Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:25][CH:24]=[N:23][CH:22]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])[CH:24]=[N:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: Clc1ccc(-c2cnc[nH]2)cc1
Product: CC1(C)Oc2ccncc2C(n2cncc2-c2ccc(Cl)cc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene (literature known compound) and 5-(4-chloro-phenyl)-1H-imidazole as starting materials, the title compound was prepare das a pale yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([OH:17])=O)=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH2:61][C@@H:62]([CH2:76][C:77]1[CH:82]=[C:81]([F:83])[CH:80]=[C:79]([F:84])[CH:78]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1.C(Cl)[Cl:86]>>[ClH:86].[ClH:86].[CH2:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([NH:61][C@@H:62]([CH2:76][C:77]3[CH:78]=[C:79]([F:84])[CH:80]=[C:81]([F:83])[CH:82]=3)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=3)=[O:17])=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCc2ccc(C(=O)O)cc2C1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: ClCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1CCc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc2C1
Product: Cl
Reaction time: 8 h

Procedure:
A solution of 2-butyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (190 mg, 0.81 mmol), HATU (465 mg, 1.2 mmol), HOBt (162 mg, 1.2 mmol), and diisopropylethylamine (250 μL, 1.6 mmol) is stirred in methylene chloride (2.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method in EXAMPLE SP-272 (332 mg, 0.81 mmol) and diisopropylethylamine (250 μL, 1.6 mmol) in methylene chloride (2.0 mL) is added, and the reaction mixture is stirred overnight. The reaction mixture is diluted with methylene chloride, washed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine. The organic layer is then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provides the title compound as the free base. The solid is dissolved in methanol (1 mL), and treated with hydrochloric acid (0.2 mL, 1.0 M diethyl ether, 0.2 mmol). The resulting precipitate was collected by filtration to provide the title compound. ESI MS m/z 550.3 [M+H]+.
Reaction SMILES: C(OC(N1CCC(C(O[C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[CH3:44][O:45][C:46](=[O:52])[CH:47]([OH:51])[CH2:48][CH2:49][Br:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1.CCOC(C)=O>[CH3:44][O:45][C:46](=[O:52])[CH:47]([O:51][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[CH2:48][CH2:49][Br:50]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)C(O)CCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C(CCBr)Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (2.8 g, 8.5 mmol), 4-bromo-2-hydroxybutyric acid methyl ester (2.5 g, 12.7 mmol) and triphenylphosphine (3.77 g, 14.3 mmol) in dioxane (30 mL) was added DIAD (2.8 ml, 14.3 mmol) and the reaction mixture was stirred at RT for 1 h. Additional amounts of DIAD (1.67 mL) and of triphenylphosphine (2.23 g) were added and stirring was continued for 1 h. The mixture was diluted with EtOAc and washed with aq. NaOH (1N). The aqueous phase was further extracted with EtOAc (×3). The combined organic layers were then washed with brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc followed by Si-PCC, gradient 0-10% MeOH in DCM) affording 4-Bromo-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]butyric acid methyl ester (2.5 g, 58%). 1H NMR (CDCl3, 400 MHz): δ 8.43 (1H, d, J=9.01 Hz), 7.57 (1H, s), 6.74 (1H, d, J=9.15 Hz), 6.55 (1H, d, J=2.56 Hz), 5.95-5.83 (1H, m), 4.92 (1H, dd, J=8.80, 3.97 Hz), 4.51-4.31 (4H, m), 3.79 (3H, s), 3.65-3.53 (2H, m), 2.58-2.36 (5H, m), 1.58-1.51 (6H, m)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:4].[NH2:19][CH:20]([CH3:25])[CH2:21][C:22]([NH2:24])=[O:23]>C(#N)C>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH:20]([CH3:25])[CH2:21][C:22](=[O:23])[NH2:24])=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(N)CC(N)=O
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Solvent: CC#N
Product: COC(=O)NC=Cc1ccc(OCC(O)CNC(C)CC(N)=O)cc1
Reaction time: 20 h

Procedure:
7.5 g (0.03 mol) of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxypropane are dissolved in 75 ml of acetonitrile and added dropwise to a boiling stirred solution of 3.34 g (0.029 mol) of β-aminobutyric acid amide in 75 ml of aceto-nitrile. The mixture is stirred for 20 hours under reflux, the solvent is removed by distillation under reduced pressure and the oil which remains is partitioned between 350 ml of 0.1 N hydrochloric acid and 300 ml of ethyl acetate. The hydrochloric acid extract is separated off, rendered alkaline with sodium carbonate and extracted four times with 100 ml of ethyl acetate at a time. The organic phases are dried over sodium sulphate and evaporated under reduced pressure. The resulting oil yields 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-(2-carbamoyl-1-methyl-ethylamino)-propane, of melting point 109°-111°C, from acetone acetate.
Reaction SMILES: [Cl-].[NH4+].O.C(O)(C)C.[C:8]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=1)(=[O:12])[C:9]([CH3:11])=[CH2:10]>C(OCC)(=O)C>[C:8]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)OCCOCCOCCOc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C=C(C)C(=O)OCCOCCOCCOc1cccc(N)c1
Temperature: 75 °C

Procedure:
A mixture of 25 g of reduced iron, 1 g of ammonium chloride, 50 ml of water, and 250 ml of isopropyl alcohol was raised to a temperature of 75° C. with stirring and after adding dropwise an ethyl acetate solution of the compound (1-B) to the aqueous solution (the mixture) over a period of one hour, the resultant mixture was further stirred for 2 hours. After removing insoluble matters from the reaction mixture by filtration, 200 ml of ethyl acetate and 500 ml of water were added to the reaction mixture and the ethyl acetate layer was extracted. The ethyl acetate layer was concentrated and the residue was purified by silica gel column chromatography using chloroform as a developing solvent to provide 15.3 g of 2-(2-(2-(3-aminophenoxy)ethoxy)ethoxy)ethyl methacrylate (1-C).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][CH:17]([CH3:25])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][CH:17]([CH3:25])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: COC(=O)C(C)(C)C(C)N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)C(C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 1.0 gm, 3.64 mmol) and methyl 3-amino-2,2-dimethylbutanoate hydrochloride (1.0 g, 5.50 mmol) in DMA (10 ml) was added DIPEA (3.14 ml, 18.2 mmol) at rt. The reaction mixture was stirred at 110° C. overnight. Upon completion, the reaction mixture was cooled to rt and DMA was removed under reduced pressure to give a dark oily compound. It was dissolved in ethyl acetate (50 ml) and washed with water (20 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over anhyd. sodium sulfate, filtered and concentrated under vacuum. The crude compound was purified by column chromatography using 40% ethyl acetate in hexanes as the eluting solvent to give the title compound (700 mg, 50%). 1NMR (400 MHz, DMSO-d6): δ 1.22-1.24 (m, 9H), 3.57-3.574 (s,3H), 4.47-4.51 (m, 1H), 7.046 (s, 1H), 7.89 (s, 1H), 8.24 (s, 1H), 10.92-10.94 (d, J=9.2 Hz).
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.Cl.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C([Si](C)(C)Cl)(C)(C)C>[CH3:20][C:19]([Si:23]([CH3:26])([CH3:25])[O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([OH:6])=[O:5])([CH3:22])[CH3:21]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 30 h
Yield: 103.5 %

Procedure:
50 g of methyl (R)-3-hydroxytetradecanoate, 35 g of t-butyldimethylchlorosilane, 6.1 g of 4-dimethylaminopyridine and 29.4 g of triethylamine were dissolved in 200 ml of methylene chloride and stirred at room temperature for 30 hours as well as under reflux for 16 hours. Thereupon, a further 2 g of t-butyldimethylchlorosilane were added. After a further 24 hours under reflux the precipitated triethylamine hydrochloride salt was filtered off, washed with ether and the filtrate was concentrated. The residue was dissolved in ether and washed in sequence with water, 0.5M citric acid, again with water and saturated sodium chloride solution, dried, concentrated and subsequently freed from volatile material at 5° C. in a high vacuum for 5 hours. There were obtained 71.8 g of (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanoic acid, IR (cm-1): 1745, 1254, 895, 776.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]1[CH:11]=[CH:10][C:9]([C:18]#[N:19])=[CH:8][C:7]=1[NH:6][C:5]2=[O:20].BrC1C=CC(S(O[C@@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:20][C@H:32]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][C:9]([C:18]#[N:19])=[CH:8]3)[CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1cc2c(cc1Br)c(=O)[nH]c1cc(C#N)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(C#N)ccc3c3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of 8-bromo-9-methoxy-6-oxo-5,6-dihydrophenanthridine-3-carbonitrile (C1), 8-bromo-9-methoxy-6-oxo-5,6-dihydrophenanthridine-3-carbonitrile (354 mg, 1.07 mmol) in NMP (10 mL) was added 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (549 mg, 1.18 mmol) and Cs2CO3 (876 mg, 2.69 mmol). The mixture was then heated to 60° C. for 18 h, and worked up with water and EtOAc. The organic layer was washed with brine, dried over MgSO4, and the solvent was removed in vacuo. The crude material was purified on silica (gradient elution, 10-50% EtOAc/hex) to yield the title compound. LRMS ((M-Boc)+H)+=456.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH:14]3[CH2:16][CH2:15]3)[N:7]=2)[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:28][C:29]([Cl:33])([Cl:32])[C:30]#[N:31].C(OCC)C>C(Cl)Cl>[Cl:28][C:29]([Cl:33])([Cl:32])[C:30](=[NH:31])[O:13][CH:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH:14]3[CH2:16][CH2:15]3)[N:7]=2)[CH:3]=[C:2]([Cl:1])[CH:10]=1)[CH3:12]
Reactant: CC(O)c1cc(Cl)cc2cn(C3CC3)nc12
Reactant: N#CC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(5-Chloro-2-cyclopropyl-2H-indazol-7-yl)ethanol (240 mg, 1.01 mmol) was dissolved in methylene chloride (5 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (31 μL, 0.2 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (1 mL, 10.1 mmol) dropwise over 10 min. The ice bath was removed and the reaction stirred at room temperature for 1 h and concentrated to give a dark brown solid. The crude product was treated with diethyl ether and stirred vigorously for 10 min. The resulting mixture was filtered through a pad of cotton and the ethereal concentrated to afford 365 mg (94%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.33 (s, 1H), 7.89 (s, 1H), 7.48 (m, 1H), 7.29 (m, 1H), 6.59 (q, J=6.6 Hz, 1H), 3.86-3.94 (m, 1H), 1.77 (d, J=6.6 Hz, 1H), 1.30-1.35 (m, 2H), 1.10-1.20 (m, 2H).
Reaction SMILES: [N:1]([CH:4]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:49][CH:48]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[NH2:1][CH:4]([C:47]1[CH:48]=[CH:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:51][CH:52]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N=[N+]=[N-])c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N)c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 62.2 %

Procedure:
To azido-bis[4-(12-docosoxydodecyloxy)phenyl]methane (72.0 mg, 58.7 μmol) were added toluene (2 ml), purified water (2 ml) and triphenylphosphine (29 mg, 110 μmol) and the mixture was vigorously stirred at 45° C. for 3 hr and 60° C. for 3.5 hr. The reaction mixture was cooled to room temperature, and 10% aqueous sodium hydrogen carbonate (2 ml) was added. After stirring for a while, toluene (8 ml) was added and the aqueous layer was discarded. The organic layer was washed with purified water (10 ml)×2. The organic layer was evaporated under reduced pressure, and the residue was crystallized from acetonitrile, and the obtained crystals were washed with purified water to give amino-bis[4-(12-docosoxydodecyloxy)phenyl]methane (44 mg, 36.5 μmol, 62%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9](S(CCC)(=O)=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.[NH:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([NH2:28])=[O:27].[CH:32]([N:35](CC)C(C)C)(C)C>O1CCCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][C:9]([C:32]#[N:35])=[N:10][C:2]=3[N:24]2[CH2:31][CH2:30][CH2:29][C@H:25]2[C:26]([NH2:28])=[O:27])=[CH:22][CH:21]=1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCS(=O)(=O)c1nc(Cl)c2ncn(-c3ccc(Cl)cc3)c2n1
Solvent: C1CCOC1
Product: N#Cc1nc(N2CCC[C@H]2C(N)=O)c2ncn(-c3ccc(Cl)cc3)c2n1
Temperature: 90 °C

Procedure:
A solution of the product from step (iii) (0.2 g), L-prolinamide (0.062 g) and N,N-diisopropylethylamine (0.19 ml) in tetrahydrofuran (10 ml) was stirred at room temperature for 24 h. The solvent was removed, the residue dissolved in N,N-dimethylformamide (10 ml) and sodium cyanide (0.05 g) added and heated at 90° C. for 10 h. The mixture was partitioned between ethyl acetate and water, the organics dried (MgSO4) and evaporated under reduced pressure. The residue was purified by RPHPLC. Yield 0.062 g
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([OH:26])=O)[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:31][O:32][C:33]1[CH:44]=[C:43]2[C:36]([NH:37][CH:38]=[C:39]2[CH2:40][CH2:41][NH2:42])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:24]([NH:42][CH2:41][CH2:40][C:39]1[C:43]2[C:36](=[CH:35][CH:34]=[C:33]([O:32][CH3:31])[CH:44]=2)[NH:37][CH:38]=1)=[O:26])[NH:8][C:9](=[O:23])[CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc2[nH]cc(CCNC(=O)[C@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c3ccccc3)c3ccccc3)c2c1
Yield: 36 %

Procedure:
Prepared analogously to Example 5d) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 5-methoxytryptamine and TBTU in a yield of 36% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.CCO.[O:17]1[CH2:22][CH2:21][CH2:20][O:19][CH:18]1[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:38][C:39]3[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][C:40]=3[F:46])[CH:30]=2)=[N:27][CH:28]=1>C1(C)C=CC=CC=1>[O:17]1[CH2:22][CH2:21][CH2:20][O:19][CH:18]1[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:38][C:39]3[CH:45]=[CH:44][C:42]([NH:43][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:41][C:40]=3[F:46])[CH:30]=2)=[N:27][CH:28]=1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a solution of isothiocyanate 2 (13.17 g, 67.4 mmol) in a mixture of toluene (100 ml)/EtOH (100 ml) in a 500 mL round-bottom flask was added aniline 31 (23.8 g, 56.2 mmol). The mixture was stirred for 1 h at room temperature and concentrated. The solid was triturated with toluene (100 mL) for 1 h, collected by filtration, washed with toluene (20 ml). The solid was dried under vacuum for 2 h to give crude 32 (35.10 g) which was used in the next step without any further purification. MS (m/z): 619.1 (M+1)
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+].[CH3:19]S(C)=O>>[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:8]2[CH:7]=[CH:19][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccncc1
Reactant: CS(C)=O
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Oc2ccc(N)cc2)cc1
Temperature: 100 °C
Yield: 94 %

Procedure:
A solution of 4-chloropyridine hydrochloride (Aldrich, 3.0 g, 20.0 mmol) in dimethyl sulfoxide (40 mL) was treated with 4-aminophenol (Aldrich, 2.1 g, 20.0 mmol) and sodium hydroxide pellets (2.0 g, 50.0 mmol) and the mixture was heated at 100° C. for 18 h. The mixture was cooled to room temperature, poured onto a mixture of ice-water (300 g) and extracted with Et2O (3×150 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give the 4-(4-aminophenoxy)aniline as a pale yellow solid (3.5 g, 94%). 1H NMR (DMSO-d6) δ 8.38 (dd, 2H, J=5.5, 1.5 Hz), 6.83-6.79 (m, 4H), 6.63-6.59 (m, 2H), 5.13 (br s, 2H); MS (ESI+) m/z 187.2 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[CH2:9]([NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]3[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)[CH:19]=2)[CH2:14]1)[CH2:10][CH3:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:9]([N:12]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]3[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)[CH:19]=2)[CH2:14]1)[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])[CH2:10][CH3:11]
Reactant: CCCNC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN(C(=O)OCC(C)C)C1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Under ice cooling, 2.46 g of isobutyl chloroformate was added to 4.07 g of 2-propylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 2.02 g of triethylamine dissolved in 40 ml of chloroform, and the mixture was stirred for 1 hour. The organic layer was washed with water and dried, and the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate to obtain 3.75 g of 2-(N-propyl-N-isobutoxycarbonylamino)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [BH4-].[Na+].[C:3](O)(=O)[CH2:4][CH3:5].[H][H].[CH2:10]([NH:13][CH:14]1[CH2:23][CH:22]=[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH2:20]2)[CH2:15]1)[CH2:11][CH3:12].[OH-].[Na+]>C1C=CC=CC=1>[CH2:10]([N:13]([CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH2:15]1)[CH2:3][CH2:4][CH3:5])[CH2:11][CH3:12]
Reactant: CCC(=O)O
Reactant: CCCNC1CC=C2CC(OC)=CC=C2C1
Reactant: [H][H]
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCN(CCC)C1CCc2cc(OC)ccc2C1

Procedure:
Sodium borohydride (26.85 g, 0.71 mol) was added in small portions to propionic acid (172.2 mL, 2.3 moles) in dry benzene (650 mL), maintaining the temperature below 20° C. When hydrogen evolution ceased, a solution of N-propyl-6-methoxy-1,2,3,5-tetrahydro-2-naphthylamine (30.93 g, 0.141 mol) in benzene (150 mL) was added and the resulting mixture was refluxed for 3 hr. The cooled mixture was shaken with excess 10% (w/v) sodium hydroxide solution. The organic layer was separated, dried over MgSO4 and evaporated to give a brown oil of N,N-dipropyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, NMR (CDCl3) δ 0.85 (t, 6H), 1.45 (m, 6H), 2.45 (t, 4H), 2.7 (m, 5H), 3.70 (s, 3H) and 6.7 (m, 3H).