Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(CC)CC)C.C[Si](Cl)(C)C.CNC1(NC)C=CN=CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][CH2:65][CH:64]([C:68]2[CH:77]=[C:76]([C:78]3[C:83]([O:84][CH2:85][C:86]4[CH:91]=[CH:90][C:89]([O:92][CH3:93])=[CH:88][CH:87]=4)=[CH:82][CH:81]=[CH:80][C:79]=3[O:94][CH2:95][CH:96]3[CH2:98][CH2:97]3)[N:75]=[C:74]3[C:69]=2[CH:70]=[C:71]([C:100](O)=[O:101])[C:72](=[O:99])[NH:73]3)[CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>C1(C)C=CC=CC=1>[CH:96]1([CH2:95][O:94][C:79]2[CH:80]=[CH:81][CH:82]=[C:83]([O:84][CH2:85][C:86]3[CH:91]=[CH:90][C:89]([O:92][CH3:93])=[CH:88][CH:87]=3)[C:78]=2[C:76]2[CH:77]=[C:68]([CH:64]3[CH2:65][CH2:66][CH2:67][N:62]([C:60]([O:59][C:55]([CH3:58])([CH3:56])[CH3:57])=[O:61])[CH2:63]3)[C:69]3[CH:70]=[C:71]([C:100]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:101])[C:72](=[O:99])[NH:73][C:74]=3[N:75]=2)[CH2:98][CH2:97]1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3cc(C(=O)O)c(=O)[nH]c3n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC1(NC)C=CN=CC1
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3cc(C(=O)NS(C)(=O)=O)c(=O)[nH]c3n2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a stirred solution of methanesulfonamide (0.026 g, 0.268 mmol) and triethylamine (0.030 mL, 0.229 mmol) in toluene (2 mL) was added trimethylsilyl chloride (0.020 mL, 0.152 mmol). The mixture was stirred at 90° C. for 1 hr, and then concentrated under reduced pressure. To the residue diluted with dichloromethane (2 mL) were added triethylamine (0.020 mL, 0.152 mmol), 4,4-dimethylaminopyridine (0.002 g, 0.015 mmol), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (0.040 g, 0.091 mmol) and 5-[1-(tert-butoxycarbonyl)-3-piperidinyl]-7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (0.050 g, 0.076 mmol) successively. The mixture was stirred at room temperature for 6 hrs. The mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (hexane/ethyl acetate=1/1×2) to give tert-butyl 3-(2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-6-{[(methylsulfonyl)-amino]carbonyl}-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate (0.024 g, yield; 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:10]1[N:11]=[C:12]2[C:18]([C:19]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])=[O:20])=[CH:17][N:16]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:13]2=[N:14][CH:15]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1.CN(C=O)C>[OH:24][CH2:23][C:22]([NH:21][C:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[N:11]=2)[N:16]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH:17]=1)=[O:20])([CH3:25])[CH3:26]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)nc1
Temperature: 140 °C
Yield: 31.5 %

Procedure:
To a mixture of 5-methylpyridin-2-amine (72.1 mg, 666 μmol), 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (197 mg, 444 μmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (13.8 mg, 22.2 μmol), palladium(II) acetate (24.9 mg, 111 μmol) and sodium tert-butoxide (107 mg, 1.11 mmol) was added DMF (2 mL) and toluene (1 mL) then heated in a microwave at 140° C. for 20 min. The dark mixture generated was poured into water and extracted with ethyl acetate (3×). The organic layers were combined, washed with brine (2×), dried over magnesium sulfate and purified by chromatography (silica, 65-100% ethyl acetate in hexanes) to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methylpyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (66 mg, 140 μmol, 32%) as a light yellow solid. MS (EI/CI) m/z: 471.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[C:14]([I:20])[C:13]([CH2:21]O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:41])[CH2:29][C:30]([OH:40])([C:33]1[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=1)[CH2:31][CH3:32])([CH3:26])([CH3:25])[CH3:24].C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:23]([O:27][C:28](=[O:41])[CH2:29][C:30]([C:33]1[CH:38]=[CH:37][N:36]([CH2:21][C:13]2[C:14]([I:20])=[N:15][C:16]3[C:11]([CH:12]=2)=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:18]([F:19])[CH:17]=3)[C:35](=[O:39])[CH:34]=1)([OH:40])[CH2:31][CH3:32])([CH3:24])([CH3:25])[CH3:26]
Reactant: OCc1cc2cc(OCc3ccccc3)c(F)cc2nc1I
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1cc[nH]c(=O)c1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCC(O)(CC(=O)OC(C)(C)C)c1ccn(Cc2cc3cc(OCc4ccccc4)c(F)cc3nc2I)c(=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
A mixture, under an argon atmosphere, of 6-benzyloxy-7-fluoro-2-iodo-3-quinolylmethanol (obtained according to 1.f, 2.05 g, 5 mmol), tert-butyl3-hydroxy-3-(2-oxo-1,2-dihydro-4-pyridinyl)pentanoate (obtained according to 1.h, 1.47 g, 5.5 mmol), and tributylphosphine (1.36 ml, 5.5 mmol) in anhydrous tetrahydrofuran (20 ml) is treated dropwise with diethyl azodicarboxylate (1.3 ml, 7.5 mmol). The reaction mixture is then agitated at ambient temperature for 6 hours, then concentrated under reduced pressure. The resulting oily residue is taken up in dichloromethane (100 ml) and washed with saturated aqueous ammonium chloride then with saturated aqueous sodium chloride. The organic phase is dried over sodium sulphate then concentrated to 5 ml and acetonitrile is added in order to obtain a white precipitate which is kept at 4° C. for 16 hours. The precipitate is collected by filtration then washed with isopropyl ether in order to produce 1.8 g (55%) of a white solid, m.p. 174° C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([O:23][C:24]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:37]#[CH:38])[CH:34]=2)[C:29]([CH3:45])([CH3:44])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:19]([O:23][C:24]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:37]#[C:38][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=3)[CH:34]=2)[C:29]([CH3:44])([CH3:45])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CC(CCCCC)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(C#Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
A mixture of 0.043 g of methyl 4-iodobenzoate, 0.093 mL of triethylamine, 4.6 mg of Pd(Ph3P)2Cl2 and 2.5 mg of copper (I) iodide in 2 ml of DMF was degassed and treated with a solution of 4,4-dimethyl-7-(1-pentyl-prop-2-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.049 g, 0.13 mmole) in 1 mL of DMF. The reaction mixture was stirred at room temperature for 18 hours, diluted with 10 mL of water and extracted with-three 10 mL portions of ethyl acetate. The combined organic extracts were washed with 10 mL of 1N HCl, 10 mL of water and 10 ml of brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to yield 0.035 g of 7-[3-(4-methoxycarbonyl-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:27][C:28]1[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>CN(C=O)C>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)#[N:35]
Reactant: N#Cc1ccccc1CBr
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2Cc2ccccc2C#N)c1
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of the product of Example 2, Step A, (75 mg, 0.25 mmol) in 3 mL of DMF was added 11 mg (0.27 mmol, 1.1 eq) of 60% NaH followed by α-bromo-o-tolunitrile (58 mg, 0.30 mmol, 1.2 eq). The mixture was stirred for 16 hours and then concentrated in vacuo. The resultant oil was flash chromatographed with 1:1 hexane/ethyl acetate to yield the titled compound (98 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.[O:36]1[CH2:39][C:38](=[O:40])[CH2:37]1>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:38]1([OH:40])[CH2:39][O:36][CH2:37]1
Reactant: O=C1COC1
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: OC1(c2cnccc2Cl)COC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
4-Chloropyridine (5 g, 44.0 mmol) hydrochloride salt was dried by azeotropic distillation with anhydrous toluene in a round bottomed flask. To this, anhydrous THF (100 mL) was added under nitrogen atmosphere and cooled to −78° C. After 15 min, LDA, 2M in THF/heptane/ethylbenzene (48.4 mL, 97 mmol) was added dropwise and the reaction stirred for 30 min. Oxetan-3-one (3.81 g, 52.8 mmol) was then added and reaction was stirred for 5 min at −78° C. and then cold bath was removed and reaction was allowed to warm to room temperature gradually (˜1 h). The reaction was quenched by addition of aqueous ammonium chloride and organics extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and concentrated under reduced pressure to afford 3-(4-chloropyridin-3-yl)oxetan-3-ol (3.8 g, 20.47 mmol, 46% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([CH2:19]Br)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][N:31]([CH2:19][CH:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[O:15]2)[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: BrCC1CCc2cc(OCc3ccccc3)ccc2O1
Solvent: Cc1ccccc1
Product: OC1(Cc2ccccc2)CCN(CC2CCc3cc(OCc4ccccc4)ccc3O2)CC1
Yield: 86.5 %

Procedure:
(RS)-6-Benzyloxy-2-bromomethyl-chroman (0.52 g, 1.56 mmol) and 4-(benzyl)-piperidin-4-ol (0.66 g, 3.43 mmol) in toluene (20 ml) was refluxed for 18 hr under argon. After removal of the solvent the crude mixture was chromatographed over SiO2 (Merck 230-400 mesh) CH2Cl2—MeOH—NH4OH (100:5:0.25) to afford the title compound (RS)-4-benzyl-1-(6-benzyloxy-chroman-2-ylmethyl)-piperidin-4-ol as a yellow oil (0.6 g, 1.35 mmol, 86%), MS: m/e=444.5 (M+H+).
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C@H:37]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15]([NH:36][C@H:37]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Boc-D-Trp(CHO)-OH (2.99 g), TsOH.H-Phe-OBzl (3.85 g, and HOBT (1.22 g) were dissolved in a mixed solvent of methylene chloride (60 ml) and DMF (15 ml). To this solution was added WSC (1.53 g) under ice cooling, and the reaction mixture was stirred for 3 hours at the same temperature. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed successively with diluted sodium hydrogencarbonate solution (twice), water, 0.5N hydrochloric acid, and saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether (1:1), which was filtered, washed with diisopropyl ether, and dried to give Boc-D-Trp(CHO)-Phe-OBzl (4.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#N)[C:3]=1[O:13][CH3:14].CC(C[AlH]CC(C)C)C.C([O:26]CC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:11][CH3:12])[CH:9]=[O:26])[C:3]=1[O:13][CH3:14]
Reactant: CCC(C#N)c1nccc(Cl)c1OC
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Product: CCC(C=O)c1nccc(Cl)c1OC
Temperature: -74 °C

Procedure:
2-(4-Chloro-3-methoxy-2-pyridinyl)-butyronitrile (2.78 g) is dissolved in diethyl ether (150 ml), the solution is cooled to −74° C. and DIBAL (29 ml 1.0M) is added over a 30 min period. The solution is allowed to stir at −74° C. for an hour then at 0° C. for another hour. The reaction is quenched by addition of 5% sulfuric acid (25 ml), keeping the temperature around 0° C. The phases are separated and the organic phase washed with a solution of sodium bicarbonate, dried and evaporated to afford the desired product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([O:12][C:13]2[C:18]([CH:19]=[CH:20][N+:21]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=2[O:24][CH3:25])[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].[ClH:28].C(OCC)(=O)C>O1CCCC1.C(OCC)(=O)C.O>[ClH:28].[CH:7]1([O:12][C:13]2[C:14]([O:24][CH3:25])=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:19][CH2:20][NH2:21])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cccc(C=C[N+](=O)[O-])c1OC1CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CCN)c1OC1CCCC1
Yield: 73 %

Procedure:
A slurry under nitrogen of lithium aluminium hydride (3.5 g, 92.28 mmoles) in dry tetrahydrofuran (35 ml) was dropwise added under stirring with a solution of 2-cyclopentyloxy-1-methoxy-3-(2-nitro-vinyl)-benzene (8.1 g, 30.76 mmoles), obtained as described in example 2, in dry tetrahydrofuran (100 ml). At the end of the addition the mixture was refluxed for 2 hours more, then cooled in ice and slowly added with water (3.5 ml), 15% NaOH (3.5 ml) and water again (10.5 ml). Off the cooling bath, the stirring was kept on for another hour, then the solid was filtered off, and the solution was concentrated to small volume, diluted with ethyl acetate, washed with water, anhydrified over Na2SO4 and dried to give an oil which was dissolved in ethyl acetate (100 ml) and acidified with HCl/ethyl acetate. The product crystallized, thus was filtered and dried under vacuum at 40° C. to give 6.07 g of the title product (yield: 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]2[CH2:14][O:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[CH2:14][OH:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(C2CO2)c1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)C(CO)c1cc(Br)cc(C(=O)OC)c1
Temperature: 50 °C

Procedure:
Into a 20 mL reaction vessel were combined methyl 3-bromo-5-(oxiran-2-yl)benzoate (0.10 g, 0.39 mmol), ethanol (10 mL), and diethylamine (120 μL, 1.2 mmol). The mixture was heated at 50° C. overnight, and then concentrated. The residue was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH2:6])=[O:5])[NH2:3].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25]([C:28](=O)[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1>>[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25](/[C:28](=[N:3]/[N:2]([CH3:1])[C:4]([NH2:6])=[O:5])/[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: CN(N)C(N)=O
Product: C/C(=N\N(C)C(N)=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 21 %

Procedure:
The title compound was prepared from 1-methylhydrazine carboxamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 21% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (dd, 1H), 8.31 (d, 1H), 8.05 (s, 2H), 7.97 (d, 1H), 7.77 (d, 1H), 7.72 (s, 1H), 7.47 (q, 1H), 6.54 (s, 2H), 4.58 (s, 2H), 3.19 (s, 3H), 2.37 (s, 3H). LCMS (method A): [MH]+=392, tR=4.76 min.
Reaction SMILES: C(O)=O.[C:4]([N:7]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:24])[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=1)(=[O:6])[CH3:5].C([O:41][C:42]1[CH:52]=[CH:51][C:45]([O:46][CH2:47][C@@H:48]2[CH2:50][O:49]2)=[CH:44][CH:43]=1)C1C=CC=CC=1>>[CH2:26]([NH:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([N:7]([C:4](=[O:6])[CH3:5])[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH2:50][C@H:48]([OH:49])[CH2:47][O:46][C:45]3[CH:51]=[CH:52][C:42]([OH:41])=[CH:43][CH:44]=3)=[CH:10][CH:9]=2)[CH2:22][CH2:21]1)=[O:24])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Reactant: CCCCCCCCNC(=O)N1CCC(N(C(C)=O)c2ccc(CCN)cc2)CC1
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(N(C(C)=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 28.3 %

Procedure:
4-[Acetyl-4-(2-aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.25 g, 0.59 mmol) was reacted with (2S)-2-{[4-(benzyloxy)phenoxy]methyl}oxirane (0.137 g, 0.53 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.1 g, 0.15 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][CH2:18]O)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:8]=2[CH:27]=1)([O-:3])=[O:2].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][CH2:18][N:32]4[C:28](=[O:38])[C:29]5=[CH:37][CH:36]=[CH:35][CH:34]=[C:30]5[C:31]4=[O:33])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:8]=2[CH:27]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCO)n1-2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, 8-nitro-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with diethyl azodicarboxylate to give 8-nitro-1-(2-phthalimidoethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.C1(P(=[N:59][CH:60]2[CH:64]([O:65][CH2:66][CH3:67])[O:63][C:62](=[O:68])[CH2:61]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:15])[NH:59][CH:60]1[CH2:61][C:62](=[O:68])[O:63][CH:64]1[O:65][CH2:66][CH3:67])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC1OC(=O)CC1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1OC(=O)CC1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
A solution of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.11 g, 0.5 mmol), di-isopropylethylamine (0.18 mL, 1.0 mmol), and tetramethylfluoroformamidinium hexafluorophosphate (TFFH) (0.13 g, 0.5 mmol) in dichloromethane (3 mL) was stirred at room temperature under nitrogen for 3 h. A solution of 4-[(triphenylphosphoranylidene)amino]-5-ethoxy-dihydrofuran -2-one (0.20 g, 0.5 mmol) in dichloromethane (3 mL) was added and the mixture was stirred for 24 h. The reaction was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided (R)-2-(2-ethoxy-5-oxo-tetrahydrofuran -3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.11 g, 65% yield) as a very viscous, pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:23]([OH:24])=[CH:22][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:7]=2[CH:6]=1)=[CH:15][C:14](Br)=[CH:13][C:12]=4[F:21])=[O:4].[CH2:25]([Sn](CCCC)(CCCC)CCCC)[CH:26]=[CH2:27].[F-].[Cs+].[OH-].[Li+]>C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd]>[CH2:27]([C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:21])[CH:13]=1)[NH:10][C:9]1[C:8]3[CH:22]=[C:23]([OH:24])[C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=3[CH2:19][CH2:18][C:17]2=1)[CH:26]=[CH2:25]
Reactant: COC(=O)c1cc2c(cc1O)-c1[nH]c3c(F)cc(Br)cc3c1CC2
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Product: C=CCc1cc(F)c2[nH]c3c(c2c1)CCc1cc(C(=O)O)c(O)cc1-3
Temperature: 100 °C

Procedure:
To a mixture 8-bromo-10-fluoro-2-hydroxy-5,11-dihydro-6H-benzo[a]carbazole-3-carboxylic acid methyl ester (50 mg, 0.13 mmol) (example 19, step 1), allyltributyl tin (56 mg, 0.15 mmol), cesium fluoride (38 mg, 0.25 mmol) dioxane (2 mL, anhydrous), is added palladium bis(tri-tert-butylphosphine) (4 mg, 5% mmol) in a microwave reaction tube. The tube is sealed and the mixture is purged with N2 for 3 min and heated at 100° C. for 3 h. Then the mixture is cooled to room temperature and filtered. The filtrate is concentrated and re-dissolved in EtOH/H2O (1 mL/0.1 mL). To the mixture is added lithium hydroxide (30 mg, 1.3 mmol). The mixture is heated at 120° C. for 6 min under microwave irradiation. Then the crude mixture is filtered and applied to mass-trigger preparative HPLC for purification. The title compound is obtained as a yellow solid; ESMS m/z 338.1 (M+H+).