Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]1([CH2:7][CH2:8][NH:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mass of 4.8 g (0.04 mol) of 2-phenylethylamine was added dropwise, at ambient temperature, to a mixture of 5.6 g (0.04 mol) of 2-fluoronitrobenzene and 11.06 g (0.08 mol) of anhydrous potassium carbonate in 30 ml of DMSO. The mixture was heated at 100° C. for 3 hours. The mixture was then cooled to ambient temperature and was added to 100 ml of water, which resulted in the precipitation of a light orange compound. The solid was recovered by filtration and dried using a desiccator at reduced pressure. A mass of 9.4 g of orange crystals was obtained with a yield of 98%. The melting point found was coherent with the theoretical value, i.e. 64-66° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:39])C(=O)C1.CN(C=O)C>C(OCC)(=O)C>[Br:39][C:29]1[S:28][C:27]([C:24]2[N:23]=[N:22][C:21]([N:13]([CH2:12][C:8]3([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:11][CH2:10][CH2:9]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:26][CH:25]=2)=[N:31][CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2nccs2)nn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(Br)s2)nn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a 100 mL round bottom flask was added t-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(thiazol-2-yl)pyridazin-3-yl)carbamate (2.0 g, 4.6 mmol), NBS (1.6 g, 9.1 mmol), and DMF (20 mL). The reaction was heated to 100° C. and stirred overnight. The reaction mixture was then was poured into ethyl acetate (200 mL), washed with water (100 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 1.8 g of t-butyl 6-(5-bromothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.
Reaction SMILES: BrCCBr.[Li+].[Br-].[C:7]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>C(O)(C)(C)C.C1COCC1.[Zn]>[C:36]([C:33]1[CH:34]=[CH:35][C:30](/[CH:29]=[CH:28]/[C:25]2[CH:26]=[CH:27][C:22](/[CH:21]=[CH:20]\[C:17]3[CH:16]=[CH:15][C:14]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:19][CH:18]=3)=[CH:23][CH:24]=2)=[CH:31][CH:32]=1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(/C=C/c3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)c1ccc(/C=C\c2ccc(/C=C/c3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1

Procedure:
272 g of zinc dust in 270 ml of tert.-butanol are boiled with 24.9 ml of 1,2-dibromoethane until evolution of gas ceases. 55.5 g of CuBr and 66.9 g of LiBr in 200 ml of THF are then carefully added at 50° C. When the exothermic reaction has died down, 272 g of E-4-(carbo-tert.-butoxy)-4'-(4-carbo-tert.-butoxy-styryl)-tolan in 1.7 l of THF and 560 ml of tert.-butanol are added and the reaction mixture is heated under reflux for 4 days. The resulting reaction mixture is then evaporated to dryness, taken up in CH2Cl2 and filtered and the filtrate is washed with dilute HCl, dried and concentrated by evaporation.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([F:23])(=[O:22])=[O:21])=[CH:11][CH:10]=1)C1C=CC=CC=1.B(F)(F)F.CCOCC>C(S)(S)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([F:23])(=[O:22])=[O:21])=[CH:13][CH:14]=1
Reactant: O=S(=O)(F)CCCCCc1ccc(OCc2ccccc2)cc1
Agent: CC(S)S
Agent: FB(F)F
Solvent: CCOCC
Product: O=S(=O)(F)CCCCCc1ccc(O)cc1
Yield: 68 %

Procedure:
5-(4-Hydroxy-phenyl)-pentanesulfonyl fluoride (14.4) was synthesized as described in 14.1 using, 13.4 (0.28 g, 0.83 mmol) in ethanedithiol (10 mL) and BF3.Et2O (0.47 g, 3.32 mmol). Purification by flash column chromatography on silica gel gave 14.4 (0.139 g, 68% yield) as a white solid (m p 32-35° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[CH2:15]([O:22]CC1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na]>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: COc1ccc2cc(Cl)nc(Cl)c2c1
Agent: [Na]
Solvent: Cc1ccccc1
Product: COc1ccc2cc(Cl)nc(OCc3ccccc3)c2c1
Temperature: 80 °C
Yield: 84.6 %

Procedure:
1,3-dichloro-7-methoxyisoquinoline (2.00 g, 8.8 mmol, 1.0 eq.) was dissolved in 30 mL anhydrous toluene and sodium benzyloxide (2.30 g, 17.6 mmol, 2.0 eq.) was added. The mixture was heated to 80° C. for 18 h. TLC indicated the reaction was complete. The mixture was concentrated to give the crude product, which was purified by chromatography on silica gel (eluted with petroleum ether) to give 2.20 g of xxxvii-a as a white solid (84.6%). LCMS m/z=300.1, 302.0 (M+1) (Method B) (retention time=2.23 min).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C:9]2([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[C:17]([O:20][CH3:21])([O:18][CH3:19])[C:13]3([C:14](=[O:16])[CH:15]=1)[CH:11]([C:12]3([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:10]2.Cl[Si:35]([CH3:38])([CH3:37])[CH3:36].C([N-]C(C)C)(C)C.[Li+]>CCOC(C)=O.CCCCCC>[CH3:6][O:7][C:8]1[C:9]2([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[C:17]([O:18][CH3:19])([O:20][CH3:21])[C:13]3([C:14](=[O:16])[C:15]=1[Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:11]([C:12]3([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:10]2
Reactant: C[Si](C)(C)Cl
Reactant: COC1=CC(=O)C23C(CC1(CC=C(C)C)C2(OC)OC)C3(C)CCC=C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=C([Si](C)(C)C)C(=O)C23C(CC1(CC=C(C)C)C2(OC)OC)C3(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
A THF (1 mL) solution of 26 (16 mg, 41 μmol, 1 equiv.) was cooled to −78° C. in a 10-mL recovery flask, and chlorotrimethylsilane (0.21 mL, 1.6 mmol, 40 equiv.) and a freshly prepared THF solution of lithium diisopropylamide (0.50 M, 1.6 mL, 0.82 mmol, 20 equiv.) were added sequentially. The resulting yellow solution was stirred at −78° C. for 45 min and then allowed to warm to room temperature over 3.5 h. The golden yellow solution was then quenched at −20° C. with saturated aqueous NaHCO3 and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow oil. Flash column chromatography (30 mL SiO2, 95:5 to 8:2 hexane:EtOAc) afforded 10.7 mg (23.2 μmol, 57% yield) of 28 as a colorless oil along with 3.9 mg (10 μmol, 24% recovery) of 26. TLC Rf 0.62 (8:2 hexane:EtOAc). 1H NMR (600 MHz; C6D6): δ 5.54 (t, J=7.1 Hz, 1H), 5.47 (t, J=7.2 Hz, 1H), 3.37 (s, 3H), 2.99 (s, 3H), 2.97 (s, 3H), 2.77-2.71 (m, 2H), 2.42 (dd, J=15.0, 7.0 Hz, 1H), 2.41-2.34 (m, 1H), 2.06 (dd, J=13.3, 6.6 Hz, 1H), 1.84 (td, J=12.3, 5.2 Hz, 1H), 1.74 (s, 3H), 1.73-1.68 (m, 4H), 1.68 (m, 4H), 1.62 (s, 3H), 1.54 (s, 3H), 0.84 (t, J=7.0 Hz, 1H), 0.48 (s, 9H). 13C NMR (126 MHz; C6D6): δ 198.9, 184.3, 131.1, 130.9, 129.2, 125.5, 123.1, 110.0, 74.1, 64.0, 53.5, 52.3, 51.0, 50.6, 41.8, 38.0, 31.7, 28.2, 26.6, 25.92, 25.87, 17.82, 17.80, 16.4, 0.9. HRMS-ESI (m/z): [M+H]+ calculated for C27H44O4Si, 461.3082. found, 461.3094.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:6][C:5]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 32.5-g (0.15 mol) sample of 5-chloro-2-thienylsulfonyl chloride was added in small portions to a stirred solution of 150 ml concentrated nitric acid and 150 ml concentrated sulfuric acid. After the addition was completed, the reaction mixture was stirred at about 25° C overnight. The reaction mixture was then diluted with ice water and filtered to give the 5-chloro-4-nitro-2-thienylsulfonyl chloride product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1.[CH3:15][O-:16].[Na+]>CO>[Cl:14][C:4]1[N:3]=[C:2]([O:16][CH3:15])[C:7]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[CH:6][CH:5]=1
Reactant: Cc1ncc(-c2ccc(Cl)nc2Cl)o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ccc1-c1cnc(C)o1

Procedure:
To a mixture of 2,6-dichloro-3-(2-methyl-1,3-oxazol-5-yl)pyridine (2.22 g) in methanol (25 mL) was added sodium methoxide (5M methanol solution, 1.9 mL) at room temperature, and the mixture was stirred under a nitrogen atmosphere over the weekend. The reaction mixture was concentrated and diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and separated by HPLC (column: Chiralpak AD, mobile phase: hexane/2-propanol) to give the title compound (867 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[NH:16])=[O:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26]([NH:28][C:29]1[CH:30]=[C:31]([C:35]#[C:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:45]=2)[C:42](O)=[O:43])[CH:32]=[CH:33][CH:34]=1)=[O:27]>>[Si:5]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[N:16][C:42](=[O:43])[C:41]2[CH:45]=[C:37]([C:36]#[C:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([NH:28][C:26]([C:22]4[O:23][CH:24]=[CH:25][C:21]=4[CH3:20])=[O:27])[CH:30]=3)[CH:38]=[N:39][CH:40]=2)=[CH:12][CH:13]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:19])[CH3:18]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)O)c2)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(S(C)(=N)=O)cc1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CO[Si](C)(C)C(C)(C)C)cc3)c2)c1
Yield: 71 %

Procedure:
In a manner similar to that described in Example 480 (step 6), tert-Butyl(dimethyl) {[4-(S-methylsulfonimidoyl)benzyl]oxy}silane (0.485 g, 1.62 mmol) and 5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinic acid (0.561 g, 1.62 mmol) were reacted to give the title compound (0.722 g, 71%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)=[O:7])C.CC(O)C>CO>[CH2:13]([C:10]1[NH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(CCc2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: O=C(O)c1ccc(CCc2ccccc2)[nH]1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 1.67 mmol) was added to a stirring, room temperature solution of 35 (0.0814 g, 0.333 mmol) in MeOH (0.83 mL, 0.4 M) under N2. 0.4 mL of iPrOH was added to solubilize 35. The reaction was heated to reflux until the reaction was judged complete by HPLC. The product was concentrated and then dissolved in 1.9 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 36 as a pale pink solid (Note: An undesired impurity has a retention time of 12.055 min by HPLC. Also, the 13C NMR of 36 at room temperature showed doublets for the peaks corresponding to the pyrrole carbons, benzyl carbon, and acid carbon. When the NMR probe was heated to 28° C., all doubled peaks collapsed into single peaks as reported below. 1H (CD3OD, 400 MHz): δ 10.97 (1H, broad s), 7.25-7.20 (2H, m), 7.18-7.11 (3H, m), 6.76 (1H, d, J=3.4 Hz), 5.90 (1H, d, J=3.4 Hz), 2.94-2.84 (4H, m) ppm. 13C (CD3OD, 100 MHz): δ 164.51, 142.68, 139.79, 129.40, 129.30, 126.98, 122.36, 117.47, 108.90, 37.00, 30.67 ppm. DEPT (CDCl3, 100 MHz): CH2 carbons: 37.00, 30.67; CH carbons: 129.40, 129.30, 126.98, 117.47, 108.90 ppm. HPLC: 11.239 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22][NH2:23]>>[O:1]=[C:2]1[CH2:3][CH2:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:8]([NH:23][CH2:22][C:21]2[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1CCC(C(=O)NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1

Procedure:
Prepared from 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2) and 3,5-bis(trifluoromethyl)benzylamine according to the method of Example 177. m/z (ES+) 444 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH2:15][CH:7]3[C:6]=2[N:24]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1
Reactant: CCOC(=O)C1Oc2ccc(Cl)nc2C2Cc3c(F)cccc3N12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Yield: 84.9 %

Procedure:
To a solution of ethyl 2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (10.22 g, 29.36 mmol) and DDQ (8.67 g, 38.17 mmol) in toluene (80 mL) was stirred at 80° C. for 2 hours. The mixture was then diluted with water (50 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EtOAc=20:1) to afford ethyl 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (8.64 g, yield: 85%), which was also prepared from 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol and methyl 2,2-dibromoacetate in the presence of base, such as DBU etc. 1H-NMR (CDCl3, 400 MHz) δ 7.33 (d, J=8.4 Hz, 1H), 7.30 (s, 1H), 7.09˜7.18 (m, 3H), 6.78˜6.83 (m, 1H), 6.52 (s, 1H), 3.96˜4.09 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). MS (M+H)+: 347.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN(C(C)C)C(C)C.[Br:37][CH2:38][CH:39]=[CH:40][C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:22][C:20]1[C:21]2[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[CH:14][N:15]([C@H:23]3[CH2:27][CH2:26][N:25]([C:41](=[O:42])[CH:40]=[CH:39][CH2:38][Br:37])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C(Cl)C=CCBr
Reactant: COc1cc(C#Cc2cn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)C=CCBr)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The crude product (100 mg) of (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 38 (Step 4)) was suspended in chloroform (3.0 ml). DIPEA (117 μl) was added to the suspension, and the mixture was cooled to 0° C. A solution of 4-bromobut-2-enoyl chloride (46 mg) obtained in Example 16 (Step 1) in chloroform (0.3 ml) was added thereto dropwise, and the resulting mixture was stirred at room temperature for 15 minutes. After halting the reaction using a saturated aqueous sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (140 mg). Physical properties: m/z[M+H]+509.9, 511.9
Reaction SMILES: [Cl:1][C:2]1[C:7]([SH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[O:26][C@H:21]2[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:1][C:2]1[C:7]([S:8][C@@H:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[C@@H:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1S
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](O)[C@@H](Sc1c(Cl)cccc1[N+](=O)[O-])c1ccc(OC)cc1

Procedure:
In a 25 ml flask equipped with thermometer and nitrogen admission, there are introduced 22 mg of zinc acetate dihydrate, 948 mg of 6-chloro-2-nitrothiophenol and 5 ml of toluene. To the suspension are added dropwise, within 5 mn, a solution of 1.093 g of methyl (-) (2R,3S) 3-(4-methoxyphenyl)-2,3-epoxy-propionate in 7.5 ml of toluene at 25° C. The temperature rises to 27°-28° C., whilst stirring is maintained for 1.5 hour. The mixture is evaporated in vacuo, and a yellow oil is obtained, which is used as it is in the subsequent example.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C@H:16]12[CH2:22][C@H:19]([NH:20][CH2:21]1)[CH2:18][N:17]2C(OC(C)(C)C)=O.[ClH:30].N1(C(=O)CC2C=NC(N3C=NN=N3)=CC=2)CCNCC1>>[ClH:30].[C@H:16]12[CH2:22][C@H:19]([NH:20][CH2:21]1)[CH2:18][N:17]2[C:13](=[O:15])[CH2:12][C:9]1[CH:10]=[N:11][C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Agent: Cl
Agent: O=C(Cc1ccc(-n2cnnn2)nc1)N1CCNCC1
Product: O=C(Cc1ccc(-n2cnnn2)nc1)N1C[C@@H]2C[C@H]1CN2

Procedure:
1-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethanone hydrochloride was prepared in two steps starting from [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid and commercially available tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in an analogous fashion as described for the synthesis of 1-(piperazin-1-yl)-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethanone hydrochloride. MS m/z 286 (M+1)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23](=[O:27])[CH2:24][O:25][NH2:26]>C(O)C>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23]([CH2:24][O:25][N:26]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11])=[O:27]
Reactant: NOCC(=O)Nc1cc(Cl)ccc1O
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Solvent: CCO
Product: O=CNc1nc(C(=NOCC(=O)Nc2cc(Cl)ccc2O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)glyoxylic acid (2.79 g.) and N-(2-hydroxy-5-chlorophenyl)-2-(aminooxy)acetamide (3.32 g.) in ethanol (30 ml.) was stirred for 5 hours at room temperature. The reaction mixture was evaporated to dryness and to the residue was added a mixture of ethyl acetate, water and 10% hydrochloric acid followed by stirring. The ethyl acetate layer was separated, washed with diluted hydrochloric acid and an aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated to a small volume and allowed to stand under ice-cooling. The resulting precipitates were collected by filtration, washed with ethyl acetate and then dried under reduced pressure to give a title compound (4.59 g.).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].C(O)(=O)C.C(O)(=O)C.[C:64]1([Bi](C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:67]=[CH:66][CH:65]=1.C(O)(=O)C.C(=O)(O)O.C1([Bi](C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:72]3[C:73]4[C:68](=[CH:67][CH:66]=[CH:65][CH:64]=4)[CH:69]=[CH:70][CH:71]=3)[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: c1ccc2c([Bi](c3cccc4ccccc34)c3cccc4ccccc34)cccc2c1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4cccc5ccccc45)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 40 °C

Procedure:
To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (250 mg, 0.32 mmol, 1 eq) and Cu(OAc)2 (15 mg, 0.08 mmol, 0.25 eq) in CH2Cl2 (5 ml) in a round bottom flask equipped with a magnetic stir-bar was added tri(1-naphthyl)bismuth diacetate [prepared immediately prior to use by addition of acetic acid (0.100 ml, 1.75 mmol, 5.46 eq) to a suspension of tri(1-naphthyl)bismuth carbonate (350 mg, 0.54 mmol, 1.69 eq) in CH2Cl2 (5 ml)]. The reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. for 5 hours then stirred at room temperature. After 16 hours the mixture was diluted with saturated aqueous NaHCO3 and extracted 2 times with CH2Cl2. The extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The products were separated and purified by preparative TLC on silica gel (eluted with 3:1 hexanes/acetone) to yield 49 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(naphth-1-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone and 39 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR analysis was consistent with the desired structure).