Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.O1[CH2:15][CH2:14][NH:13]C1=O.COCCOCCO>[OH-].[Na+]>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:15][CH2:14][NH2:13])=[CH:6][CH:5]=1
Reactant: O=C1NCCO1
Reactant: Nc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCO
Product: NCCNc1ccc(N)cc1
Temperature: 189 °C
Yield: 120.2 %

Procedure:
A mixture of p-diaminobenzene dihydrochloride (20.1 g, 0.11 mole), 2-oxazolidinone (17.4 g, 0.20 mole) and 100 ml of 2-(2-methoxyethoxy)ethanol was heated to 189° C. in an oil bath while being vigorously stirred mechanically. After two and one-half hours, all gas evolution had ceased and the dark purple reaction mixture was allowed to cool to room temperature. Most of the solvent was removed in vacuo while applying heat (95° C./10 mm Hg) to give a viscous, dark purple oil. After dissolution of the crude triamine dihydrochloride in 100 ml of a 10 percent aqueous sodium hydroxide solution, the free amine was extracted with three portions of chloroform. During the extraction, solid sodium chloride was added to help break up the emulsion which formed. The combined chloroform portions were dried over anhydrous potassium carbonate and filtered. After removal of the solvent in vacuo, approximately 20 g of the crude amine was obtained as a dark yellow oil. Kugelrohr distillation (bulb to bulb) at 160° C. to 190° C. (0.1 mm Hg) afforded a 29 percent yield of the triamine as a pale yellow oil. The product structure was confirmed by spectral studies.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([C:8](N)=[O:9])[CH2:5][CH2:6][CH3:7].C(Cl)(=O)C(Cl)=[O:13].C1C(/C=C/[N+]([O-])=O)=CC(O)=C(O)C=1>ClCCCl>[C:8]([OH:9])(=[O:13])[CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1]
Reactant: CCCC(CCC)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Agent: O=[N+]([O-])/C=C/c1ccc(O)c(O)c1
Solvent: ClCCCl
Product: CCCC(CCC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of valpromide (3.0 g, 20.95 mmol) in DCE (30 mL) at 0-5° C. was added oxalyl chloride (1.3 mL, 15.08 mmol) and refluxed overnight. The reaction mixture was cooled to RT, a solution of SL-1 (0.808 g, 5.24 mmol) in DCE (3 mL) was added and stirred overnight. After usual work-up and chromatographic purification, 1.97 g (43%) of I-AA-MPD22 were obtained as a white solid. 1H NMR (CDCl3, 300 MHz): δ 0.89 (t, 12H, J=7.18 Hz), 1.28-1.66 (m, 16H), 2.94-2.95 (m, 2H), 3.02 (t, 6H, J=6.51 Hz), 4.42 (t, 4H, J=6.47 Hz). MS: m/z 493.2 [M+H]+, 510.0 [M+NH4]+, 515.10 [M+Na]+.
Reaction SMILES: C(OC1C2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CCC=2C=C(OCC)C=1)C.C(OC1C=C(OC)C2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CCC=2C=1)C.COC1C2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CCC=2C=C(OC)C=1.[C:73]([CH2:75][CH2:76][O:77][C@H:78]1[CH2:83][CH2:82][C@H:81]2[C@H:84]3[C@H:93]([CH2:94][CH2:95][C@:79]12[CH3:80])[C:92]1[C:91]([O:96][CH2:97]C)=[CH:90][C:89]([O:99][CH2:100]C)=[CH:88][C:87]=1[CH2:86][CH2:85]3)#[N:74].C(CCO[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)C1C(OC)=CC(OCC)=CC=1CC3)#N>>[C:73]([CH2:75][CH2:76][O:77][C@H:78]1[CH2:83][CH2:82][C@H:81]2[C@H:84]3[C@H:93]([CH2:94][CH2:95][C@:79]12[CH3:80])[C:92]1[C:91]([O:96][CH3:97])=[CH:90][C:89]([O:99][CH3:100])=[CH:88][C:87]=1[CH2:86][CH2:85]3)#[N:74]
Reactant: CCOc1cc2c(c(OCC)c1)[C@H]1CC[C@]3(C)[C@@H](OCCC#N)CC[C@H]3[C@@H]1CC2
Agent: CCOc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Agent: CCOc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](OCCC#N)CC[C@H]3[C@@H]1CC2
Agent: CCOc1cc2c(c(OCC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](OCCC#N)CC[C@H]3[C@@H]1CC2

Procedure:
When in the above procedure 1,3-diethoxy-17β-hydroxyestra-1,3,5(10)-triene and 3-ethoxy-17β-hydroxy-1-methoxyestra-1,3,5(10)-triene are employed in place of 1,3-dimethoxy-17β-hydroxyestra-1,3,5(10)-triene, 17β-(2-cyanoethoxy)-1,3-diethoxyestra-1,3,5(10)-triene and 17β-(2-cyanoethoxy)-3-ethoxy-1-methoxyestra-1,3,5(10)-triene are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:17]([CH2:18][N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:20][CH3:21])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl)=[O:7])=[CH:4][C:3]=1[Br:28].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][C:45]([O-:47])=[O:46].[Na+].Cl>>[NH2:1][C:2]1[C:17]([CH2:18][N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:20][CH3:21])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:47][C:45](=[O:46])[CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[NH:37][C:31]2[C:30]([Cl:29])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:36])=[O:7])=[CH:4][C:3]=1[Br:28]
Reactant: CCN(Cc1cc(C(=O)NCCCCCCCl)cc(Br)c1N)C1CCCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)NCCCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from 6-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzamido]-n-hexyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8. Amorphous hydrochloride.
Reaction SMILES: C[Si](C)(C)C#[C:4][O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1.[F-].[CH2:20]([N+](CCCC)(CCCC)CCCC)[CH2:21]CC.Cl>O1CCCC1>[C:20]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([O:5][CH3:4])=[O:16])=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14])#[CH:21]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)C#COC(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: -22.5 °C
Yield: 65.8 %

Procedure:
15 g (0.054 mol) Methyl 4-(2-trimethylsilyl)ethynyl-3-nitrobenzoate (Compound III) and 225 ml tetrahydrofuran were added into a reaction flask, and started to stir, and cooled to −20 to −25° C., then 35 ml solution of 7.1 g (0.027 mol) tetrabutylammonium fluoride in tetrahydrofuran was added dropwise, and continued to react for 20 min after completing the dropwise addition. After the completion of the reaction monitored by TLC, the pH was adjusted to 4˜5 by adding 0.5 M hydrochloric acid. The mixture was concentrated under reduced pressure to evaporated most of the tetrahydrofuran, and then extracted with 300 ml ethyl acetate, the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, to obtain about 10.5 g crude product, which was separated by column chromatography to obtain methyl 4-ethynyl-3-nitrobenzoate (compound II-1), 7.3 g (0.036 mol), yield 65.8%.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[O:17][CH:18]=[C:19]([CH3:21])[N:20]=1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH3:21][C:19]1[N:20]=[C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)[O:17][CH:18]=1
Reactant: Cc1coc([C@@H]2CCCN2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1coc([C@@H]2CCCN2)n1

Procedure:
A solution of 100 mg (S)-2-(4-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester in 5 ml EtOH was stirred in the presence of 15 mg Pd/C (10%) under an atmosphere of hydrogen (1 bar) for 2 h. The reaction mixture was filtered over a plug of Celite and washed with EtOH. Evaporation of the solvent gave the product as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:24]1[S:28][C:27]([C:29]2[CH2:33][CH:32]([CH2:34][OH:35])[O:31][N:30]=2)=[CH:26][CH:25]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1[C:24]1[S:28][C:27]([C:29]2[CH2:33][CH:32]([CH2:34][OH:35])[O:31][N:30]=2)=[CH:26][CH:25]=1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO)C5)s4)c(F)c3)C(=O)O2)nn1
Temperature: 90 °C
Yield: 60.6 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (232 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (160 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([O:27][CH3:28])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>C(Cl)Cl>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([O:27][CH3:28])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-[N-((1R)-1-[(4-chlorophenyl)methyl]-2-(4-[2-(methoxycarbonylamino)-phenyl]-piperidyl}-2-oxoethyl)-carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (412 mg, 0.61 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound as a white foam (159 mg). MS (ESI, pos. ion) m/z: 575 (M+1); (ESI, neg. ion) m/z: 573 (M−1). Calc'd for C32H35ClN4O4: 574.23. Anal. Calcd for C32H35ClN4O4.18C2HF3O2: C, 57.45; H, 5.06; N, 7.75. Found: C, 57.66; H, 5.09; N, 7.62.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[N:71]1([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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:13]([O:12][C:11]([NH:10][C:4]1[C:3]([Cl:18])=[C:2]([N:74]2[CH2:73][CH2:72][N:71]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:76][CH2:75]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Temperature: 105 °C
Yield: 50.6 %

Procedure:
(I11A): Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1) (4.5 g, 13.57 mmol), Pd2 dba3 (0.746 g, 0.814 mmol), BINAP (0.676 g, 1.086 mmol) and Cs2CO3 (8.84 g, 27.1 mmol) were suspended in toluene (12.0 mL) at room temperature. Tert-butyl piperazine-1-carboxylate (3.29 g, 17.64 mmol) was added and the reaction was degassed and purged with Argon, degassed for 6 times. The reaction mixture was heated at 105° C. for overnight. On completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through celite and concentrated. The Crude material was purified by column chromatography (ISCO), using 0-10% ethyl acetate-hexane as eluent. Pure fractions were concentrated to obtain tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (3.0 g) as an off-white solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NCCOc1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A solution of 4-nitro 2-aminoethyl ether (610 mg, 2.93 mmol) from Example 213 in 10 mL of THF/water (9:1 ) was treated with triphenyl phosphine (768 mg, 3.0 mmol) at ambient temperature. After stirring for 3 h, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel (eluant 1:9 methanol/methylene chloride) to give 480 mg (95%) of the title compound: 1H NMR (200 MHz, CD3OD) δ8.18 (d, 2H, J=9Hz), 6.96 (d, 2H, J=9Hz), 4.13 (t, 2H, J=5.5Hz), 3.27 (t, 2H, J=5.5Hz).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.[C:38]([CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49]O)[CH2:43][CH2:42]1)#[N:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:38]([CH2:40][N:41]1[CH2:42][CH2:43][N:44]([CH2:47][CH2:48][CH2:49][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([O:23][C:22]4[C:14]([F:13])=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][C:17]([CH3:37])=[CH:16]5)=[CH:25][N:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:45][CH2:46]1)#[N:39]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: N#CCN1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
Diethyl azodicarboxylate (0.095 ml, 0.6 mmol) was added dropwise to a suspension of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.1 g, 0.3 mmol), prepared as described in Example 4), 3-(4-cyanomethylpiperazin-1-yl)propan-1-ol (0.085 g, 0.45 mmol) and triphenylphosphine (0.155 g, 0.6 mmol) in methylene chloride (2.5 ml). The mixture was stirred for 30 minutes at ambient temperature. Further 3-(4-cyanomethylpiperazin-1-yl)propan-1-ol (0.085 g, 0.45 mmol), triphenylphosphine (0.155 g, 0.6 mmol) and diethyl azodicarboxylate (0.095 ml, 0.6 mmol) were added. The mixture was stirred for 30 minutes and the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with ethylacetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (5/45/50 followed by 10/40/50 and 10/0/90). The fractions containing the expected product were combined and evaporated to give 7-(3-(4-cyanomethylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (0.035 g, 24%).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([OH:13])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[CH:1]1([CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCCC(O)CC1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCCC(=O)CC1CCCCC1
Yield: 73 %

Procedure:
A solution of 1-cyclohexyl-5-hexen-2-ol (2.75 g, 15 mmol; prepared according to X. Wang et al, in Org. Lett., 2003, 5, 2699, supplementary materials) in CH2Cl2 (5 ml) was added to a suspension of PCC (4.9 g, 22 mmol) and Celite® (7.35 g) in CH2Cl2 (70 ml) at 20°. After 4 hours at that temperature, 10 mol % of PCC was added and after a supplementary hour Et2O was added and the reaction filtrated over SiO2 before to be concentrated. Purification by chromatography on silica with cyclohexane/AcOEt 95:5 afforded the desired ketone in 73% yield.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)=[CH:18][CH:19]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: N#Cc1ccc(C(O)c2ccc(F)cc2)cc1
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(C#N)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 961 mg (4.23 mmol) of the compound from Example 173A in analogy to the synthesis of the compound from Example 278. 276 mg (17% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[N:24][C:25]([N+:28]([O-])=O)=[CH:26][CH:27]=3)[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[C:34]([O:33][C:31]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Yield: 97.4 %

Procedure:
A solution of 6′-(bis(tert-butoxycarbonyl)amino)-4-((6-nitropyridin-3-yl)oxy)-[2,3′-bipyridine](0.600 g, 1.178 mmol) in EtOAc (15 mL) and MeOH (5 mL) was treated with 10% Pd/C (50% wet, 0.125 g, 1.178 mmol) and hydrogenated (1 atm) for 16 h. The solids were removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to dryness to afford 6′-(bis(tert-butoxycarbonyl)amino)-4-((6-aminopyridin-3-yl)oxy)-[2,3′-bipyridine](0.55 g, 97%) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 9.06 (d, J=2.5 Hz, 1H), 8.53 (d, J=5.7 Hz, 1H), 8.46 (dd, J=8.5, 2.5 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.32 (dd, J=8.9, 3.0 Hz, 1H), 6.79 (dd, J=5.7, 2.4 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.03 (s, 2H), 1.40 (s, 18H); MS (ESI) m/z: 480.2 (M+H+).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].F[C:12]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:13]=1[CH:14]=[O:15].O.C(OCC)(=O)C>O1CCOCC1>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:12]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:13]=2[CH:14]=[O:15])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cc(F)cc(F)c1F
Reactant: CC(C)(C)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N1CCN(c2c(F)cc(F)cc2C=O)CC1
Temperature: 80 °C
Yield: 21 %

Procedure:
1-tert-Butylpiperazine (2.3 g, 16.2 mmol) and 2,3,5-trifluorobenzaldehyde (2.6 g, 16.2 mmol) were combined in dioxane and heated to 80° C. overnight. The yellow suspension was poured into H2O/ethyl acetate and the organic layer extracted with 1N HCl. The acidic extract was neutralized with 6N NaOH and extracted with ethyl acetate to yield the crude product as a yellow solid. This solid was purified by silica column to give 2-(4-tert-butylpiperazin-1-yl)-3,5-difluorobenzaldehyde as a yellow solid (0.96 g., 3.4 mmol, 21% yield) 1H-NMR (300 MHz, CDCl3) δ 10.52, (1H, s); 7.35 (1H, m); 7.07 (1H, m); 3.22 (4H, m); 2.71 (4H, m); 1.12 (9H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[NH:22]2.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[N:22]2[CH2:7][C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ccc(Cl)s1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(Cl)s2)c2cccc(Cl)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 4′-chloro-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 167-168° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.20-7.18 (m, 2H), 7.08 (dd, J=8.0, 0.7 Hz, 1H), 6.77 (d, J=3.4 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H), 5.94 (s, 2H), 5.09 (ABq, 2H), 4.92 (d, J=9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 156.2, 148.5, 143.3, 141.5, 137.5, 130.5, 129.8, 127.8, 127.7, 127.3, 126.5, 123.6, 116.5, 108.3, 102.4, 101.4, 92.9, 77.0, 57.8, 38.7; MS (ES+) m/z 446.2 (M+1), 448.2 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([N+:22]([O-])=O)=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1.C([O-])=O.[NH4+]>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1

Procedure:
4-(6-Chloro-2,3-dihydro-indol-1-yl)-7-nitro-quinazoline hydrochloride (2.16 g, 5.90 mmol) was slurried in 250 mL of ethanol containing 0.21 g of 10% paladium on carbon and treated with ammonium formate (1.68 g, 26.6 mmol). After 16 hours the mixture was filtered through celite and evaporated in vacuo to a residue. This was dissolved in chloroform, filtered and washed with sodium bicarbonate and brine then dried with magnesium sulfate, filtered and evaporated in vacuo to give crude product which was recrystallized from 50% aqueous ethanol. The solid was dissolved in methanol containing anhydrous hydrogen chloride and poured into ether to yield the title compound after filtration and drying in vacuo; 0.687 g (35%) M.P. 282°-283° C.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.Cl[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[C:13]([Si:10]([CH3:12])([CH3:11])[O:7][C:3]1[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
1,3-Benzenediol (5 g, 45 mmol) in dichloromethane (150 mL) was treated with chloro(t-butyl)dimethylsilane (7.5 g, 50 mmol) and triethylamine (5 g, 50 mmol). The resulting mixture was stirred at rt for 16 h then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 6N NaOH, then concentrated in vacuo. The residue was purified by column chromatography eluting with 20% ethyl acetate in hexane to afford the title compound (4.3 g, 42%). MS (ES+) m/e 225 [M+H]+.