Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:20]([C:24]1[NH:25][C:26]([CH:30]=[O:31])=[C:27]([Cl:29])[N:28]=1)[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:20]([C:24]1[N:25]([CH2:2][C:3]2[C:11]3[N:10]=[CH:9][N:8]([C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[C:14]#[N:15])[C:7]=3[CH:6]=[CH:5][CH:4]=2)[C:26]([CH:30]=[O:31])=[C:27]([Cl:29])[N:28]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: N#Cc1ccccc1-n1cnc2c(CBr)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1cccc2c1ncn2-c1ccccc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
2-[4-(Bromomethyl)-1H-benzimidazol-1-yl]-benzonitrile (0.65 g, 2.08 mmol, prepared as described in part C of Example 8) and 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.409 g, 2.19 mmol, prepared as described in part C of Example 5) were placed in 20.8 mL anhydrous dimethylformamide. Freshly ground cesium carbonate (1.02 g, 3.12 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The reaction was then partitioned between ethyl acetate and water and the organic phase was washed with brine, dried and concentrated. The crude oil was purified by flash chromatography (SiO2, 80:20 hexane:acetone) to yield the title A compound (0.68 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7]1.ClC1[N:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:23]=1[C:24]([NH:26][C:27]1([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:25]>>[Cl:44][C:41]1[CH:42]=[N:43][C:11]([N:8]2[CH2:9][CH2:10][C@H:6]([O:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)[CH2:7]2)=[C:23]([CH:40]=1)[C:24]([NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[CH2:29][CH2:28]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC[C@H](Oc4cccc(F)c4)C3)CC2)cc1
Yield: 111.9 %

Procedure:
The title compound (D204) (101 mg) was prepared according to the experimental procedure described in Description 160 starting from (S)-tert-butyl 3-(3-fluorophenoxy)pyrrolidine-1-carboxylate (D46) (100 mg, 0.355 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D) (D021/056/3) (65 mg, 0.177 mmol).
Reaction SMILES: [Cl:1][CH:2]([CH3:7])[C:3]([NH:5][OH:6])=[NH:4].C(N(CC)CC)C.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O>C(Cl)Cl>[Cl:1][CH:2]([C:3]1[N:4]=[C:15]([C:16]2[CH:17]=[C:18]([CH3:19])[CH:22]=[CH:23][CH:24]=2)[O:6][N:5]=1)[CH3:7]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC(Cl)C(=N)NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C(C)Cl)no2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
2-Chloro-N-hydroxy-propionamidine (218 mg, 1.78 mmol) and triethylamine (0.677 ml, 4.86 mmol) were added to 3-methyl-benzoyl chloride (250 mg, 1.62 mmol) in DCM (10.0 ml) at 0° C. and the resulting mixture was stirred for 20 min. The solution was concentrated and DMF (20 ml) was added to the residue and heated at 120° C. for 20 min. The product was purified by flash chromatography using 10-20% EA in hex. affording 0.250 g (59% yield over 2 steps) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:26](C=O)C.C(Cl)(=O)C(Cl)=O.N>C1COCC1>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH2:26])=[O:21])=[N:14][N:15]=3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution mixture of 3-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine-3-yl]benzoic acid (430 mg), a catalytic amount of DMF and THF (10 ml), oxalyl chloride (0.44 ml) was added with cooling in ice, and the mixture was stirred at room temperature for 2 hours and then ammonia gas was passed with cooling in ice for 15 minutes. The reaction solution was concentrated under reduced pressure, and the resultant residue was combined with chloroform:methanol (10:1), and then insoluble materials were filtered off. The filtrate was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from ethanol to obtain 3-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]benzamide (242 mg) as slightly tan crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(=O)C>Br.O>[CH2:21]([C:18]1[CH:19]=[N:20][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=1)[CH3:22]
Reactant: CCc1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCc1cnc(NC2CCNCC2)nc1
Yield: 92.2 %

Procedure:
A solution of 4-(5-ethyl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.53 g, 16.3 mmol) in 48% HBr in water (45 mL) and acetic acid (45 mL) was heated to 100° C. After 4 h the solvents were removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure to yield 3.1 g (92%) of the title compound which was directly used in the consecutive step. MS (ISP): 207.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:4]=1.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][NH:26][CH3:27].C([O-])(O)=O.[Na+]>CS(C)=O>[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:4]=1
Reactant: CNCCCN(C)C
Reactant: ClCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCCN(C)Cc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Temperature: 25 °C

Procedure:
(4-Chloromethyl-pyridin-2-yl)-(5-phenyl-thiazol-2-yl)-amine 8-8 (0.050 g, 0.166 mmol) was dissolved in 0.50 mL DMSO. N,N,N′-trimethyl-1,3-propanediamine was added and the reaction was stirred at RT. After 1 h a copious amount precipitate had formed. Saturated NaHCO3 (aq) was added and the resulting precipitate was filtered and washed with water to afford pure compound 8-9. 1H NMR (CDCl3) δ 9.16 (bs, 1H), 8.31 (d, 1H, J=5.1 Hz), 7.63 (s, 1H), 7.59 (d, 2H, J=7.4 Hz), 7.38 (t, 2H, J=7.6 Hz), 7.26 (overlapping with CHCl3), 6.91 (s, 1H), 6.88 (d, 1H, J=5.1 Hz), 3.49 (s, 2H), 2.43 (t, 2H, J=7.4 Hz), 2.30 (t, 2H, J=7.5 Hz), 2.34 (s, 3H), 2.21 (s, 6H), 1.68 (overlapping with water). MS [M+H]+382.3. mp 190-193.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([CH:22]4[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)[C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[ClH:36].O1CCOCC1>ClCCl>[ClH:20].[ClH:36].[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:33][CH2:34][CH3:35])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[F:21])[CH2:25]1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate (275 mg, 0.544 mmol) in dichloromethane (2.4 mL) was added 4.0 M hydrogen chloride in dioxane (1.1 mL, 4.4 mmol). The reaction solution was stirred at room temperature for 6 h. The solvent was removed under reduced pressure to give the desired product as a white solid (250 mg, 96%). LCMS calculated for C19H23ClFN6O (M+H)+: m/z=405.2; Found: 405.1.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccc(Cl)cc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-4-chlorobenzene and isolated as white solid (5.8 mg, 35%). MS(m/e): 407.4 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>CO.O>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([S:14][C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=2[N+:11]([O-:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1

Procedure:
The product from Example 351B (1 equiv) was dissolved in a methanol/water 3/1 mixture followed by the addition of lithium hydroxide (5 equiv). The resultant solution was stirred at room temperature for 24 hours followed by the addition of 1N aqueous hydrochloric acid until the solution was a pH of 2. The mixture was then extracted with ethyl acetate, the organic extracts dried and concentrated under vacuum to provide the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[N+:19]([C:22]1[CH:23]=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]2=[CH:31][CH:32]=1)([O-:21])=[O:20]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[C:26]2=[O:27])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 86.5 %

Procedure:
A stirred mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 4-nitrophthalic anhydride (706 mg, 3.66 mmol) was heated to melt for 6 min. The mixture was allowed to cool to room temperature. Chromatography of the resulting oil gave 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-nitro-isoindoline-1,3-dione as a solid (1.42 g, 87% yield): mp, 255.0-256.0° C.; 1H NMR (CDCl3); δ 1.47 (t, J=7 Hz, 3H, CH3), 2.91 (s, 3H, CH3), 3.71 (dd, J=4.2, 14.3 Hz, 1H, CHH), 3.85 (2, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.59 (dd, J=11.1, 14.1, Hz, 1H, CHH), 5.94 (dd, J=4.1, 10.9 Hz, 1H, NCH), 6.82-6.86 (m, 2H, Ar), 7.09-7.14 (m, 2H, Ar), 8.01-8.04 (m, 1H, Ar), 8.56-8.65 (m, 1H, Ar), 13C NMR (CDCl3) δ 14.67, 41.61, 49.16, 53.99, 55.96, 64.54, 111.48, 112.39, 118.98, 120.48, 124.79, 128.73, 129.39, 133.06, 136.03, 148.71, 149.92, 151.79, 165.56, 165.74; Anal Calcd for C20H20NO8S: C, 53.57; H, 4.50; N, 6.23. Found: C, 53.59; H, 4.58; N, 5.88.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].N1C=CC=CC=1>ClCCl>[CH3:16][O:17][C:18](=[O:36])[C@@H:19]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:31][CH:30]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Trifluoromethanesulfonic anhydride (3.27 ml, 19.47 mmol) was slowly added to a solution of Boc-L-tyrosine methyl ester (5.0 g, 16.93 mmol) and pyridine (4.11 ml, 50.79 mmol) in dichloromethane (145 ml) at 0° C. and the resulting orange solution was stirred at room temperature for 4 h. The reaction was quenched by addition of NaHCO3 solution (150 ml) and the organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 ml) and brine (1×100 ml), and dried (MgSO4). The solvent was concentrated under reduced pressure to yield (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl) propionic acid methyl ester (6.52 g, 90%) that was used in the next step without further purification.
Reaction SMILES: N1C=CC([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=CC=1.[BrH:30].O1[CH2:36][CH2:35]OCC1>O>[BrH:30].[BrH:30].[N:10]1[CH:36]=[CH:35][C:16]([CH:9]2[CH2:8][NH:7][CH2:12][CH2:11][N:10]2[CH2:13][C:14]([C:16]2[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[O:15])=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reactant: C1COCCO1
Agent: Br
Solvent: O
Product: CC(C)(Oc1ccc(C(=O)CN2CCNCC2c2ccncc2)cc1)C(=O)O
Temperature: 95 °C

Procedure:
A mixture of methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]-acetyl]phenoxy]isobutyrate (50 mg), 48% w/v hydrobromic acid (0.74 ml), dioxane (1 ml) and water (3 ml) was heated at 95° C. for 4 hours. The solution was cooled, diluted with water and freeze-dried to give the title compound, 40 mg, as a pale yellow solid: m.p. 163°-167° C.; NMR (D2O) δ 8.40 (2H, d), 8.16 (2H, d), 7.40 (2H, d), 7.21 (2H, d), 5.21 (2H, s), 4.32 (4H, b), 3.89 (4H, bt), 1.86 (6H, s); m/e 384 (M+H)+ ; calculated for C21H25N3.2HBr.2H2O: C, 43.3; H, 5.3; N, 7.2. found: C, 43.6; H, 5.3; N, 7.3%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:34]([O:33][C:31]([CH2:30][O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])=[O:32])[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCC1OC1(C)C1C(OC)C(OC(=O)N2CCOCC2)CCC12CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (76.2 mg) in a mixture of toluene (2 ml) and N,N-dimethylformamide (1 ml) was added sodium hydride (20.5 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and ethyl bromoacetate (68.5 mg) was added. After stirred for 3 hours at ambient temperature, the reaction mixture was quenched with aqueous saturated ammonium chloride solution (2 ml). The organic layer was washed with brine, dried, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (diethyl ether) to give 4-[3-(2-ethoxycarbonylmethoxyethyl)-2-methyl-oxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro-[2,5]octane (66.9 mg).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]12.[C:22]1(C)[CH:27]=CC=C[CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]12)[CH:22]=[CH2:23]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3c(Br)cccc3C21
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1cccc2c1CC1CC(=O)N(C(=O)OC(C)(C)C)C21

Procedure:
A solution tert-butyl 5-bromo-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Step 3, 500 mg), Pd(PPh3)4 (80 mg, 0.1 equiv.), allyltributylstannate (0.56 g, 1.20 equiv.) in toluene (17 mL) was degassed and stirred at reflux overnight. The solvent was removed under vacuum. The residue was taken up in acetonitrile (40 mL) and washed twice with n-hexane. The acetonitrile was removed in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate and cyclohexane (1 to 25%) to give 210 mg of the desired product E1; LCMS (Method B), RT: 1.05 min; ES+ 649 (2M+Na+).
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[O:10][C:11]2=[O:12])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C.Cl.O>C(O)C>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[O:10][C:11]2=[O:12])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CCCCC1OC(=O)c2cc(NC(C)=O)c([N+](=O)[O-])cc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCC1OC(=O)c2cc(N)c([N+](=O)[O-])cc21
Reaction time: 8 h

Procedure:
To a suspension of 29.2 g of compound obtained in Step A in 25 ml of 95% ethanol there are added 15 ml of hydrochloric acid and 20 ml of water. The mixture is refluxed for 3 hours and put aside at room temperature overnight The solvents are removed under reduced pressure. The residue is treated with 5% NaOH; the solid is collected and washed with water, dried, and crystallised from ethanol giving the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:30]=[CH:29][N:28]=[CH:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=[O:13])=[CH:5]2
Reactant: NCCCCCCn1ccnc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCCCCCn1ccnc1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
When 5-chloroindole-2-carboxylic acid is reacted with 1,1'-carbonyldiimidazole and 1H-imidazole-1-hexanamine by the procedure of Example 29, the compound of the Example is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH3:16]>>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:15][CH3:16]
Reactant: O=C1CCNCC1
Reactant: CCCOCCCCCl
Product: CCCOCCCCN1CCC(=O)CC1

Procedure:
1-(4-Propoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-propoxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [C:1]1([C:7]2[C:19]([C:20]([OH:22])=[O:21])=[C:10]3[C:11]4[C:16]([CH2:17][CH2:18][N:9]3[N:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.C(=O)(O)[O-].[Na+].[CH2:32](O)[CH3:33]>>[CH2:32]([O:21][C:20]([C:19]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=12)=[O:22])[CH3:33]
Reactant: CCO
Reactant: O=C(O)c1c(-c2ccccc2)nn2c1-c1ccccc1CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccc2)nn2c1-c1ccccc1CC2
Reaction time: 0.25 h

Procedure:
2-Phenyl-5,6-dihydro-pyrazolo[5,1-a]isoquinoline-1-carboxylic acid (7.48 g.) is stirred at 90° C. for three hours with 3.77 ml. of SOCl2. The thionyl chloride excess is eliminated in vacuo and the residual acid chloride is dissolved in 80 ml. of ethanol at 40°-50° C. After 15 minutes, the reaction mixture is neutralized by addition of aqueous sodium bicarbonate and the solvent is eliminated by distillation. The residue is extracted with ethyl ether and, after evaporation of the organic solution, is crystallized from isopropyl ether. Yield of title compound 2.47 g.; m.p. 84°-5° C.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1.[CH2:28]([C:31]1[CH:41]=[C:40]([CH2:42][CH2:43][O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:39]=[CH:38][C:32]=1[O:33][CH2:34][CH:35]1[O:37][CH2:36]1)[CH:29]=[CH2:30]>C(O)CC>[OH:37][CH:35]([CH:34]([CH2:20][C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[O:33][C:32]1[CH:38]=[CH:39][C:40]([CH2:42][CH2:43][O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)=[CH:41][C:31]=1[CH2:28][CH:29]=[CH2:30])[CH2:36][NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:18][CH:19]=1)=[O:12]
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCc2ccccc2)cc1
Reactant: C=CCc1cc(CCOCC2CC2)ccc1OCC1CO1
Solvent: CCCO
Product: C=CCc1cc(CCOCC2CC2)ccc1OC(Cc1ccccc1)C(O)CNCCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 89.9 %

Procedure:
A mixture of 6-[4-(3-benzylaminopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (5.5 g; 0.015 mol), 1-[2-allyl-4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2,3-epoxypropane (8.65 g; 0.03 mol) and n-propanol (100 ml) was stirred under reflux for 24 hours. The mixture was cooled, filtered and the filtrate was evaporated under reduced pressure and chromatographed on a silica gel column, using ethyl acetate as eluant, to give as a glass 6-[4-[3-[2-hydroxy-3-[2-allyl-4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-N-benzylpropylamino]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (4.4 g).
Reaction SMILES: C[Mg]Br.[CH2:4]([N:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[CH2:18](OCC)C>O1CCCC1>[CH2:4]([N:11]1[CH2:15][CH2:14][C:13]([CH3:18])([OH:16])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)CCN(Cc2ccccc2)C1

Procedure:
Methylmagnesium bromide (4 ml of 3M solution in diethyl ether) was added dropwise to a solution of 1-benzylpyrrolidin-3-one (1.75 g) in tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour before water and diethyl ether were added and the layers separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2, 5% methanol/dichloromethane as eluent) to afford the subtitle compound as a pale brown oil (0.8 g).