Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].Cl[C:38]1[CH:39]=[CH:40][C:41]2[O:54][CH2:53][N:44]3[C:45]4[CH:46]=[CH:47][CH:48]=[C:49]([F:52])[C:50]=4[CH:51]=[C:43]3[C:42]=2[N:55]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19]([C:38]4[CH:39]=[CH:40][C:41]5[O:54][CH2:53][N:44]6[C:45]7[CH:46]=[CH:47][CH:48]=[C:49]([F:52])[C:50]=7[CH:51]=[C:43]6[C:42]=5[N:55]=4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Yield: 21.9 %

Procedure:
To a solution of 2-(4-cyanophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (115 mg, 0.22 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (75 mg, 0.27 mmol) K2CO3 (60 mg, 0.44 mmol), Pd2(dba)3 (30 mg) and X-Phos (30 mg) in dioxane/H2O (3 mL/0.6 mL) was stirred at 100° C. for 3 h. The reaction was filtered to remove the solid and then the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to get the product of 2-(4-cyanophenyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 21%). 1H-NMR (CDCl3, 400 MHz) δ 8.16 (d, J=8.4 Hz, 2H), 7.96 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.70 (s, 1H), 7.23˜7.19 (m, 3H), 7.13 (d, J=8.4 Hz, 2H), 6.87 (m, 1H), 6.14 (d, J=4.4 Hz, 1H), 6.00 (s, 2H), 3.35 (s, 3H), 3.05 (d, J=5.2 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 622.
Reaction SMILES: [Si](OC1C=CC2CC(C3C=CC(OC)=CC=3CCN)CCCC=2C=1)(C(C)(C)C)(C)C.Cl.N1(CCOC2C=CC(C(O)=O)=CC=2)CCCCC1.[Si]([O:57][C:58]1[CH:59]=[CH:60][C:61]2[CH2:67][CH:66]([C:68]3[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][C:69]=3[N:76]([CH2:93][CH3:94])[CH2:77][C:78]3[CH:83]=[CH:82][C:81]([O:84][CH2:85][CH2:86][N:87]4[CH2:92][CH2:91][CH2:90][CH2:89][CH2:88]4)=[CH:80][CH:79]=3)[CH2:65][CH2:64][CH2:63][C:62]=2[CH:95]=1)(C(C)(C)C)(C)C>>[CH2:93]([N:76]([CH2:77][C:78]1[CH:83]=[CH:82][C:81]([O:84][CH2:85][CH2:86][N:87]2[CH2:92][CH2:91][CH2:90][CH2:89][CH2:88]2)=[CH:80][CH:79]=1)[C:69]1[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:68]=1[CH:66]1[CH2:65][CH2:64][CH2:63][C:62]2[CH:95]=[C:58]([OH:57])[CH:59]=[CH:60][C:61]=2[CH2:67]1)[CH3:94]
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCCc2cc(O[Si](C)(C)C(C)(C)C)ccc2C1
Agent: COc1ccc(C2CCCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCN)c1
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCCc2cc(O)ccc2C1
Yield: 90.3 %

Procedure:
Synthesized from {2-[2-(tert-butyldimethylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenyl}ethylamine and 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, {2-[2-(tert-butyldimethylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenyl}ethyl[4-(2-piperidin-1-ylethoxy)benzyl]amine (481 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (357 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Temperature: 0 °C

Procedure:
To a solution of 5 (1 g) in chloroform (70 mL) was added N-bromosuccinimide (0.82 g) and azobis(isobutyronitrile) (0.010 g). A light source was directed onto the flask and the mixture was refluxed for 18 h. The solution was cooled to 0° C., a precipitate was filtered, and flitrate was concentrated in vacuo to obtain the crude product. Purification on silica gel with hexane/ethyl acetate 9/1 afforded the product as a solid. NMR (300 MHz, CDC3) δ 8.10 (1H, d, J=9 Hz), 7.95 (1H,d, J=9 Hz), 7.54 (1H,t, J=9 Hz), 5.14 (2H, s), 3.99 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH3:31])[N:24]([CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])[C:20]=2[C:19]2[N:18]=[CH:17][C:16](Br)=[CH:15][C:14]=2[N:13]=1.C(O)CC.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH3:31])[N:24]([CH2:25][C:26]([CH3:27])([OH:28])[CH3:29])[C:20]=2[C:19]2[N:18]=[CH:17][C:16]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:15][C:14]=2[N:13]=1
Reactant: CCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: OB(O)c1ccc(F)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CCc1nc2c(N)nc3cc(-c4ccc(F)nc4)cnc3c2n1CC(C)(C)O
Yield: 73.6 %

Procedure:
2-Fluoropyridine-5-boronic acid (0.468 g, 3.32 mmol) was added to 1-(4-amino-7-bromo-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol (1.1 g, 3.0 mmol) and 1-propanol (10 mL). The mixture was degassed and backfilled with nitrogen. Triphenylphosphine (23.8 mg, 0.0900 mmol), aqueous sodium carbonate (4.53 mL of 2 M), and water (2 mL) were added followed by palladium (II) acetate (6.8 mg, 0.030 mmol). The yellow suspension was heated at reflux for two hours. Water (20 mL) was added, and the 1-propanol was removed under reduced pressure. The remaining mixture was extracted with chloroform (2×100 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with acetonitrile and isolated by filtration to provide 0.84 g of 1-[4-amino-2-ethyl-7-(6-fluoropyridin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol as a white powder, mp 250-251° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][Zn+])=[CH:31][N:30]=1.Cl.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@:15]3([CH2:35][C:32]4[CH:31]=[N:30][C:29]([Cl:28])=[CH:34][CH:33]=4)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: Clc1ccc(C[Zn+])cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@]3(Cc4ccc(Cl)nc4)CCc4cccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (84 mg), (2-chloro-pyrid-5-yl)methylzinc chloride (0.5 moL/L in tetrahydrofuran, 1.2 mL) and tetrakis(triphenylphosphine)palladium (23 mg). Degassed tetrahydrofuran (1 mL) is added under Ar atmosphere, and the mixture is heated to 60° C. and shaken at this temperature overnight. The mixture is acidified with 4 N aqueous hydrochloric acid (1 mL) and then neutralized with saturated aqueous ammonia solution. The organic phase is separated, diluted with N,N-dimethylformamide (1 mL), and purified by HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=1.04 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[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>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([CH3:33])=[CH:25][CH:26]=2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccc(C)cc2)nc1-c1ccc(C)cc1
Yield: 73.8 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.30 mmol), 4-tolylboronic acid (123 mg; 0.901 mmol) and tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 86 mg (74%) of the title compound. ESI/APCI(+): 389 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3]1[C:8]2[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:12]([CH3:20])([CH3:13])[C:7]=2[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: COc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(OC)c2c1C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution, stirred at 0° C. under an inert atmosphere, of 165.5 g of 1,4-dimethoxybenzene and 218.7 g of 2,5-dichloro-2,5-dimethyl hexane, obtained in Example I(a), in 750 cm3 of anhydrous 1,2-dichloroethane, there are added, all at once, 31.9 g of powdered anhydrous aluminum chloride. The mixture is stirred for 1 hour at ambient temperature and then left to stand overnight. The next day after 4 hours stirring at this temperature, 600 cm3 of ice water are added. The organic phase is decanted and the aqueous phase is extracted three time with 400 cm3 of methylene chloride. The organic phases are combined, washed with water until neutral pH of the wash waters, then dried on sodium sulfate and concentrated. The resulting crude product is treated with animal charcoal in boiling ethanol, then recrystallized in this solvent. 195 g of 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene are obtained in the form of white needles having a melting point of 195° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH3:18])[C:10]([N:12]1[CH2:15][CH:14]([C:16]#[N:17])[CH2:13]1)=[O:11].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([C:30]3[N:31]=[C:32]4[C:38]([C:39](O)=[O:40])=[CH:37][N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:33]4=[N:34][CH:35]=3)=[N:25][N:26]2[CH3:29])=[C:22]([F:50])[CH:21]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C.O>[C:16]([CH:14]1[CH2:13][N:12]([C:10](=[O:11])[C@H:9]([NH:8][C:39]([C:38]2[C:32]3[C:33](=[N:34][CH:35]=[C:30]([C:24]4[C:23]5[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][C:22]=5[F:50])[N:26]([CH3:29])[N:25]=4)[N:31]=3)[N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:37]=2)=[O:40])[CH3:18])[CH2:15]1)#[N:17]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Reactant: C[C@@H](N)C(=O)N1CC(C#N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
1-((R)-2-Amino-propionyl)-azetidine-3-carbonitrile trifluoroacetate (crude from Step 7) was dissolved in acetonitrile (2 ml) to which was then added 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.168 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (81 mg, 0.252 mmol) and N,N-diisopropylethylamine (0.15 ml, 0.84 mmol). The reaction was stirred at room temperature for 18 h and then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to afford 84 mg (82%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. (M+Na)+=633.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.C([Li])CCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>CCOCC>[CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[N:3]1
Reactant: CC1(C)COC(c2cccs2)=N1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1C1=NC(C)(C)CO1
Temperature: -70 °C
Yield: 134.1 %

Procedure:
To a solution of 5.0 g of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)-oxazole in 20 ml of ether is added dropwise 18.75 ml of butyl lithium while maintaining the temperature at -70° C. with stirring under nitrogen. The reaction mixture is stirred at -70° C. for 15 minutes and 30 minutes at 0° C. The reaction mixture is cooled to -70° C. and 10.0 g of tributyl tin chloride added. The reaction mixture is quenched with water and extracted with ether. The organic layer is washed with water (2×100 ml), dried and evaporated in vacuo to give 17.4 g of residue which is purified by chromatography on silica gel by elution with 7:1 hexane:ethyl acetate to give 12.4 g of a yellowish oil. MS(M+H=472) the next step is example 19.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]2[CH2:11][CH2:10][CH:9]=[CH:8]2)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:1][C:2]1[C:6]([CH:7]2[CH2:11][CH2:10][CH:9]=[CH:8]2)=[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:4][N:3]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc(-c2ccccc2)c1C1C=CCC1
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C1C=CCC1
Yield: 79.7 %

Procedure:
3-Hydroxy-4-(2-cyclopentenyl)-5-phenylisoxazole (227 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (295 mg, 80%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30](=[O:38])[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH2:13]1)[CH:6]=[CH:5]2.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:29][C:30](=[O:38])[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][CH2:20][OH:21])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC[C@H](NCCO)C3)ccc12
Yield: 35.2 %

Procedure:
Prepared according to the method of example 50(b), using N-[6-chloro-2-[(3S)-3-[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]amino]-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 61(a)) (200 mg) and 4M hydrogen chloride in 1,4-dioxane (2 mL). Purification (SiO2, methanol:dichloromethane 5:95 as eluant) gave the title compound as a solid (56 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CN(C=O)C.[C:16]([O-:19])(=[S:18])[CH3:17].[K+]>O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][S:18][C:16](=[O:19])[CH3:17])=[CH:5][CH:6]=1
Reactant: Fc1ccc(CCCl)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SCCc1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 2.4 g of 1-(2-chloro-ethyl)-4-fluoro-benzene, 30 mL of DMF and 25 mL of potassium thioacetate was stirred under nitrogen for 24 h. The mixture was diluted with 200 mL of water and extracted with 3×50 mL of dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave an oil:
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:20][C:21]1([CH2:28][CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>CO>[NH2:5][CH:24]1[CH2:25][CH2:26][C:21]([CH2:28][CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)([OH:20])[CH2:22][CH2:23]1
Reactant: COc1ccc2ncnc(CCC3(O)CCC(=O)CC3)c2c1
Reactant: [NH4+]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncnc(CCC3(O)CCC(N)CC3)c2c1
Reaction time: 8 h

Procedure:
Ammonium acetate (14 g, 44 mmol) and sodium triacetoxyborohydride (1.2 g, 5 mmol) were added to a solution of 4-hydroxy-4-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-cyclohexanone (1.25 g, 4.2 mmol) in methanol (50 ml). The reaction mixture was stirred overnight and concentrated to dryness by rotary evaporation. The residue was diluted with water (100 ml) and dichloromethane (100 ml), the phases were separated and the aqueous phase was extracted twice using 50 ml of dichloromethane each time. The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[C:16]1([S:22]([N:25]2[C:29]3[CH:30]=[N:31][C:32]([C:35]#[N:36])=[C:33](O)[C:28]=3[C:27]3[CH:37]=[CH:38][CH:39]=[N:40][C:26]2=3)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[C:16]1([S:22]([N:25]2[C:29]3[CH:30]=[N:31][C:32]([C:35]#[N:36])=[C:33]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:28]=3[C:27]3[CH:37]=[CH:38][CH:39]=[N:40][C:26]2=3)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#Cc1ncc2c(c1O)c1cccnc1n2S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ncc2c(c1OS(=O)(=O)C(F)(F)F)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.91 g, 0.54 mL, 3.22 mmol) was added dropwise to a suspension of 9-benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1.03 g, 2.93 mmol) in pyridine (1.2 mL, 14.7 mmol) and dry DCM (20 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was treated with 1N hydrochloric acid (10 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×10 mL), the combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by chromatography (silica, 5 g column, Si-SPE, DCM) to afford the title compound as a white solid (855 mg, 60%). LCMS (Method B): RT=4.22 min, M+H+=483.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C(OCC)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([Cl:17])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Yield: 98.9 %

Procedure:
4.66 g of 2-(4-isobutylphenyl)propionic acid is agitated in 150 ml of diethyl ether with 5.04 g of phosphorus pentachloride for one hour at 20° C. The mixture is then concentrated under vacuum, thus obtaining 5.02 g of 2-(4-isobutylphenyl)propionyl chloride. This compound is reacted with trimethyl phosphite as described in Example 2, thus producing the dimethyl ester of 2-(4-isobutylphenyl)propionylphosphonic acid. The dimethyl ester is reacted with dimethyl phosphite under the conditions described in Example 2, thus obtaining the 2-(4-isobutylphenyl)-1-hydroxypropane-1,1-bis(phosphonic acid dimethyl ester).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 70 °C
Reaction time: 19 h

Procedure:
2.28 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 4 g of toluene and 1.02 g of acetic anhydride were fed, and the mixture was heated to 70° C. A toluene (0.56 g) solution of 61 mg of 4-dimethylaminopyridine, and then 0.59 g of pyridine were slowly added in dropwise, and the mixture was stirred for 19 hours to heat to 80° C. The mixture was cooled to room temperature and separated by adding water, and the solvent was distilled off under reduced pressure. 2.20 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.