Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.[NH2:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23]>CS(C)=O>[CH3:19][C:4]1[N:3]=[C:2]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=1
Reactant: CC[C@H](N)CO
Reactant: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Solvent: CS(C)=O
Product: CC[C@@H](CO)Nc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (30 mg) and 2-(S)-amino-1-butanol (0.5 ml) in 0.5 ml of DMSO was heated at 130° C. for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a crude material. The crude residue was purified through silica gel column chromatography to give 24 mg of the title compound as white crystals. High MS for (C19H27N3O2) calc. 329.2103, found 329.21249; IR(KBr) 3400, 2940, 1580 cm-1; 1H NMR (CDCl3) δ 6.841 (s, 2H), 5.72 (brs, 1H), 4.45 (d, 1H), 3.82–3.96 (m, 1H), 3.72–3.9 (m, 1H), 3.5–3.6 (m, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 2.02 (s, 6H), 1.4–1.7 (m, 2H), 1.03 (t, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:16])=[C:5]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[O:6][CH2:7][C:8]([OH:10])=[O:9])#[N:2].[OH-:17].[Na+]>>[C:1]([C:3]1[C:4]([I:16])=[C:5]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:17])[NH2:2]
Reactant: N#Cc1c(I)cc(I)c(OCC(=O)O)c1I
Reactant: [OH-]
Agent: [Na+]
Product: NC(=O)c1c(I)cc(I)c(OCC(=O)O)c1I

Procedure:
27.3 g (49 mmol) of 3-cyano-2,4,6-triiodophenoxyacetic acid is stirred in 100 ml of 2 N sodium hydroxide solution for 3 hours at 50° C. The resultant alkaline solution is filtered over active carbon for purifying and decolorizing and then brought to pH 2 by adding 2 N hydrochloric acid. After several hours of stirring in an ice bath, the yield is 23.9 g (85% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp 211°-213° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[C:9](O)[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]=1)([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:20])=O>>[CH3:1][C:2]([C:5]1[N:10]=[C:9]([Cl:20])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1cnc(C(C)(C)C)nc1O
Product: CCOC(=O)Cc1cnc(C(C)(C)C)nc1Cl

Procedure:
Phosphorus oxychloride (30 cm3) was added portionwise to ethyl 2-[2-(1,1-dimethylethyl)-4-hydroxypyrimidin-5-yl]-acetate (15.0 g). An exothermic reaction occurred and the resultant mixture was poured onto ice. After neutralisation with sodium carbonate the mixture was extracted with ethyl acetate and the extracts washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yielded ethyl 2-[2-(1,1-dimethylethyl)-4-chloropyrimidin-5-yl]acetate (11.35 g, oil, solidified on standing, mp. 42°-44° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C(OCC)=O.Cl.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C)cc1F)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Cc2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Ethyl 3-(2-fluoro-4-methylphenyl)-3-oxo-2-phenylpropanoate (8.0 g, 26.6 mmol) was dissolved in THF (20 mL) and hydrogen chloride (37% wt., 32.0 mL, 400 mmol) was added. The reaction was brought to reflux overnight. After cooled to room temperature, the reaction was diluted with H2O (100 mL) and neutralized to pH 8 with NaOH (4.0 M aq.). The mixture was extracted with EtOAc (3×75 mL), dried over MgSO4, and purified by column chromatography to give the title compound as a clear oil (4.81 g). LCMS m/z=229.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 4.28 (s, 2H), 7.11-7.18 (m, 2H), 7.19-7.26 (m, 3H), 7.27-7.34 (m, 2H), 7.77 (t, J=8.21 Hz, 1H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:27]([N:29]1[CH2:88][CH2:87][CH2:86][C@H:30]1[C:31]([NH:33][C@H:34]([C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:67]([NH:69][C@H:70]([C:83]([NH2:85])=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][NH:75][C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])=[O:68])[CH2:60][CH2:61][CH2:62][NH:63][C:64](=[NH:66])[NH2:65])=[O:57])[CH2:49][CH2:50][CH2:51][NH:52][C:53](=[NH:55])[NH2:54])=[O:46])[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)=[O:32])=[O:28])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:27]([N:29]1[CH2:88][CH2:87][CH2:86][C@H:30]1[C:31]([NH:33][C@H:34]([C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:67]([NH:69][C@H:70]([C:83]([NH2:85])=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][NH:75][C:76]([O:78][C:79]([CH3:82])([CH3:80])[CH3:81])=[O:77])=[O:68])[CH2:60][CH2:61][CH2:62][NH:63][C:64](=[NH:65])[NH2:66])=[O:57])[CH2:49][CH2:50][CH2:51][NH:52][C:53](=[NH:54])[NH2:55])=[O:46])[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)=[O:32])=[O:28])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(N)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(N)=O

Procedure:
A methanol solution of 1.00 equivalent of 2TPB.Z-TrpTrp-Pro-Trp-Arg-Arg-Lys(Boc)-NH2 (Mw=1347.5; purity=64.0%) was passed several times through a column containing a methanol washed resin IRA 958 (or Amberjet Cl 1000; 6.00 equivalents). After checking the exchange by HPLC, the resin was filtered, washed three times. The combined organic phases were partially concentrated in vacuo and then diluted with water. Finally, 2% (weight) of Pd catalyst were added and the suspension hydrogenated for at least 3 hours at 40° C. The catalyst was filtered off, washed three times with a mixture of methanol/water. The combined filtrates were evaporated in vacuo, the residue suspended in DMA and further concentrated in order to eliminate the remaining water. After checking the water content, the solution was titrated by HCl (0.1 N), AgNO3 (0.1 N) or NMR and further used without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([CH2:24]Cl)[N:23]=2)[CH:20]=1.C(N(CC)CC)C>C(O)CO>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([CH2:24][N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[CH2:13][CH2:12]3)[N:23]=2)[CH:20]=1
Reactant: Clc1ccc(N2CCNCC2)nc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Clc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)nc1

Procedure:
Following the general procedure of Example 33, Step 2, and making non-critical variations, 1-(5-chloropyridin-2-yl)piperazine (0.424 g), 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.517 g), triethylamine (0.282 g), and ethylene glycol (2 mL) give, after crystallization from dichloromethane/ethyl ether, 0.621 g of the title compound; mp 137-138° C.; MS m/z 361, 363; IR 1593, 1480, 1245, 1324, 801, 1304 cm-1 ; 1H NMR (CDCl3) δ2.67, 3.55, 3.75, 6.57, 7.13, 7.41, 7.52, 7.53, 8.10, 8.14.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: C1COCCN1
Product: O=C(CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCOCC1
Yield: 94.3 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)propanoic acid (0.2 g, 0.66 mmol) and morpholine (0.058 g, 0.66 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)phenoxy)-1-morpholinopropan-1-one as a white solid (0.23 g, 93.4% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH2:11](OC1C=C(COC2C=C([C@@H](C)CC(O)=O)C=CC=2)C=CC=1C1C=C(OC)C=CC=1F)[CH2:12][CH2:13]C>>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[C:12]([CH3:13])[CH3:11])[C:4](=[O:9])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCOc1cc(COc2cccc([C@@H](C)CC(=O)O)c2)ccc1-c1cc(OC)ccc1F
Product: CC(C)=C1C(=O)OC(C)(C)OC1=O

Procedure:
The 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione (85.B) was prepared from 2,2-dimethyl-1,3-dioxane-4,6-dione 85.A (commercially available from Aldrich) via the same procedure described in Vogt, P. F.; et. al.; Synthetic Communications; 2001, (5); pp. 679-684.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCc1ccccc1
Yield: 102.4 %

Procedure:
Operating analogously to example 19 using 5-phenylpentanol (7.18 ml, 7 g, 42.6 mmoles) in methylene chloride (8 ml) and methyl-sulfonyl chloride (3.63 ml, 5.37 g, 46.9 mmoles) in methylene chloride (4 ml), and also using triethylamine (6.82 ml, 4.96 g, 49 mmoles) to adjust the pH after the addition of methyl-sulfonyl chloride, 10.57 g of the title product were obtained after half an hour of reaction (stoichiometric yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[ClH:40]>CO.O1CCOCC1>[ClH:40].[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:8]3[CH:9]=[C:10]([CH:11]4[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnn2c(C3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
To a suspension of tert-butyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate in MeOH (8 mL) was added 4M HCl in dioxane (4 mL). The mixture was stirred at rt for 17 h. The mixture was concentrated to dryness to afford 1.5 g (100%) of the desired product. ES-MS m/z 424.21 [M+H]+, HPLC RT (min) 2.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:13]2[CH2:16][N:15](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14]2)[C:10]([CH3:12])=[CH2:11])[CH:5]=[C:6]([F:8])[CH:7]=1>CO.Cl.CCOCC.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:13]2[CH2:14][NH:15][CH2:16]2)[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=C(C)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)[C@H](c1cc(F)cc(F)c1)C1CNC1
Reaction time: 8 h

Procedure:
A mixture of 250 mg (0.64 mmole) of 3-[(1R)-1-(3,5-difluorophenyl)-2-methylprop-2-en-1-yl]-1-(diphenylmethyl)azetidine and 50 mg of 10% Pd/C in 10 mL methanol and 2 mL of 1M HCl in ether was shaken under 40 psi H2. After 8 h, the solution was filtered and the filtrate was concentrated. The residue was triturated with hexane to remove diphenylmethane and the residue was collected to afford the title compound as a white solid; Mass Spectrum: m/e=226 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.[Br:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[C:8]([NH2:9])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncccc1N
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Br)ccc1N
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A solution of 2-methoxypyridin-3-amine (39.4 g) in N,N-dimethylformamide (200 mL) was cooled to −30° C., and a solution of N-bromosuccinimide (62.1 g) in N,N-dimethylformamide (100 mL) was added dropwise. After stirring for 30 minutes, the reaction solution was poured into water and extracted with chloroform. The organic layer was sequentially washed with a saturated sodium sulfite solution, water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give 6-bromo-2-methoxypyridin-3-amine as a yellow powder (51.9 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])=[CH:7][CH:6]=1.C(OC([N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][C:48](O)=[O:49])[CH2:42][CH2:41]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:48](=[O:49])[CH2:47][CH2:46][N:43]2[CH2:44][CH2:45][NH:40][CH2:41][CH2:42]2)=[CH:7][CH:6]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccc(CC(=O)OC)cc3)C(=O)CCN3CCNCC3)c2n1

Procedure:
The product of example 1, step (ix) (0.27 g) was dissolved in DCM (10 ml) and treated with 4-(2-carboxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.16 g) and HATU (0.23 g). The reaction was stirred at rt for 16 h, before 2 mls of TFA added. The mixture was purified by RPHPLC, to give the title compound. Yield 3 mg.
Reaction SMILES: [OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:50])[CH3:49])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35]C(OC(C)(C)C)=O)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1.C(N(C(C)C)CC)(C)C.[C:73]1([N:79]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:80](Cl)=[O:81])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>ClCCl>[OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:49])[CH3:50])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][C:80](=[O:81])[N:79]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)N(c2ccccc2)c2ccccc2)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 110 h
Yield: 97 %

Procedure:
150 mg (0.17 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3) and 150 μl (0.89 mmol) of diisopropylethylamine are dissolved in 6 ml of dichloromethane, mixed with 155 mg (0.37 mmol) of diphenylcarbamoyl chloride and stirred for 110 hours at room temperature. The residue that remains after removal of the solvent i.vac. is chromatographed. Gradient chromatography (Lichroprep Si60A pre-packed column, hexane→hexane/dichloromethane/methanol 30:60:10) yields 158 mg (97%) of N-(N -(N-(N-(diphenylcarbamoyl)-L-alanyl)-L-alanyl)-L-prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna -1,4-dien-21-yl] ester, and after recrystallization, 112 mg (68%) in crystalline form from dichloromethane/diisopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(C)=O)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.080 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: S(OCC)(O[CH2:5][CH3:6])(=O)=O.[CH3:10][C:11]1[CH2:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[C:12]=1/[CH:19]=[CH:20]/[CH:21]([OH:23])[CH3:22].[H-].[Na+]>>[CH3:5][CH2:6][O:23][CH:21](/[CH:20]=[CH:19]/[C:12]1[C:13]([CH3:17])([CH3:18])[CH2:14][CH2:15][CH2:16][C:11]=1[CH3:10])[CH3:22]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC1=C(/C=C/C(C)O)C(C)(C)CCC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(C)/C=C/C1=C(C)CCCC1(C)C

Procedure:
74.0 g (0.48 mol) of diethyl sulphate were added dropwise to a suspension of β-ionol alcoholate [obtained from 65.8 g (0.34 mol) of β-ionol and 18.4 g (ca 0.44 mol) of 55%-60% sodium hydride in 600 ml of benzene] in such a manner that the temperature did not exceed 50° C. Subsequently, the mixture was stirred at reflux for 3 hours, cooled and worked-up as described in Example 1. Crude distillation of the crude product (72.0 g) gave 50.2 g of crude product which were subsequently purified by distillation over a 20 cm Widmer column. There were obtained 47.0 g (66.1%) of pure and olfactorily good β-ionyl ethyl ether 2 of boiling point 120°-122° C./10 mmHg.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10](O)=[O:11])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.S(Cl)([Cl:21])=O>ClCCl.CN(C)C=O>[C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([Cl:21])=[O:11])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12
Reactant: O=C(O)COCCN1C(=O)c2ccccc2C1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COCCN1C(=O)c2ccccc2C1=O
Reaction time: 48 h

Procedure:
To a suspension of 6 g of 2-(phthalimido)ethoxyacetic acid in dichloromethane are added 2.05 ml of thionyl chloride and 3 drops of dimethylformamide, and the mixture is stirred for 2 days. The solvent is distilled off to give 2-(phthalimido)ethoxyacetyl chloride. A solution of 2-(phthalimido)ethoxyacetyl chloride in 10 ml of dichloromethane is added dropwise to a solution, maintained at -5° C., of 3.6 g of Meldrum's acid in 20 ml of dichloromethane and 4.3 ml of pyridine. Then, the mixture is stirred overnight at room temperature. To the resultant mixture is added 2 normal hydrochloric acid and the dichloromethane layer is extracted. The extract is washed with sodium chloride solution three times, dried over sodium sulfate and the solvent is distilled off. To the residue is added 50 ml of isopropyl alcohol and refluxed for 5 hours. The solvent is distilled off and the residue is purified by column chromatography on silica gel to give 3.7 g of isopropyl 4-[2-(phthalimido)ethoxy]-3-oxobutylate.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:12][NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:29]O>>[CH3:29][O:10][C:9](=[O:11])[C:8](=[N:12][NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(Cc1ccccc1)=NNc1nc(-c2ccccc2)cs1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(Cc1ccccc1)=NNc1nc(-c2ccccc2)cs1
Temperature: 25 °C

Procedure:
To a suspension of 4b (0.1 mmol, 34 mg) in MeOH (2 mL), was added dropwise thionylchloride (22 μL, 0.3 mmol) at −30° C. Then, the solution was allowed to warm at room temperature. The reaction mixture was heated to reflux and concentrated to afford the desired product. The crude is purified by silica gel chromatography (EtOAc/MeOH 10/1) to give the pure compound as a yellow solid (11 mg, 32%).
Reaction SMILES: Cl.[NH:2]([C:4](=[S:6])[NH2:5])[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]/[NH:2][C:4](=[S:6])[NH2:5])/[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1
Reactant: NNC(N)=S
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Agent: Cl
Product: C/C(=N\NC(N)=S)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 60 %

Procedure:
The title compound was prepared from hydrazine carbothioamide hydrochloride 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 60% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.88 (dd, 1H), 8.53 (s, 1H), 8.47 (d, 1H), 8.34 (m, 2H), 8.10 (d, 1H), 7.99 (d, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.50 (q, 1H), 4.59 (s, 2H), 2.34 (s, 3H). LCMS (method A): [MH]+=394, tR=4.91 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([CH2:13][CH3:14])[CH:3]=1.C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:25])[OH:21])=[CH:3][C:4]=1[CH2:13][CH3:14])[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCc1cc(Br)ccc1N(CC)CC
Agent: [Li]CCCC
Product: CCc1cc(B(O)O)ccc1N(CC)CC
Yield: 34.8 %

Procedure:
In a manner similar to that of Example 1c, by reacting 3 g of (4-bromo-2-ethylphenyl)diethylamine (11.7 mmol) with 5.2 mL of a 2.5 M solution of n-butyllithium and 3.2 mL (14 mmol) of triisopropyl borate, 0.9 g of 4-diethylamino-3-ethylphenylboronic acid (yield=35%) is obtained in the form of a white solid.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)N.Cl.[C:18]1([CH2:24][C:25](=O)[CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH3:26][C:25]1[NH:2][C:4]2[C:9]([C:24]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:8][C:7]([C:10]1[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=1)=[CH:6][CH:5]=2
Reactant: CC(=O)Cc1ccccc1
Reactant: NNc1ccc(C2=NNC(=O)CC2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1[nH]c2ccc(C3=NNC(=O)CC3)cc2c1-c1ccccc1

Procedure:
4.8 g. (20 mmole) 6-(4-hydrazinophenyl)-2,3,4,5-tetrahydropyridazin-3-one hydrochloride (according to Example 2 (a)) are suspended in 75 ml. 2N hydrochloric acid and 75 ml. ethanol, mixed with 2.8 g. (21 mmole) phenylacetone, stirred for 3 hours at 25° C., filtered off with the suction and the title compound obtained is recrystallised from methanol. Yield 4.85 g. (80% of theory); m.p. 297°-299° C.