Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.N([O-])=[O:11].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:9][C:5]1[CH:6]=[C:7]([I:8])[C:2](=[O:11])[NH:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]cc(Br)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-5-bromopyridine (CAS No. 1072-97-5) (300 g) was dissolved in a mixed solvent consisting of 1000 ml of acetic acid and 200 ml of water, 30 ml of concentrated sulfuric acid were gradually dropped thereinto under stirring. Then, 79.1 g of periodic acid hydrate and 176 g of iodine were added thereto, followed by stirring at 80° C. for 4 hours. To the reaction mixture were added periodic acid hydrate (40 g) andiodine (22 g), followed by further stirring at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured onto ice (3000 ml) and neutralized to pH 7.0 with 5N aqueous sodium hydroxide. The resulting crystals were collected by filtration, dissolved in a mixed solvent of ethyl acetate/diethyl ether, successively washed with aqueous sodium thiosulfate, water, 1N aqueous sodium hydroxide and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated, to give 392 g of 2-amino-5-bromo-3-iodopyridine (yield: 76%). 2-Amino-5-bromo-3-iodopyridine (100 g) was gradually added to 300 ml of concentrated sulfuric acid under ice-cooling. After the reaction mixture was stirred at room temperature for 2 hours, it was ice-cooled again. 35 g of sodium nitrite were gradually added thereto, followed by stirring at room temperature for 3 days and nights. The reaction solution was poured onto ice (3000 ml) and neutralized to pH 4.0 with sodium hydroxide. The resulting crystals were collected by filtration, washed with water and warm air-dried at 60° C. for one day and night, to give 102 g (quantitative) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.Cl.[CH:22]1([C:25]2[C:26]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[C:26]([N:32]3[CH2:37][CH2:36][N:35]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:20])=[CH:8][C:9]=4[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:34][CH2:33]3)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C2CC2)c1
Yield: 69.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 85 and by the reaction and treatment in the same manner as in Example 86, the title compound (360 mg) was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]1[N:19]3[CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:18]3=[N:17][C:10]=1[CH:11]=[N:12]2.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([N:23]1[CH2:22][CH2:21][CH2:20][N:19]2[C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[CH:16][CH:7]=4)[N:12]=[CH:11][C:10]=3[N:17]=[C:18]2[CH2:24]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc2c(c1)ncc1nc3n(c12)CCCNC3
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Methanesulfonyl chloride (2.54 mL, 32.6 g) was added to a solution of 9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline hydrochloride (7.47 g, 27.2 mmol) and triethylamine (22.73 mL, 163.1 mmol) in DMF (50 mL). The reaction was stirred overnight at ambient temperature and then concentrated under reduced pressure to provide 3.065 g of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline.
Reaction SMILES: [C:1](=O)([O-])[O-:2].[Cs+].[Cs+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C2C(=CC=CC=2)C=CC=1C(C)C)(C)(C)C.Cl[C:40]1[N:41]=[C:42]([CH2:70][C:71]([CH3:74])([CH3:73])[CH3:72])[CH:43]=[C:44]2[C@@H:49]([NH:50][CH2:51][C@@H:52]([OH:66])[C@@H:53]([NH:62][C:63](=[O:65])[CH3:64])[CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([F:61])[CH:56]=3)[CH2:48][C:47]3([CH2:69][CH2:68][CH2:67]3)[O:46][C:45]=12.CO>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:72][C:71]([CH3:74])([CH3:73])[CH2:70][C:42]1[CH:43]=[C:44]2[C@@H:49]([NH:50][CH2:51][C@@H:52]([OH:66])[C@@H:53]([NH:62][C:63](=[O:65])[CH3:64])[CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([F:61])[CH:56]=3)[CH2:48][C:47]3([CH2:69][CH2:68][CH2:67]3)[O:46][C:45]2=[C:40]([O:2][CH3:1])[N:41]=1
Reactant: CC(=O)N[C@@H](Cc1cccc(F)c1)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2Cl
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)ccc3ccccc23)c1C
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1nc(CC(C)(C)C)cc2c1OC1(CCC1)C[C@@H]2NC[C@@H](O)[C@H](Cc1cccc(F)c1)NC(C)=O
Temperature: 110 °C

Procedure:
To a 2 mL microwave vial is added cesium carbonate (283 mg, 869 μmol), di-tert-butyl(2-(2-isopropylnaphthalen-1-yl)-3,4,5,6-tetramethylphenyl)phosphine (71 mg, 159 μmol), palladium(II) acetate (33 mg, 145 μmol), and N-((1S,2R)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide (75 mg, 145 μmol) were added and the vial was flushed with N2 5×, then methanol (160 μl, 3619 μmol) and toluene (1 mL) were added simultaneously. The reaction was heated in the microwave at 110° C. for 30 min. LCMS shows 100% conversion. The reaction mixture was filtered through a small plug of silica gel, and the residue purified by reverse phase HPLC on a Phenomenex Synergi column (5 micron, MAX-RP, 80 Å, 150×30 mm) eluting at 45 ml/min with an linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 30 minutes to give the title compound as a tan amorphous solid. MS m/z: 514.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].CCN(CC)CC.[CH:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]([C:41]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:42])[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:18][CH2:19]1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(Nc3ccc(F)cc3)CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1CC(N1CCC(N(C(=O)C3CCCCC3)c3ccc(F)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(4-Fluoro-phenylamino)-piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (50 mg; 0.13 mmol; 1 eq.) was dissolved in DCM (3 mL) and Et3N (0.056 mL; 0.39 mmol; 3 eq.) was added. Cyclohexylcarbonyl chloride (30 mg; 0.2 mmol; 2 eq.) was then added and the solution was stirred at room temperature for 18 hours (overnight). 1N NaOH (10 mL) was added and the solution was extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified using reversed-phase HPLC (2-99% CH3CN/H2O gradient with 0.05% TFA). LC/MS M/Z=432.4, Retention time=2.12; 10-99% CH3CN/H2O gradient with 0.05% TFA over 5 minutes. H NMR (400 MHz, MeOD, TFA salt) δ 7.33-7.22 (m, 4H), 4.75 (tt, J=12.3 Hz, 3.8 Hz, 1H), 4.39 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.75-3.58 (m, 3H), 3.09 (t, J=11.9 Hz, 2H), 2.14-1.89 (m, 7H), 1.79-1.40 (m, 14H), 1.27 (t, J=7.1 Hz, 3H), 1.26-1.11 (m, 1H), 1.02-0.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]=O)=[N:6][CH:7]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[N:13]=1
Reactant: O=CNc1ccc(Cl)cn1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccc(Cl)cn3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(5-chloro-pyridin-2-yl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14](F)=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:22])=[C:11]([C:23]#[N:24])[C:9]=2[N:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([N:36]3[CH2:37][CH2:38][C@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]3)=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:22])=[C:11]([C:23]#[N:24])[C:9]=2[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 150 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
Ethyl-4-cyan-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate 111) (200 mg, 0.62 mmol) was dissolved in dimethyl sulfoxide (12 ml), and at room temperature, triethylamine (112 μl, 0.80 mmol) was added. Next, the solution was heated at 150° C., and a solution of (3S)-3-(dimethylamino)pyrrolidine (94 μl, 0.74 mmol) dissolved in dimethyl sulfoxide (2 ml) was added all at a time, followed by further stirring for 1 hour. The mixture liquid was cooled to room temperature, then this was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, this was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=98:2) to obtain the entitled compound (17.5 mg, 7%) as a yellow powdery crystal.
Reaction SMILES: BrC[C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[N-]=[N+]=[N-].[Na+].CCOCC>CN(C=O)C>[S:11]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:8]=2[N:9]=[CH:10]1
Reactant: BrCc1cccc2scnc12
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc2scnc2c1
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
A solution of 4-Bromomethyl benzothiazole (20.4 g, 89.9 mmol) in 272 mL of dry DMF was treated with NaN3 (7.00 g, 108 mmol) at 20° C. and stirred at the same temperature for 5 min. The resulting mixture was quenched by addition of NaCl (5 g in 150 mL of H2O) at 0° C., diluted with Et2O (200 mL) and extracted with Et2O (200 mL×6). The organic phase was washed with NaCl (2 g in 100 mL of H2O) twice and brine (100 mL). The resulting solution was dried over MgSO4 and concentrated in vacuo. The residue was submitted to silica gel column chromatography with toluene:Et2O=50:3 to 50:5 as eluate to afford 4-azidemethyl benzothiazole as a colorless oil (15.5 g, 81.5 mmol, 91%). Rf=0.48 (toluene:Et2O=10:1); 1H NMR (400 MHz, CDCl3) δ 9.03 (1H, s), 7.95 (1H, d, J=7.7 Hz), 7.49 (2H, m), 5.01 (2H, s); 13C NMR (99.5 MHz, CDCl3) δ 154.2, 151.7, 134.3, 130.6, 126.0, 125.7, 122.1, 51.6.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[C:14]([CH3:15])=[C:13]([C:16]([F:19])([F:18])[F:17])[NH:12][C:11]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O.O>[CH2:1]([N:12]1[C:13]([C:16]([F:19])([F:17])[F:18])=[C:14]([CH3:15])[C:10]([Br:9])=[C:11]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c(C(F)(F)F)c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Br)c(C)c(C(F)(F)F)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 13 h
Yield: 89.2 %

Procedure:
Benzyl bromide (10.9 mL, 91.66 mmol) was added to the solution of crude ethyl 3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (25 g, 83.33 mmol) and K2CO3 (23.03 g, 166.66 mmol) in acetonitrile. The reaction mixture was stirred for 13 h at 80° C. Then the reaction mixture was cooled to RT and then diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×400 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was then purified by column chromatography (100-200 mesh Silica gel; 10% ethyl acetate/hexane; Rf-value 0.8) to afford title compound (29 g, 89.18% yield, pale yellow color oil).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])/[C:5](/[CH3:23])=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH2:18])=[CH:16][C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14]2)[CH:8]=1)[CH3:2]>CO.[Pd]>[NH2:18][C:17]1[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH:5]([CH3:23])[C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH:12]=[CH:11][CH:10]=2)[N:14]=[C:15]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:16]=1
Reactant: CCOC(=O)/C(C)=C/c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)Cc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of (E)-3-(3-(3-t-butyl-5-amino-1H-pyrazol-1-yl)phenyl)-2-methylacrylic acid ethyl ester (3.0 g, 9.14 mmol) and Pd/C (0.3 g) in methanol (50 mL) was stirred at RT under 40 psi of H2 for 2 h. The reaction mixture was filtered and the filtrate was concentrated to afford ethyl 3-[3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl]-2-methylpropanoate (2.5 g, 83% yield). MS (ESI) m/z: 330 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:17][CH2:18][P:19]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:11]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:29].[Na+]>CC(C)=O>[CH2:1]([O:8][CH2:9][C@H:10]([O:17][CH2:18][P:19]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:11][I:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OP(=O)(CO[C@H](COCc1ccccc1)COS(C)(=O)=O)OC(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)OP(=O)(CO[C@H](CI)COCc1ccccc1)OC(C)C
Yield: 88.7 %

Procedure:
A mixture of (R)-3-O-benzyl-2-O-[(diisopropylphosphono)methyl]-1-O-(methanesulfonyl)glycerol (10.0 g, 22.8 mmol) and sodium iodide (5.15 g, 34.4 mmol) in 70 mL of acetone was heated at reflux for 14 hours. The mixture was concentrated to about 30 mL volume, and insoluble material was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (methylene chloride:acetone=1:0 to 5:1) to give 9.51 g (89%) of the title compound as an oil.
Reaction SMILES: [NH:1](F)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])O.N[C@H](C(O)=O)C[C:14](O)=[O:15].C(OC(=O)C)(=O)C>C(O)=O>[CH:14]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:15]
Reactant: O=C(O)C[C@H](NF)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
F-Asp=O is prepared by reacting L-aspartic acid with formic acid in the presence of an effective amount of acetic anhydride under conditions sufficient to form N-formyl-L-aspartic anhydride. Then an effective amount of acetic anhydride and a C3 -C6 secondary alcohol are added to the reaction mixture to consume excess formic acid. The resulting N-formyl-L-aspartic anhydride reaction mixture is suitable for further reactions without modifications.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([OH:22])[CH2:19][C@H:18]1[C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[CH2:19][C@H:18]1[C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N1CC(=O)C[C@H]1C(=O)OC
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A methylene chloride solution (200 ml) of dimethyl sulfoxide (15.1 ml) was cooled to -70° C. and oxalyl chloride (19.3 ml) was added thereto below -50° C. The mixture was stirred for 15 minutes, at the end of which time a solution of (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (16.3 g) in methylene chloride was added below -50° C. The mixture was stirred at the same temperature for 1 hour and, then, triethylamine (50 ml) was added at a temperature below -50° C. The mixture was further stirred at that temperature for 30 minutes. Thereafter, the temperature was allowed to rise gradually to room temperature and the reaction mixture was diluted with water and allowed to stand. The aqueous layer was then separated and extracted with 2 portions of methylene chloride. The organic layers were combined, washed with 1N hydrochloric acid twice and, then, with saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution successively, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give (2S)-1-allyloxycarbonyl-2-methoxycarbonyl-4-oxopyrrolidine (15.5 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]2[N:7]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH:15]([CH3:21])[C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[OH-].[Na+].Cl>C(O)C>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:25]=[CH:24][C:6]2[N:7]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH:15]([CH3:21])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)C(C)Oc1ccc(-n2cnc3cc(C(F)(F)F)ccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ccc(-n2cnc3cc(C(F)(F)F)ccc32)cc1)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 3.7 g of 1, 0.39 g of sodium hydroxide and 50 ml of ethanol was refluxed for two hours, then it was cooled to room temperature, acidified with hydrochloric acid and extracted with ether. Concentration of the ether extract gave 2, as a white solid, m.p.: 181°-182° C.
Reaction SMILES: [Na].[O:2]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4]P(=O)(OC)OC.[C:16]([O:19][CH:20]1[CH2:27][CH2:26][CH:25]2[CH:21]1[CH2:22][CH2:23][CH:24]2[CH:28]=O)(=[O:18])[CH3:17].C(O)(=O)C>O1CCCC1.C(OCC)C>[C:16]([O:19][CH:20]1[CH2:27][CH2:26][CH:25]2[CH:21]1[CH2:22][CH2:23][CH:24]2/[CH:28]=[CH:4]/[C:3](=[O:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:18])[CH3:17]
Reactant: CC(=O)OC1CCC2C(C=O)CCC12
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCC(=O)/C=C/C1CCC2C(OC(C)=O)CCC12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of the sodium salt of dimethyl (2-oxoheptyl)phosphonate (0.105 g; prepared as described in Reference Example 55) in tetrahydrofuran (5.3 ml) at 0° C. was treated dropwise with a solution of 6-acetoxy-2-formylbicyclo[3,3,0]octane (70 mg; prepared as described in Reference Example 21 and predominantly in the 2β-configuration) in tetrahydrofuran (1.0 ml) with stirring. The resulting mixture was stirred for 18 hours at ambient temperature under an atmosphere of argon. The mixture was then treated dropwise with a solution of glacial acetic acid (200 mg) in diethyl ether (1 ml), and then the solution was concentrated in vacuo. The residue was treated with diethyl ether (20 ml) and water (20 ml) and the organic layer was separated. The aqueous layer was extracted with diethyl ether (3×20 ml). The combined extracts were washed with water and then with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo, to give an oil which was subjected to chromatography on a silica gel column, to give (E)-6-acetoxy-2-(3-oxooct-1-enyl)bicyclo[3,3,0]octane (65.7 mg), predominantly in the 2β-configuration.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[B:17](OC)([O:20]C)[O:18]C.C(O)(=O)C>O1CCCC1.C(OCC)C.O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([B:17]([OH:20])[OH:18])[CH:11]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1F
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A solution of lithium diisopropylamide (165 mL of a 2.0 M solution in tetrahydrofuran, 0.33 mol) in tetrahydrofuran (600 mL) at −70° C. is treated with 1-bromo-4-fluorobenzene (33.0 mL, 0.30 mol), stirred at −70° C. for 90 minutes and added to a solution of trimethyl borate (41.0 mL, 0.36 mol) in diethyl ether (300 mL) at −70° C. The resulting solution is stirred at −70° C. for 15 minutes, warmed to 15° C. over 90 minutes, treated with acetic acid (51.5 mL, 0.9 mol) and water (375 mL), and stirred at room temperature for 30 minutes. The organic layer is separated and the aqueous layer is extracted with ether. The organic extracts are combined with the organic layer and the resulting solution is washed sequentially with 10% hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an off-white solid (65 g, 99% yield).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:39]3[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 4-methylsulfonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (41%).