4-dichlorophenyl)-ethanone (5.58 g), is added to 5.10 g of imidazole (75 mmole) in 25 ml of acetonitrile, and the reaction medium is stirred at ambient temperature for 24 hours. Then 50 ml of dichloromethane and 50 ml of water are added, followed by extracting, decanting, washing then re-extracting with dichloromethane. The organic phases are dried and evaporated under reduced pressure until a dry extract is obtained, which is purified by chromatography on silica eluting with a CH2Cl2/MeOH mixture 96/4 to afford 4.76 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:25](O)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:29]=[C:30]([CH:32]1[CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]3)[O:26][N:29]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccc(OC(F)(F)F)cc2)C1
Reactant: NC(=NO)C1CC1
Product: CC(C)(C)OC(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
1.00 g (2.57 mmol) of the compound from Example 173A and 386 mg (3.86 mmol) of the compound from Example 78A were reacted according to the General Method 2. Yield: 185 mg (16% of theory)
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:30])[CH2:6][CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:31]([O:10][C:9](=[O:11])[CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:7][CH2:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:30])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCc1ccccc1
Reactant: C=CCOC(=O)CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CCOC(=O)CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Temperature: 22 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
Treatment with Fmoc-Cl followed by coupling to benzyl alcohol using 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide [by] hydrochloride (EDCl) provided 2-(9H-Fluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 5-allyl ester 1-benzyl ester 6 in 82% yield. To a solution of 1.5 g (36.6 mmol) of 5 in 5 mL of CH2Cl2 was added 0.42 mL (40.3 mmol) of benzyl alcohol, 0.912 g (47.6 mmol) of EDCI, and 45 mg (3.66 mmol) of dimethylaminopyridine (DMAP). The reaction mixture was stirred at 22° C. for 6 h, diluted with 20 mL of CH2Cl2, and extracted with H2O (1×15 mL), 0.1M HCl (2×15 mL), and brine (2×10 mL). The organic layer was dried (Na2SO4), concentrated in vacuo, and chromatographed on SiO2 (Hexanes/EtOAc, 5:1) to give 1.83 g (82%) of 6 as a white solid: Mp 66.2°-67.1° C. (EtOAc/Hexanes); [α]D +1.4° (C 1.64, CHCl3, 21° C.); IR (neat) 3314, 1726, 1682, 1527, 1443, 1414, 1383, 1254, 1173, 1099, 1082, 980, 754, 735 cm-1 ; 1H NMR δ 7.75 (d, 2 H, J=7.4 Hz), 7.59 (d, 2 H, J=7.1 Hz), 7.41-7.27 (m, 9 H), 5.95-5.85 (m, 1 H), 5.44 (d, 1 H, J=8.2 Hz), 5.34-5.19 (m, 4 H), 4.56(d, 2 H, J=5.6 Hz), 4.5-4.4 (m, 3 H), 4.21 (t, 1 H, J=7.0 Hz), 2.5-2.0 (m, 4 H); 13C NMR δ 172.2, 171.6, 155.8, 143.7, 143.5, 141.1, 135.0, 131.8, 128.5, 128.3, 128.1, 127.6, 126.9, 124.9, 119.8, 118.3, 67.2, 66.9, 66.2, 53.3, 47.0, 28.0, 27.3; MS (FAB, MNBA/MeOH) m/z (relative intensity) 500 ([M+H]+, 40), 465 (8), 448 (14), 433 (12), 413 (8), 386 (38), 371 (24), 349 (9), 324 (16), 309 (26), 293 (11), 265 (10), 247 (24), 231 (56), 215 (39), 202 (26), 191 (24), 179 (67), 165 (48), 154 (67), 143 (31), 133 (71), 117 (100).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:3]=1[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[C:31]([F:37])[CH:30]=1.[NH4+].[Cl-]>CN(C)C=O.CCOC(C)=O>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[C:3]([C:18]([O:20][CH3:21])=[O:19])[C:4]([C:11]4[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=4)=[C:5]3[CH:10]=[CH:9]2)=[C:31]([F:37])[CH:30]=1
Reactant: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: Fc1cc(Cl)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)nc2c(ccn2Cc2ccc(Cl)cc2F)c1-c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Methyl 6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (300 mg, 1.070 mmol) (example 1 step F) was dissolved in N,N-dimethylformamide (DMF) (10.700 ml). Cesium carbonate (418 mg, 1.284 mmol) and 4-chloro-2-fluorobenzyl bromide (263 mg, 1.177 mmol) were added to the solution. The reaction was set to stir at 65° C. overnight. The reaction was worked up by adding a saturated aqueous solution of NH4Cl followed by EtOAc. The layers were separated and the organic fraction was washed with water and brine. The reaction was dried over sodium sulfate and concentrated. The crude oil was passed on silica (0-60% AcOEt/Hex) and methyl 1-(4-chloro-2-fluorobenzyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (250 mg, 0.591 mmol, 55.2% yield) was recovered as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.46-7.39 (m, J=8.0 Hz, 2 H), 7.35-7.26 (m, J=7.9 Hz, 2 H), 7.18 (d, J=3.5 Hz, 1 H), 7.15-7.08 (m, 2 H), 7.07-7.00 (m, 1 H), 6.43 (d, J=3.5 Hz, 1 H), 5.53 (s, 2 H), 3.67 (s, 3 H), 2.75 (s, 3 H), 2.44 (s, 3 H) LCMS (m/z) ES+=423.2 (M+1).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:21]1[N:22]=[C:23]([NH2:39])[C:24]2[N:25]=[CH:26][N:27]([C:37]=2[N:38]=1)[C@@H:28]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]1[OH:30]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:21]2[N:22]=[C:23]([NH2:39])[C:24]3[N:25]=[CH:26][N:27]([C:37]=3[N:38]=2)[C@@H:28]2[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]2[OH:30])[CH2:5][CH2:6]1)=[O:11]
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2Cl)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccccc3Cl)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
2-Chlorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.588 g, 2.117 mmol) was added to a solution of 2-iodoadenosine (0.602 g, 1.531 mmol) according to general procedure 2: yield 733 mg, 88%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.45-7.40, 7.33-7.26, 7.22-7.16 (3×m, 4H), 5.95 (d, 1H, J=6.3 Hz), 4.74 (t, 1H), 4.41-4.30 (m, 2H), 4.20-4.11 (m, 2H), 3.94-3.86, 3.78-3.71, (2×m, 2H), 3.08, 2.92 (2×br t, 2H), 2.43 (d, 2H, J=6.2 Hz), 2.01-1.78, 1.54-1.28 (2×m, 5H). 13C NMR (CD3OD) δ 157.2, 154.3, 150.1, 148.9, 147.4, 142.6, 131.1, 129.0, 128.3, 127.9, 125.4, 120.4, 91.3, 88.2, 86.7, 82.2, 75.5, 72.6, 64.7, 63.5, 45.8, 36.4, 32.4, 26.5, 25.2. LRMS ESI (M+H+) 543.1. HPLC rt=6.2 min.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([S:21]C2C=CC=CC=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br-:28].[Al+3].[Br-].[Br-].Br>CCCCCC.CC(C)=O>[Br-:28].[C:1]1([S+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Al+3]
Agent: [Br-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: c1ccc(Sc2ccc([S+](c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
In 200 ml of n-hexane were suspended 6.07 g (0.03 mol) of diphenylsulfoxide and 11.2 g (0.06 mol) of diphenylsulfide, and 48.0 g (0.18 mol) of aluminum bromide was added thereto at 20 to 40° C., followed by reacting at 60 to 65° C. for 6 hours with stirring. After completion of the reaction, the reaction solution was poured into 500 ml of 12% hydrobromic acid, followed by washing with 200 ml of n-hexane five times and extracting with 200 ml of dichloromethane. The obtained dichloromethane layer was washed with 200 ml of water five times, followed by concentration under reduced pressure to obtain a crude product. Then, 120 ml of acetone was added to the crude product to dissolve at 55° C., followed by cooling to 5° C. to obtain crystal. The crystal was filtered off to obtain 5.3 g (Yield: 39%) of dipheny-4-phenylthiophenylsulfonium bromide as a pale yellow crystal.
Reaction SMILES: O.NN.[OH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6]1.[CH2:25]([OH:27])[CH3:26]>>[OH:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][NH:14][C:22](=[O:23])[O:27][CH2:25][C:26]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(O)CC1
Reactant: CCO
Agent: NN
Solvent: O
Product: O=C(NCCCN1CCC(O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanol (100 ml) and hydrazine hydrate (1.5 g) were added to 2-(3-(4-hydroxypiperidino)propyl)isoindolin-1,3-dione (4.5 g); the reaction mixture was heated to reflux for 2.5 hours; and the produced crystals were filtered off. N-Methylmorpholine (2.5 ml) and N-(benzyloxycarbonyloxy)succinimide (5.2 g) were added to the filtrate; and the reaction mixture was stirred at room temperature overnight. Aqueous solution of sodium hydrogencarbonate was added to the reaction mixture; extraction was performed with ethyl acetate; and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield the title compound (2.96 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH:8]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[N:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a cooled (−15° C.) solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.100 g; 0.295 mmol) in dry DMF (1.5 mL) was wadded a 1N solution of LHMDS in THF (0.324 mL; 0.324 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of benzyl bromide (0.070 mL; 0.589 mmol). After stirring for 2 h at (−15° C.) the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.087 g (60%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][O:14][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Prepare by the method of Example 1.5 using (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and methanesulfonyl chloride to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:16][CH:17]=[CH2:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[C:3]([CH2:16][CH2:17][CH3:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: [H][H]
Reactant: C=CCc1c(O)ccc2[nH]c(C(=O)OCC)cc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc2[nH]c(C(=O)OCC)cc12
Yield: 74.2 %

Procedure:
Ethyl 5-hydroxy-4-(2-propenyl)-1H-indole-2-carboxylate (2.16 g) was dissolved in dry ethanol (100 ml) and hydrogenated at atmospheric pressure in the presence of 5% palladium on charcoal (0.2 g) until hydrogen uptake had ceased. The catalyst was filtered off, washed with hot ethanol, the filtrate evaporated and the residue recrystallised from aqueous ethanol to give 1.616 g of the desired product mp 185°-186°: