Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]([CH:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)=[C:49]=[O:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:49]([NH:48][CH:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[O:50])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)NC2CCCC2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 68 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 68% yield. LCMS for C31H37ClN7O2 (M+H)+: m/z=574.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1.Cl[CH:16]([CH2:19]Cl)[C:17]#[N:18]>O>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:19]=[CH:16][C:17]([NH2:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: N#CC(Cl)CCl
Reactant: NNc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccn(-c2ccncc2)n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of potassium carbonate (4.46 g, 32 mmol) in water (20 ml) was added pyridine-4-yl-hydrazine×2HCl (1.47 g, 8 mmol) and the mixture was cooled to 10° C. 2,3-Dichloropropionitrile (1.0 g, 8 mmol) was added dropwise at that temperature. Subsequently, the mixture was stirred at 45° C. for 3 h and at ambient temperature overnight. The reaction mixture was extracted with dichloromethane, the organic phases were combined, washed with brine, dried and the solvent was evaporated. Silica gel chromatography using a heptane/ethyl acetate gradient yielded the amine as yellow solid (80 mg, 6%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4].[O:42]1[CH:47]=[CH:46][CH2:45][CH2:44][CH2:43]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(OCC)(=O)C>[O:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:30])=[CH2:4]
Reactant: C1=COCCC1
Reactant: C=C(CO)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(COC1CCCCO1)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1

Procedure:
A solution of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (106 mg) and dihydropyran (25 mg) in dry dichloromethane (1 ml) was treated with p-toluenesulfonic acid (1 mg) at room temperature for 50 minutes. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by thin-layer chromatography (SiO2) to yield (3S,4S)-4-(1-tetrahydropyranyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:12][CH2:11]OC1=O)=[NH:5].[BrH:14]>CC(O)=O>[BrH:14].[BrH:14].[CH3:2][NH:3][C:4]([CH2:6][CH2:7][NH:8][CH2:12][CH2:11][Br:14])=[NH:5]
Reactant: CNC(=N)CCN1CCOC1=O
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: CNC(=N)CCNCCBr
Reaction time: 8 h
Yield: 80 %

Procedure:
Compound 19 (10 g, 0.048 mol) was added in portions to a well stirred saturated solution of 100 mL of HBr in AcOH at room temperature. After addition, the mixture was stirred overnight, the precipitated solid was separated by filtration, washed with ether (200 mL) and dried in vacuo over KOH. Recrystallization from methanol-ether afforded 14.2 g (80%) of 20 as colorless crystals: mp 155° C. (dec); 1H NMR (CD3OD) δ 2.96 (s, 3, NCH3), 3.05 [t, 2, CH2CH2 (NH)], 3.49-3.64 (m, 4, CH2N--CH2) and 3.8 (t, 2, CH2CH2Br).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13]1(=[O:18])[CH2:17][CH2:16][CH:15]=[CH:14]1>CC#N>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:15]1[CH2:16][CH2:17][C:13](=[O:18])[CH2:14]1)([O-:3])=[O:2]
Reactant: O=C1C=CCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: CC#N
Product: O=C1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of 5-nitroindole (2.0 g, 12.80 mmol) in dry MeCN (10.0 mL) was added cyclopent-2-enone (2.0 mL, 23.87 mmol) and Bi(NO3)3 (0.06 g, 0.13 mmol) and the mixture stirred overnight at room temperature. The solvent then was evaporated and the crude was purified by column chromatography (50% Hexane: 50% EtOAc) to obtain the title compound (1.63 g, 52%) as a yellow solid. 1H-NMR (CDCl3) δ 2.05-2.18 (m, 1H), 2.37-2.48 (m, 3H), 2.54-2.66 (m, 1H), 2.80 (dd, 1H, J=7.2, 7.8 Hz), 3.72-3.82 (m, 1H), 7.15 (d, 1H, J=1.5 Hz), 7.42 (d, 1H, J=9.0 Hz), 8.15 (dd, 1H, J=2.4, 9.0 Hz), 8.39 (brs, 1H, NH), 8.62 (d, 1H, J=2.4 Hz); ESI-MS (m/z, %) 267 (MNa+, 100).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Br[CH2:20][CH:21]([F:23])[F:22]>CO>[F:22][CH:21]([F:23])[CH2:20][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: FC(F)CBr
Reactant: NS(=O)(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: CO
Product: NS(=O)(=O)c1ccccc1SCC(F)F
Reaction time: 16 h

Procedure:
A mixture of 145.2 g of the triethylamine salt of 2-mercaptophenylsulfonamide obtained in accordance with Example P6 and 79.7 g of 2-bromo-1,1-difluoroethane in 600 ml of methanol is stirred for 16 hours at a temperature of from +55° C. to +60° C. The reaction mixture is then concentrated by evaporation. The residue is stirred with ice-water and the resulting suspension is filtered to yield 120 g (95% of the theoretical yield) of 2-(2,2-difluoroethylthio)-phenyl-sulfonamide having a melting point of from +111° C. to +112° C.
Reaction SMILES: O1CCCCC1O[CH:8]([CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH3:9].CO.Cl.C(OCC)(=[O:26])C>O>[C:18]([O:17][CH:11]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:8][CH2:9][OH:26])(=[O:20])[CH3:19]
Reactant: CCOC(C)=O
Reactant: CCCOCC(CC(C)OC1CCCCO1)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCOCC(CCCO)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2-tetrahydropyranyloxy-4-acetoxy-5-propoxypentane (11.5 g., 0.42 mole), methanol (700 ml.), concentrated hydrochloric acid (3 ml.) and ethyl acetate (70 ml.) is stirred at room temperature for 1 hour. The reaction mixture is poured into cold H2O (1500 ml.) and the organic layer is extracted with ether. The combined extracts are washed with saturated sodium bicarbonate solution, then brine, and dried over anhydrous magnesium sulfate. The solvent is removed under vacuum and the residual oil is distilled to give the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[O:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:14].Cl[C:16](OC(Cl)(Cl)Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:13][C:5]1[C:6]2[O:7][C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[C:2]([N:1]=[C:16]=[O:17])=[C:3]([F:14])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)Oc2c(Cl)cc(F)c(N)c2O1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2c(Cl)cc(F)c(N=C=O)c2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.5 g (0.0069 mole) of 4-amino-7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxole in 50 mL of toluene was added slowly 0.41 mL (0.0035 mole) of trichloromethyl chloroformate. This mixture was stirred at ambient temperature for one hour and then was heated at reflux for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl isocyanate as a residue which was used in the next step without further purification.
Reaction SMILES: C([C:5]1[C:10]2[C:11]([N:14](C3C4C(C(C)(C)C)=C(C5C=C(Cl)C=CC=5OC5C=C(F)C(S(=O)(=O)N(C6N=CC=CN=6)CC6C=CC=CC=6)=CC=5F)C=CC=4ON=3)C(=O)[O-])=[N:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[C:64]1[CH:69]=[C:68]([Cl:70])[CH:67]=[CH:66][C:65]=1[O:71][C:72]1[CH:77]=[C:76]([F:78])[C:75]([S:79](=[O:95])(=[O:94])[N:80](CC2C=CC=CC=2)[C:81]2[N:86]=[CH:85][CH:84]=[CH:83][N:82]=2)=[CH:74][C:73]=1[F:96])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[NH2:14][C:11]1[C:10]2[CH:5]=[C:6]([C:64]3[CH:69]=[C:68]([Cl:70])[CH:67]=[CH:66][C:65]=3[O:71][C:72]3[C:73]([F:96])=[CH:74][C:75]([S:79]([NH:80][C:81]4[N:86]=[CH:85][CH:84]=[CH:83][N:82]=4)(=[O:94])=[O:95])=[C:76]([F:78])[CH:77]=3)[CH:7]=[CH:8][C:9]=2[O:13][N:12]=1
Reactant: CC(C)(C)c1c(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)N(Cc3ccccc3)c3ncccn3)cc2F)ccc2onc(N(C(=O)[O-])c3noc4ccc(-c5cc(Cl)ccc5Oc5cc(F)c(S(=O)(=O)N(Cc6ccccc6)c6ncccn6)cc5F)c(C(C)(C)C)c34)c12
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Nc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncccn4)cc3F)cc12
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of bis(tert-butyl (5-(2-(4-(N-benzyl-N-(pyrimidin-2-yl)sulfamoyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-yl))carbamate (2.03 g, 2.47 mmol) in trifluoroacetic acid (50 mL) were added triethylsilane (2.0 mL, 13 mmol) and trifluoromethanesulfonic acid (0.5 mL). This mixture was heated at reflux for 5 h and allowed to cool to ambient temperature. The mixture was concentrated in vacuo to afford a brown residue that was triturated in diethyl ether (40 mL) to afford 4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide as an off-white solid in 72% yield (0.95 g): 1H NMR (300 MHz, 5% D2O in DMSO-d6) δ 8.35 (d, J=4.9 Hz, 2H), 7.90 (s, 1H), 7.72 (dd, J=9.9, 6.6 Hz, 1H), 7.58-7.55 (m, 2H), 7.47 (dd, J=8.7, 2.3, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 6.96 (t, J=4.8 Hz, 1H), 6.90 (dd, J=10.3, 6.6 Hz, 1H) (NH not observed); MS (ES+) m/z 529.6 (M+1), 531.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][N:21]=3)[N:19]=2)=[C:11]([F:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[CH2:33][CH2:32]OC1=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:32][CH2:33][OH:29])[CH:17]=[C:18]([C:20]3[N:24]([CH:25]([CH3:26])[CH3:27])[N:23]=[CH:22][N:21]=3)[N:19]=2)=[C:11]([F:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(OCc3ccccc3)cc2F)n1
Reactant: O=C1OCCO1
Solvent: Cc1ccccc1
Product: CC(C)n1ncnc1-c1cn(CCO)c(-c2ccc(OCc3ccccc3)cc2F)n1
Temperature: 130 °C
Yield: 70.3 %

Procedure:
A suspension of 5-[2-(4-benzyloxy-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole (84 g, 0.22 mol) and [1,3]dioxolan-2-one (48 g, 0.55 mol) in toluene (100 mL) was heated at 130° C. for 7.5 h allowing some solvent to evaporate until reaction was initiated. The cooled reaction mixture was concentrated in vacuo and the residue treated with acetonitrile (50 mL), stirred, sonicated and cooled in an ice bath. The resultant solid was collected by filtration, washed with cold acetonitrile then diethyl ether and dried in vacuo at 60° C. to give 2-[2-(4-Benzyloxy-2-fluoro-phenyl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (65.2 g, 70%). 1H NMR (400 MHz, CDCl3): 8.04 (1H, s), 7.80 (1H, d, J=0.71 Hz), 7.43-7.41 (6H, m), 6.89 (1H, dd, J=8.59, 2.50 Hz), 6.79 (1H, dd, J=11.73, 2.47 Hz), 5.93-5.92 (1H, m), 5.11 (2H, s), 4.02 (2H, t, J=4.93 Hz), 3.89 (2H, t, J=4.96 Hz), 1.49 (6H, d, J=6.61 Hz). LCMS: RT=3.30 min, [M+H]+=422.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([NH:8][NH2:9])=O.[CH3:13][N:14]=[C:15]=[S:16].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:14]([CH3:13])[C:15]([SH:16])=[N:9][N:8]=2)[CH:10]=[CH:11][N:12]=1
Reactant: CN=C=S
Reactant: COc1cc(C(=O)NN)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(-c2nnc(S)n2C)ccn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
The title compound of example 23.1 (18.35 g, 109.8 mmol) and methyl isothiocyanate (8.83 g, 120 mmol) were stirred together at 60° C. for 30 minutes. Sodium hydroxide (4.83 g, 120 mmol) in water (32 mL) was added to the reaction mixture it was allowed to continue to stir at 60° C. for 12 hours. The reaction mixture was concentrated and diluted with water. It was acidified to pH 4-5 with 3 M HCl. A solid precipitated out which was filtered, washing with portions of water, then dried to afford the product as a beige solid (21.2 g, 87%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9](C(C)C=O)=[CH:10][C:5]=2[CH2:4][O:3]1.N1(C(=O)CC2C=CC(N3C=NN=N3)=CC=2)CCNCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CC(C=O)c1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolved 2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl) propanal (38 mg, 0.2 mmol) in dichloroethane (10 mL) and added 1-(piperazin-1-yl) 2-[4-(1H-tetrazol-1yl)phenyl]ethanone (50.1 mg, 0.162 mmol) followed by sodium triacetoxyborohydride (127 mg, 0.599 mmol) then stirred at room temperature for 16 h. The reaction mixture was washed with saturated NaHCO3 solution, brine, dried and concentrated. Purified by MPLC using a 40 g ISCO Redi-sep column and eluted with 0%-10% methanol/ethyl acetate to yield racemate 5-[1-4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)propan-2-yl]-2-benzofuran-1(3H)-one. The isomers were separated on Chiracel OD, 2 cm×25 cm, 10μ column using 45% ethanol: 55% heptane solvent system. The retention times for isomer A was at 42 minutes and for isomer B was at 47 minutes.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:18])([CH3:17])[O:6][CH:7]([CH2:15][CH3:16])[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]=[CH:11]1)([CH3:4])[CH3:3].[Cl:19][C:20](Cl)([Cl:24])[C:21](Cl)=[O:22].P(Cl)(Cl)(Cl)=O>CCOCC.[Zn].[Cu]>[Cl:19][C:20]1([Cl:24])[CH:12]2[CH:11]([CH:10]([CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([CH3:17])[CH3:18])[CH2:15][CH3:16])[CH2:14][CH2:13]2)[C:21]1=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCC(CCC1C=CCC1)O[Si](C)(C)C(C)(C)C
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(CCC1CCC2C1C(=O)C2(Cl)Cl)O[Si](C)(C)C(C)(C)C
Yield: 62.5 %

Procedure:
In the next step, the procedure of Example 6C is used, but there are substituted: 3-(3-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)cyclopentene ([3-(2-cyclopenten-1-yl)-1-ethylpropoxy](1,1-dimethylethyl)dimethylsilane) (15 g, 0.056 moles) dissolved in ether (100 ml), trichloroacetyl chloride (20.3 g, 0.11 moles) and phosphorous oxychloride (17.2 g, 0.11 moles) both dissolved in ether (50 ml), zinc/copper couple (10 g, 0.16 moles). The crude product is subjected to short path vacuum distillation leaving a clear yellow oil (13.5 g, 0.035 moles) of 7,7-dichloro-4-[3-[[1,1-dimethylethyl)dimethylsilyloxy]pentyl]bicyclo[3.2.0]heptan-6-one.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[CH2:14][CH:13]=[CH:12][CH2:11][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1C2=C(CC=CC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Mn+4]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Yield: 91.2 %

Procedure:
15 g (58.8 mmol) of 1-nitro-5,8-dihydroanthraquinone and 20.45 g of manganese dioxide are stirred at reflux for 2 hours in 150 ml of methylene chloride. After addition of 15 g of anhydrous sodium sulfate, the mixture is filtered hot and the residue is repeatedly extracted by boiling in methylene chloride. Concentration of the mother liquors by evaporation gives 13.58 g (91%) of crude 1-nitroanthraquinone (melting point: 225°-230° C.), which can be recrystallised from toluene (melting point: 228°-232° C.).
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](OCC)=[O:23].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][OH:23]
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCBr)c1ccccc1
Yield: 98.2 %

Procedure:
According to the procedure given for the synthesis of 206e, 205b (23.70 g, 79.21 mmol) was reduced with LiBH4 (3.45 g, 158.4 mmol) and methanol (5.24 g, 163.5 mmol) in anhydrous CH2Cl2 (150 mL) to give 206b (20.0 g, 98%) as an oil. 1H NMR (CDCl3): δ 7.34-7.14 (m, 5 H), 3.60 (m, 1 H), 3.48 (m, 1 H), 3.29 (t, 2 H, J=6.0), 1.96-1.44 (m, 5 H), 1.32 (s, 3 H). 13C NMR (CDCl3): δ 144.25, 128.59, 126.71, 126.41, 72.44, 43.15, 37.06, 34.64, 27.58, 21.61. HRMS (LSIMS, nba): Calcd for C12H16Br (MH+-H2O): 239.0435, found: 239.0444.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:18]([OH:19])=[N:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[OH:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].O>ClCCl>[Cl:1][C:2]1[C:3]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: Oc1nc2nccnc2c(O)c1-c1ncc(Cl)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)Oc1c(-c2ncc(Cl)cc2Cl)c(=O)[nH]c2nccnc12
Reaction time: 0.17 h

Procedure:
7-(3,5-Dichloro-pyrid-2-yl)-pyrido[2,3-b]pyrazine-6,8-diol (Example 1.2) (1.6 g) was dissolved in dichloromethane (50 ml) containing pyridine (0.445 g) and the reaction mixture stirred for 10 minutes. Isobutyryl chloride (0.556 g) was added dropwise over 5 minutes and the reaction mixture stirred for two hours. Water was added and the mixture extracted with ethyl acetate. The phases were separated and the organic fraction was washed with aqueous sodium carbonate (1M). The organic fraction was dried over sodium sulfate and concentrated to give a pale yellow solid which was recrystallized from ethyl acetate/hexane to give Compound No. A5 of Table A (1.02 g).
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[F:6])/[CH2:3]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>C1COCC1>[C:38]1(=[O:48])[N:42]([CH2:1]/[C:2](/[CH3:3])=[CH:5]/[F:6])[C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12
Reactant: C/C(=C\F)CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C/C(=C\F)CN1C(=O)c2ccccc2C1=O
Yield: 69 %

Procedure:
A solution of (E)-2-methyl-3-fluoroallyl alcohol (prepared in Step D) (17.11 g), triphenylphosphine (49.80 g), diethyl azodicarboxylate (33.06 g) and phthalimide (27.93 g) in THF (500 ml) is stirred at room temperature overnight. The THF is evaporated and the oily residue is extracted three times with hexane giving a powdery solid which is subsequently extracted three times with ether. The combined extracts are evaporated and the residue (63 g) is purified by chromatography on silica gel (950 g) using a mixture of 20% diethyl ether/light petroleum. The major fraction is a colorless crystalline mass (28.6 g, 69% yield) which is essentially pure product. A small portion can be crystallized from hexane to give (E)-1-phthalimido-2-methyl-3-fluoro-2-propene as colorless plates: m.p. 57°-58° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[C:9]3[C:13]([O:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=3[O:7][C:6]=2[CH:21]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:22]1([C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][C:10](=[O:12])[C:9]4[C:13]([O:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=4[O:7][C:6]=3[CH:21]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(OC)c2c(c1)Oc1cc(I)ccc1CC2=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(OC)c2c(c1)Oc1cc(-c3ccccc3)ccc1CC2=O
Temperature: 125 °C
Reaction time: 19 h
Yield: 31.2 %

Procedure:
To 3-iodo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one (52) (403 mg, 1.0 mmol), phenyl boronic acid (186 mg, 1.5 mmol), a 2M potassium carbonate aqueous solution (0.6 mL, 1.2 mmol) and tetrakis(triphenylphosphine) palladium (118 mg, 0.10 mmol) was added 5 mL of toluene and stirred at 125° C. for 19 hours. After completion of the reaction, the reaction solution was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1) to obtain 108 mg (yield 31%) of 3-phenyl-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one. Demethylation reaction was carried out according to the method of Example 1 to obtain the title compound.
Reaction SMILES: BrC1C(C)=CC2C(C)(C)CCC(C)(C)C=2C=1.C([N:20](C(C)C)[C:21]([C:23]1[C:28](C(=O)C)=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:22])(C)C>>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]([NH2:20])=[O:22]
Reactant: CC(=O)c1cccnc1C(=O)N(C(C)C)C(C)C
Agent: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Product: NC(=O)c1ccccn1
Yield: 80 %

Procedure:
2-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene 33 (620 mg, 2.2 mmol) and the acetylpyridineamide 36a (500 mg, 2 mmol) were converted by a similar method as described above to obtain the intermediate 34 in over 80% yield. To a solution of the pyridine amide 34 (432 mg, 1 mmol) in 5 mL of THF at −78° C. was added 1.5 M DIBAL toluene solution (0.7 mL, 1.05 mmol) and the resulting yellow clear solution was warmed up to −20° C. slowly in 60 min. and then was quenched with water. Removal of solvent and chromatography of the crude mixture afforded the pyridinealdehyde 35 in 83% yield as a white solid. 1H-NMR (CDCl3) δ1.25 (s, 2(CH3)), 1.29 (s, 2(CH3)), 1.70 (s, 2(CH2)), 1.96 (s, CH3), 5.47 (s, ═CH), 5.92 (s, ═CH), 7.10 (s, Ar—CH), 7.11 (s, Ar—CH), 7.70 (d, J=8.0 Hz, Pyr-CH), 7.88 (d, J=8.0 Hz, Pyr-CH), 8.72 (s, Pyr-CH), 10.06 (s, CHO).