Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Yield: 41.5 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (152 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (200 mg, 0.77 mmol) according to the general procedure K. Obtained as a yellow oil (107 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:13]([CH3:17])([C:15]#[CH:16])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][C:13]([CH3:17])([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[C:15]#[CH:16]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C#CC(C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(C)(C)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
1.62 g of 4-(trifluoromethyl)phenol, 1.53 g of 2-chloro-2-methyl-3-butyne and 10 g of potassium carbonate were heated at reflux in 50 ml of acetone. After 18, 42 and 66 hours further batches of 1 53 g of 2-chloro-2-methyl-3-butyne were added. 72 hours after the final addition the mixture was allowed to cool to room temperature and was partitioned between diethyl ether and water. The organic phase was washed with aqueous sodium hydroxide solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 5% (v/v) ethyl acetate/petroleum ether for the elution. 1.8 g of 4-(1,1-dimethyl-2-propynyloxy)trifluoromethylbenzene were obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[C:8]([N+:13]([O-])=O)=[CH:7][C:6]=1[CH3:16]>C1(C)C=CC=CC=1.[Pt]>[CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[C:8]([NH2:13])=[CH:7][C:6]=1[CH3:16]
Reactant: Cc1ccc(Oc2c(C)cc([N+](=O)[O-])c(C)c2Cl)c(C)c1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1ccc(Oc2c(C)cc(N)c(C)c2Cl)c(C)c1
Reaction time: 4.5 h

Procedure:
To a solution of 4-(2,4-dimethylphenoxy)-3,6-dimethyl-5-chloronitrobenzene (25 g, 81.8 mmol) in toluene (250 ml) was added 5% platinum on carbon (1.0 g). The resulting mixture was subjected to hydrogenation at 20 psi. After 4.5 hours, the reaction mixture was filtered through celite and concentrated to given an oil (24.5 g). It turned to a pinkish solid after high vacuum drying; mp 86°~88° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[C:18]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=5)[N:23](S(C5C=CC=CC=5)(=O)=O)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:15]=2)[C:10]([C:48]#[N:49])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[C:18]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH:27]=5)[NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:15]=2)[C:10]([C:48]#[N:49])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4ccc5c(C#N)cn(Cc6ccccc6)c5c4)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4ccc5c(C#N)cn(Cc6ccccc6)c5c4)ncnc3[nH]2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 22C (500 mg, 0.75 mmol) in tetrahydrofuran (5 mL) and methanol (3 mL) was added 1M sodium hydroxide (2.24 mL, 2.24 mmol) and the mixture was stirred at 50° C. overnight. The mixture was diluted with water, extracted with dichloromethane, dried over sodium sulfate, filtered, and concentrated to provide the title compound. LCMS: 531.2 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH3:33])/[C:28](O)=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:48][C@@H:49]1[C:80](=[O:81])[N:51]2[C:52]([C:64]([O:66][CH:67]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])=[C:53]([CH2:56][S:57][C:58]3[CH2:62][O:61][C:60](=[O:63])[CH:59]=3)[CH2:54][S:55][C@H:50]12>CN(C)C=O.N1C=CC=CC=1>[O:63]=[C:60]1[CH:59]=[C:58]([S:57][CH2:56][C:53]2[CH2:54][S:55][C@@H:50]3[C@H:49]([NH:48][C:28](=[O:29])/[C:27](/[C:25]4[N:26]=[C:22]([NH:21][C:2]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[S:23][CH:24]=4)=[N:31]\[O:32][CH3:33])[C:80](=[O:81])[N:51]3[C:52]=2[C:64]([O:66][CH:67]([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[O:65])[CH2:62][O:61]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A stirred solution of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid hydrochloride (528 mg) and N,N-diisopropylethylamine (0.383 ml) in dry dimethylformamide (4 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.085 ml) was added. The mixture was stirred at the same temperature for 30 mins, and then diphenylmethyl 7β-amino-3-(2,5-dihydro-2-oxofuran-4-ylthiomethyl)ceph-3-em-4-carboxylate (494 mg), dimethylformamide (2 ml) and pyridine (0.08 ml) were added. The mixture was then stirred at 0° for 90 mins. The mixture was partitioned between ethyl acetate and citric acid solution, and the ethyl acetate phase was washed twice with water, then with saturated sodium bicarbonate solution, then water and finally with brine. The solution was dried over magnesium sulphate and evaporated. The title compound (703 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 5:2 going to 3:7 hexane:ethyl acetate). υmax (CHCl3), 3400, 1785, 1745, and 1685cm-1. δH (CDCl3) 3.42 (1H, d, J 18.3Hz), 3.61 (1H, d, J 18.4Hz), 3.89 (1H, d, J 12.6Hz), 4.04 (1H, d, J 12.6Hz), 4.08 (3H, s), 4.71 (2H, s), 5.08 (1H, d, J 5.0Hz), 5.65 (1H, s), 5.97 (1H, dd, J 4.9 and 8.8Hz), 6.73 (1H, s), 6.84 (1H, d, J 8.7Hz), 6.96 (1H, s), 7.03 (1H, s), 7.2-7.45 (25H, m). [mass spectrum: +ve ion (3 NOBA, Na+) M Na+ 942].
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:41][CH2:42][CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][N:45]=1>CC(=O)CC>[NH:46]1[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44]([CH2:43][CH2:42][CH2:41][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[N:45]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: ClCCCc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCc4n[nH]c5ccccc45)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide (0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added 3-(3-chloropropyl)-1H-indazole (0.092 g, 0.47 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered, concentrated and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.06 g, 22%); 1H NMR (DMSO-d6): δ 1.52 (s, 9H), 1.64 (d, 2H, J=14 Hz), 1.95 (t, 2H, J=6.4 Hz), 2.59-2.85 (m, 8H), 2.96 (t, 2H, J=7.6 Hz), 4.60 (d, 4H, J=9.6 Hz), 6.76 (t, 1H, J=7.2 Hz), 6.85 (d, 2H, J=8 Hz), 7.06 (t, 1H, J=6.8 Hz), 7.21 (t, 2H, J=7.6 Hz), 7.31 (t, 1H, J=7.2 Hz), 7.44-7.53 (m, 3H), 7.74-7.84 (m, 3H), 12.63 (s, 1H); MS for C35H41N5O3 m/z 580.13 (M+H)+.
Reaction SMILES: BrC1C=CC(C(CCCCl)C(O)=O)=CC=1.[CH3:16][O:17][C:18](=[O:31])[CH:19]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][Cl:23].[C:32]([O:36][C:37](=[O:50])[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][C:46](=[O:49])[CH:47]=[CH2:48])([CH3:35])([CH3:34])[CH3:33]>>[CH3:16][O:17][C:18](=[O:31])[CH:19]([C:24]1[CH:29]=[CH:28][C:27](/[CH:48]=[CH:47]/[C:46](=[O:49])[NH:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[NH:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:50])=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][Cl:23]
Reactant: COC(=O)C(CCCCl)c1ccc(Br)cc1
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: O=C(O)C(CCCCl)c1ccc(Br)cc1
Product: COC(=O)C(CCCCl)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1

Procedure:
Key building block (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-5-chloro-pentanoic acid methyl ester (VIII) can be prepared according to Scheme 7. Starting with commercially available 4-(bromo-phenyl)-acetonitrile (XVI), deprotonation with strong base followed by alkylation using 1-bromo-3-chloropropane gives 2-(4-bromo-phenyl)-5-chloro-pentanenitrile (XXXII). Hydrolysis of XXXII under acidic conditions furnishes 2-(4-bromo-phenyl)-5-chloro-pentanoic acid (XXXIII). Nucleophilic acyl substitution converts XXXIII to 2-(4-bromo-phenyl)-5-chloro-pentanoic acid methyl ester (XXXIV), which undergoes Heck reaction with (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester to give key building block (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-5-chloro-pentanoic acid methyl ester (VIII).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:5](=[CH:6][C:7]3[CH2:11][CH2:10][O:9][C:8]=3[CH:12]=2)[CH2:4][CH2:3]1.Br[CH:16]([OH:18])[CH3:17].C(Cl)Cl.[OH-].[Na+]>O>[OH:18][CH2:16][CH2:17][NH:1][CH:2]1[CH2:14][C:13]2[C:5](=[CH:6][C:7]3[CH2:11][CH2:10][O:9][C:8]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: CC(O)Br
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCNC1CCc2cc3c(cc2C1)OCC3

Procedure:
7.7 g of 7-amino-2,3,5,6,7,8-hexahydronaphtho-[2,3-b]furan, 5 g of bromoethanol, 40 ml of methylene chloride, 12 ml of 40% strength sodium hydroxide in water and 1 g of Triton B are stirred vigorously at room temperature for 48 hours. After separation following settling, the methylene chloride is evaporated off in the cold and the residue is taken up with ethyl ether, which is exhaustively extracted with hydrochloric acid. The alkalinized acid phases yield an oil having the expected structure.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C@@H:5]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:4]1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1.C(Cl)Cl>[Si:10]([O:9][CH2:8][C@H:7]1[O:6][C@@H:5]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:4][C@@H:3]1[CH2:2][O:1][C:36](=[O:38])[CH3:37])([C:23]([CH3:26])([CH3:24])[CH3:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn([C@H]2C[C@H](CO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 20 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
Compound 106 (0.5 g, 1.01 mmol) was dissolved in pyridine (10 ml) and acetic anhydride (0.20 ml, 2.12 mmol) was added under an argon atmosphere at room temperature. After being stirred for 24 hours at 20° C., the pyridine was removed in vacuo to give an oil. The oil was diluted with CH2Cl2 (20 ml) and washed with water (20 ml) and saturated NaHCO3 (20 ml). The organic layer was dried over anhydrous MgSO4 and the solvent was evaporated in vacuo to give a white foam. The foam was then purified by flash chromatography in EtOAc/Hexane (6:4) to give 183 (0.44 g, 81%) as a white foam. Tlc (Rf 0.80; EtOAc); 1H NMR (CDCl3): δ8.93 (br, 1 H, NH), 7.69-7.66 (m, 4 H, Ph), 7.48 (d, 1 H, J=1.1 Hz, H-6), 7.46-7.37 (m, 6 H, Ph), 6.17 (dd, 1 H, J=5.7, 6.7 Hz, H-1'), 4.09-4.05 (m, 3 H, H-5' & CH2 -OAc), 3.93-3.91 (m, 1 H, H-5'), 3.79 (dd 1 H, J=11.5, 3.2 Hz, H-5"), 2.80-2.78 (m, 1 H, H-3'), 2.33-2.21 (m, 1 H, H-2'), 2.19-2.16 (m, 1 H, H-2"), 2.03 (s, 3 H, COCH3), 1.62 (s, 3 H, CH3), 1.10 (s, 9 H, C(CH3)3); 13C NMR (CDCl3): δ170.7 (C=O), 163.7 (C4), 150.3 (C2), 135.5-135.2 (d), 133.0, 132.5, 130.1 (C6), 127.9-127.8 (d), 110.9 (C5), 84.7 (C1'), 82.9 (C4'), 64.4 (CH2 -OAc), 64.2 (C5'), 37.3 (C3'), 35.8 (C2'), 26.9, 20.8, 19.4, 12.1; Anal. Calcd for C29H36N2O6Si (536.699): C, 64.90; H, 6.76; N, 5.22. Found: C, 64.57; H 6.79; N, 5.12.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19]1([NH:25][C:26]2([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClC(Cl)Cl>[C:19]1([NH:25][C:26]2([C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:28][N:29]([C:1]([O:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:10])[CH2:30][CH2:31]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1(Nc2ccccc2)CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(Nc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3.7 parts of (phenylmethyl) carbonochloridate and 2.1 parts of N,N-diethylethanamine in 75 parts of trichloromethane is added dropwise a solution of 4.6 parts of methyl 4-(phenylamino)-4-piperidinecarboxylate in 30 parts of trichloromethane (exothermic reaction: cooling with ice-water is necessary to keep the temperature below 25° C). Upon completion, stirring is continued for 5 hours at room temperature. The reaction mixture is washed twice with water, dried filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 4.2 parts of O4 -methyl O1 -(phenylmethyl) 4-(phenylamino)-1,4-piperidinedicarboxylate; mp. 105.8° C.
Reaction SMILES: [Cl-:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[Cl-:1].[Cl:1][CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:2])[CH2:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Product: O=C(CCCCCl)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution consisting of 18.5 parts of [(tetrahydro-2H-pyran-2-ylidene)methyl]triphenylphosphonium chloride in 100 parts by volume of concentrated hydrochloric acid is heated at the reflux temperature for about 36 hours, then is cooled to room temperature. The solvent is removed by distillation under reduced pressure to afford (6-chloro-2-oxohexyl)triphenylphosphonium chloride, identical with the product of Example 2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][C:23](O)=[O:24])[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C)C=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=4[O:20][CH3:21])[C:23](=[O:24])[CH2:22][N:7]3[C:6]=2[C:5]([CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(=O)N3c1c(C)cc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.2 %

Procedure:
To a solution of [4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetic acid (Reference Example 13; 770 mg, 1.71 mmol) in N,N-dimethylformamide (6 mL) was added HOBt (288 mg, 1.88 mmol), triethylamine (0.595 mL, 4.28 mmol) and WSC (426 mg, 2.22 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×2). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine (×2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by basic silica gel column chromatography eluting with a 10-25% ethyl acetate/n-hexane gradient mixture to give the crude title compound as an oil. The oil was crystallized from diisopropyl ether-n-hexane to give the title compound (519 mg, 1.20 mmol, 70%) as a colorless crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:11]([CH:12]=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[C:14]=2[CH2:18][CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:40]([O:42][CH3:43])=[O:41])#[C:35][C:36]([O:38][CH3:39])=[O:37].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]3[C:12]([C:13]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:24][CH:25]=4)=[C:14]([CH2:18][CH3:19])[C:15]3=[CH:16][CH:17]=1)=[C:34]([C:40]([O:42][CH3:43])=[O:41])[C:35]=2[C:36]([O:38][CH3:39])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(OCc3ccccc3)ccc12
Reactant: COC(=O)C#CC(=O)OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)OC)c(C(=O)OC)c3c(OCc4ccccc4)ccc1n32
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
6-Benzyloxy-2-(4-benzyloxyphenyl)-1-ethylindolizine (50.0 g, 115 mmol) and dimethyl acetylene dicarboxylate (18.5 ml, 150 mmol) was dissolved in 1100 ml of dry toluene at 0° C. The reaction was slowly heated to room temperature and stirred for 3 hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (26 g, 115 mmol) was added and stirring was continued for 1/2 hour. The mixture was filtered through celite and the solvent removed. The crude product was crystallised from methanol to afford 47.4 g (71%) of dimethyl 7-benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate as yellow crystals. M.p. 115-120° C. 1H-NMR (DMSO-d6, 300 MHz) δ: 1.32 (t, 3H); 3.01 (q, 2H); 3.56 (s, 3H); 3.72 (s, 3H); 5.21 (s, 2H); 5.50 (s, 2H); 7.17 (d, 2H; 7.32-7.53 (m, 10H); 7.60 (d, 2H); 7.67 (d, 1H); 8.22 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:46](O)(=[O:52])[CH:47]=[CH:48][CH:49]=[CH:50][CH3:51]>ClCCl>[C:46]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:52])[CH:47]=[CH:48][CH:49]=[CH:50][CH3:51]
Reactant: CC=CC=CC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC=CC=CC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 112 mg (1 mmole) of 2,4-hexadienoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 152 mg (Yield: 40%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [CH:1]([O-])([O-])OCC.[NH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][Si:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>C(O)C>[CH2:19]([O:18][Si:14]([O:21][CH2:22][CH3:23])([O:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][N:7]=[CH:1]1)[CH3:20]
Reactant: CCOC([O-])[O-]
Reactant: CCO[Si](CCCNCCN)(OCC)OCC
Solvent: CCO
Product: CCO[Si](CCCN1C=NCC1)(OCC)OCC

Procedure:
53.2 g of ethyl orthoformate (0.36 mol) is added at +20° C. to 80 g of N-(2-aminoethyl)-3-aminopropyltriethoxysilane (0.3 mol). The temperature of the mixture is brought up to reflux until formation of ethanol is no longer observed. The reaction mixture is then distilled under partial vacuum (2-5 mbar) and the desired product (69.1 g) is recovered (temperature: 130-135° C.)
Reaction SMILES: [NH2:1][C:2](=[O:28])[CH2:3][N:4]1[CH:9]=[C:8]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:21])[C:6]2[S:22][C:23]([CH2:26]O)=[C:24]([CH3:25])[C:5]1=2.N1C(C)=CC(C)=CC=1C.CS([Cl:42])(=O)=O.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2](=[O:28])[CH2:3][N:4]1[CH:9]=[C:8]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:21])[C:6]2[S:22][C:23]([CH2:26][Cl:42])=[C:24]([CH3:25])[C:5]1=2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12
Agent: CN(C)c1ccncc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.8 %

Procedure:
To a mixture of 4-(2-amino-2-oxoethyl)-N-(4-chlorobenzyl)-2-(hydroxymethyl)-3-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (58 mg, 0.13 mmol), collidine (44 μL, 0.33 mmol) and DMAP (2.4 mg) in DMF (2.25 mL) was added methanesulfonyl chloride (26 μL, 0.33 mmol). The mixture was stirred at room temperature for 48 hrs. Additional reagents (half original amounts) were added and the reaction was stirred another 4 hrs. The reaction was chilled in ice before the addition of water (8 mL). The ppt was collected by filtration, washed with water and dried in vacuo, giving the title compound as a white solid (58 mg).