Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]1[C:48]2[C:44](=[CH:45][N:46]([CH3:49])[N:47]=2)[CH:43]=[C:42]([N+:50]([O-:52])=[O:51])[CH:41]=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([C:40]2[C:48]3[C:44](=[CH:45][N:46]([CH3:49])[N:47]=3)[CH:43]=[C:42]([N+:50]([O-:52])=[O:51])[CH:41]=2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: Cn1cc2cc([N+](=O)[O-])cc(Br)c2n1
Agent: [Cu+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1cc2cc([N+](=O)[O-])cc(C3CC3)c2n1
Temperature: 100 °C
Reaction time: 11 h

Procedure:
A solution of cyclopropyl boronic acid (347 mg), palladium acetate (II) (31 mg), tricyclohexylphosphine tetrafluoroborate (99 mg), and potassium phosphate (1 g) in toluene (20 mL) and water (1 mL) was added to 7-bromo-2-methyl-5-nitro-2H-indazole obtained in Example 65 (Step 1) (361 mg), and the reaction solution was stirred at 100° C. for 11 hours. After dilution with ethyl acetate, the reaction solution was washed successively with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 7-cyclopropyl-2-methyl-5-nitro-2H-indazole.
Reaction SMILES: OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:61][CH2:62][N:63]([CH:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)[C:64](=[O:65])[C:39]=12)C1C=CC=CC=1>>[OH:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:61][CH2:62][N:63]([CH:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)[C:64](=[O:65])[C:39]=12
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CCOCC1
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c21
Product: O=C1c2c(O)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CCOCC1

Procedure:
This compound was prepared by following the same method as described for pure 9-hydroxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (349) from 9-benzyloxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-2-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (368) (85 mg, 0.15 mmol). The yield was 55 mg, 77%, of a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CC(C)C[Mg]Br
Product: COc1ccc2c(CC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 416 was used, staring from (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isobutyl-magnesium bromide to give (1-Isobutyl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 311 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:43]=[CH:42][C:29]([CH2:30][N:31]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:28][CH:27]=2)[O:21][N:20]=1)(=[O:12])=[O:11].CN>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][NH2:31])=[CH:42][CH:43]=2)[O:21][N:20]=1)(=[O:12])=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1
Agent: CN
Solvent: CCO
Product: NCc1ccc(OCc2nc([C@@H]3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
2-[4-(3-[(2S)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione (885 mg) [see Example 10] was added to a solution of 33% w/w methylamine in ethanol (2.2 ml). The reaction mixture was stirred at room temperature for 5 hours after which time the solvent was removed under reduced pressure. The resulting solid was dissolved in 1N aqueous hydrochloric acid solution and dichloromethane. The aqueous layer was then separated and basified to pH 12 with 0.88 aqueous ammonia solution. The mixture was then extracted with ethyl acetate, the organic layer dried over magnesium sulphate and the solvent removed under reduced pressure to afford 4-(3-[(2S)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzylamine (369 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[C:19]1([CH2:18][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2c(OCc3ccccc3)cccc21

Procedure:
To a solution of 4.44 g (0.03 m) of 4-hydroxy-1-indanone in 50 ml of dimethylformamide is added 4.15 g (0.03 m) of potassium carbonate with stirring followed by the dropwise addition of 3.8 g (0.03 m) of benzyl chloride. The reaction mixture is heated at steam bath temperature for 3 hours, then cooled and diluted with water. The aqueous mixture is extracted with ethyl acetate and the extract is washed with water, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue is triturated with ether and concentrated to dryness to yield: 5.86 g (82%) of a brown solid, m.p. 70°-73° C., sufficiently pure to be used in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C@@H:14]([CH2:16][CH:17]=O)[CH3:15])[CH2:4][O:3]1.C(N1CCC(N)CC1)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C:50](Cl)([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>C1COCC1.O>[CH2:53]([O:52][C:50]([CH2:17][CH2:16][C@H:14]([C@H:5]1[CH2:4][O:3][C:2]([CH3:19])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:15])=[O:51])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](CC=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCC(=O)OCc1ccccc1)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product from Step c dissolved in THF (20 mL) was added 1-isopropylpiperidin-4-amine (0.5 mL, excess) followed by the addition of sodium triacetoxyborohydride (0.85 g, 4.02 mmol). The mixture was stirred at rt. over night. Into the same pot mixture were added water (6.0 mL), sodium carbonate (0.5 g), and CBZCl (0.5 mL). The mixture was stirred at rt. for 2 hr. The mixture was extracted with ethyl acetate. Organic phase was washed with sodium bicarbonate and brine and dried over sodium sulfate. The product, (S)-tert-butyl 4-((R)-4-(benzyloxycarbonyl)butan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate, was obtained after reverse phase HPLC purification (acetonitrile/water 30% to 100% gradient). LC-MS found: (M+1)+=532.47.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:45])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([CH3:43])([CH3:42])[CH2:39][O:40][CH3:41])=[CH:34][C:33]=3[NH2:44])=O)[CH2:24]2)[O:12]1>CC(O)=O>[CH3:41][O:40][CH2:39][C:38]([C:35]1[CH:36]=[CH:37][C:32]2[NH:31][C:29]([CH2:28][CH2:27][CH:25]3[CH2:24][CH:23]([N:22]([CH2:21][C@@H:13]4[C@H:14]5[O:18][C:17]([CH3:19])([CH3:20])[O:16][C@H:15]5[C@H:11]([N:6]5[CH:5]=[N:4][C:3]6[C:7]5=[N:8][CH:9]=[N:10][C:2]=6[NH2:1])[O:12]4)[CH3:45])[CH2:26]3)=[N:44][C:33]=2[CH:34]=1)([CH3:42])[CH3:43]
Reactant: COCC(C)(C)c1ccc(NC(=O)CCC2CC(N(C)C[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@@H]4OC(C)(C)O[C@@H]43)C2)c(N)c1
Solvent: CC(=O)O
Product: COCC(C)(C)c1ccc2[nH]c(CCC3CC(N(C)C[C@H]4O[C@@H](n5cnc6c(N)ncnc65)[C@@H]5OC(C)(C)O[C@@H]54)C3)nc2c1
Temperature: 50 °C
Yield: 48.3 %

Procedure:
3-[3-({[(3aR,4R,6R,6aR)-6-(6-Amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}(methyl)amino)cyclobutyl]-N-[2-amino-4-(1-methoxy-2-methylpropan-2-yl)phenyl]propanamide (1.036 g, 1.66 mmol) was dissolved in AcOH (17 ml) and heated to 50° C. for 5 h. The reaction was concentrated in vacuo and the residue was dissolved in DCM (75 ml) and sat. NaHCO3 solution (75 ml) was added. The organic layer was separated and the aqueous layer was extracted with DCM (2×75 nil). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product as a dark orange oil (0.850 g, 94%). The product was purified using neutral prep-HPLC to give the product as a pale yellow oil (0.485 g, 47%, 88% pure): MS (ESI+) for C32H44N8O4 m/z 605.4 [M+H]+; LC purity 88% (ret. time, 1.25 min); 1HNMR (500 MHz, CDCl3) δH 10.44 (dd, J=207.7, 22.9 Hz, 1H), 8.41 (d, J=17.1 Hz, 1H), 8.16 (d, J=13.8 Hz, 1H), 7.89-7.58 (m, 1H), 7.54-7.29 (m, 2H), 6.15 (d, J=10.9 Hz, 1H), 5.92-5.56 (m, 3H), 4.98 (d, J=12.5 Hz, 1H), 4.76-4.39 (m, 1H), 3.47 (d, J=6.2 Hz, 2H), 3.33 (d, J=4.8 Hz, 3H), 2.98-2.43 (m, 4H), 2.42-2.00 (m, 6H), 1.99-1.88 (m, 2H), 1.77-1.66 (m, 1H), 1.64 (s, 3H), 1.61-1.48 (m, 1H), 1.44 (d, J=8.1 Hz, 3H), 1.40 (d, J=7.9 Hz, 6H), 1.28 (dd, J=16.0, 9.0 Hz, 1H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[CH:10]1(CO)[CH2:12][CH2:11]1>>[C:1]([O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1)(=[O:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6]
Reactant: OCC1CC1
Reactant: CC/C=C/CC(=O)OC
Product: CC/C=C/CC(=O)OCC1CC1

Procedure:
Prepared from (E)-methyl hex-3-enoate and cyclopropanemethanol according to the ester preparation method B described above.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18](O)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[OH:19][CH2:18][C@@H:12]1[CH2:13][C@@H:14]([O:16][CH3:17])[CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of borane-tetrahydrofuran complex in THF (1M, 53.0 mL, 53.0 mmol, 3.50 equiv) was added to a solution of (2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxy-2-pyrrolidinecarboxylic acid (3-2, 4.23 g, 15.1 mmol, 1 equiv) in THF (200 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 1 h. Excess borane was carefully quenched with water. The mixture was then partitioned between a 1:1 mixture of saturated sodium carbonate solution and brine (300 mL) and ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane initally, grading to 100% EtOAc) to provide benzyl (2S,4R)-2-(hydroxymethyl)-4-methoxy-1-pyrrolidinecarboxylate (3-3) as a colorless oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ 7.37-7.25 (br m, 5H), 5.18 (d, 1H, J=12.4 Hz), 5.13 (d, 1H, J=12.2 Hz), 4.51 (dd, 1H, J=8.3, 2.2 Hz), 3.86 (m, 1H), 3.78 (dd, 1H, J=11.7, 2.2 Hz), 3.72 (br d, 1H, J=11.7 Hz), 3.61 (ddd, 1H, J=9.8, 7.4, 2.2 Hz), 3.44 (dd, 1H, J=12.2, 4.4 Hz), 3.30 (s, 3H), 2.18 (m, 1H), 1.64 (m, 1H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:7][CH:6]=1)(O)=[O:2].[NH:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47][CH2:46][CH2:45]1.C(N(CC)CC)C>ClCCl.COC(C)(C)C>[N:44]1([C:1](=[O:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:13][CH:12]3[O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]4[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=4[CH:43]=3)=[CH:9][CH:10]=2)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47][CH2:46][CH2:45]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CC(=O)O)cc3)cc21
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CC(=O)N4CCCc5ccccc54)cc3)cc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.151 g of benzyl 4-(4-carboxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 3 ml of dichloromethane is admixed with 0.0376 g of 1,2,3,4-tetrahydroquinoline and 0.101 ml of triethylamine, cooled to 0° C. and subsequently admixed with 0.231 g of N-propylphosphonous anhydride (cyclic trimer). The reaction mixture is stirred at 0° C. for another 1.5 hours, then diluted with 70 ml of tert-butyl methyl ether. The organic phase is washed with 15 ml of water and then 15 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.75 (EtOAc). Rt=5.62.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C.CCOCC>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:5][C:4]3[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=3)[CH:1]=[O:10])=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C

Procedure:
A solution of isophthalaldehyde (4.0 g) and 7-chloroquinaldine (5.39 g) in acetic anhydride was heated at 125° C. in an oil bath for 48 hours. The reaction was cooled to room temperature, diluted with ether (30 mL) and the resulting suspension was stirred vigorously. The solid title compound was collected by filtration and was used as such in the next step.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:11][O:12][CH2:13][C:14]([O:16][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:15]
Reactant: COCC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)COC(=O)COC

Procedure:
71 ml of ethyl 4-chloro-3-oxo-butyrate are reacted with 89.5 g of methoxyacetic acid and 132 ml of triethylamine in 1 l of toluene by the procedure described in Example 4. The product is purified by bulb tube distillation.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.Cl.C([N:17]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(C(=CC)C=CCN)C>ClCCl.C(=O)([O-])O.[Na+].C(N(CC)CC)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH2:17])=[O:13])[CH:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: CC=C(C=CCN)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.1 %

Procedure:
To a mixture of 3-quinolinecarboxylic acid (3.32 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.37 g), N-hydroxybenzotriazole (2.6 g) and dichloromethane (50 ml) at 0° C. was added triethylamine (2.3 ml). After 15 minutes, a solution of 4-ethyl-2,4-hexadien-1-ylamine (2.0 g) in dichloromethane (10 ml) was added dropwise to the solution over a period of 10 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was diluted with aqueous sodium hydrogen carbonate. The separated organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (1% methanol-chloroform) to give N-[(2E,4E)- and (2Z,4E)-4-ethyl-2,4-hexadien-1-yl]-3-quinoline-carboxamide (3.18 g) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([CH2:15][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.CO.O>>[N:18]1([C:16](=[O:17])[CH2:15][CH:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]([OH:24])=[O:3])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Solvent: CO
Solvent: O
Product: O=C(O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid ethyl ester (604 mg, 1.81 mmol) in a 2:1 mixture of MeOH—H2O (12 ml) LiOH.H2O (228 mg, 5.43 mmol) was added and stirred overnight at room temperature. Ethanol was removed under reduced pressure, residue diluted with water (40 ml) and washed with ether. The aqueous layer was acidified to pH1 with 1N HCl and extracted with diethyl ether (3×25 ml). The combined organic extracts were dried with MgSO4 and concentrated under reduced pressure to give 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid as a white solid (492 mg); 1H NMR (CDCl3) 8.0–7.5 (1H), 7.4–7.1 (m, 5H), 3.8–3.4 (m, 8H), 3.0 (m, 1H), 2.8 (dd, J=16.4, 9.6 Hz, 1H), 2.65 (t, J=7.2 Hz, 2H), 2.40 (dd, J=16.4, 4.3 Hz, 1H), 1.9–1.5 (m, 4H). MS: 306 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:33])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[N+:30]([O-])=O)[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>CO.[Pd]>[NH2:30][C:19]1[CH:20]=[C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:23][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:10]([CH3:11])[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:33])[CH:13]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2N)c1
Yield: 100 %

Procedure:
In a manner similar to that of Example (18e), by reaction of 400 mg (10% by mass) of 10% palladium-on-charcoal and 4.0 g (8.8 mmol, 1 eq) of methyl (E)-3-[3′-(3-heptyl-1-methylureido)-2-nitrobiphenyl-4-yl]acrylate in 80 ml of methanol, and after purification by chromatography on silica gel (50/50 heptane/ethyl acetate), 3.81 g of methyl 3-[2-amino-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate are obtained in the form of a colorless oil. Yield=100%
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:14]([Cl:16])=[O:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8](Cl)=[O:9])#[N:2].[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>O1CCOCC1>[C:1]([C:3]1[C:11]([I:12])=[C:7]([C:8](=[O:9])[NH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[C:6]([I:13])=[C:5]([C:4]=1[I:17])[C:14]([Cl:16])=[O:15])#[N:2]
Reactant: NCC(O)CO
Reactant: N#Cc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: C1COCCO1
Product: N#Cc1c(I)c(C(=O)Cl)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 2 h

Procedure:
18.1 g of 5-cyano-2,4,6-triiodoisophthalic acid dichloride is combined in 750 ml of dioxane at 80° C. with 7.1 g of 1-amino-2,3-propanediol and stirred for 2 hours. The mixture is then separated from the precipitated hydrochloride of 1-amino-2,3-propanediol, and the filtrate is concentrated under vacuum. The residue is extracted by boiling with 800 ml of ethyl acetate. After concentration and cooling, 11.7 g (59% of theory) of 5-cyano-3-[N-(2,3-dihydroxypropyl)carbamoyl]-2,4,6-triiodobenzoyl chloride is crystallized from the extract as a white powder; mp 285°-288° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[F:14][C:15]([F:26])([F:25])[CH2:16]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][C:15]([F:26])([F:25])[F:14])=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C

Procedure:
Under an atmosphere of nitrogen a solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.31 mmol) in N,N-dimethylformamid (2 ml) was treated at room temperature with sodium hydride (55% dispersion in oil, 64 mg). After the gas formation had ceased, the suspension was cooled to 0° C. and trifluoro-methanesulphonic acid 2,2,2-trifluoro-ethyl ester (364 mg, 1.57 mmol) was added. After stirring at room temperature for 2 hours about 50% of the starting material was left. Another 364 mg of trifluoro-methanesulphonic acid 2,2,2-trifluoro-ethyl ester were added and after 30 minutes the reaction was complete. For the workup, the reaction mixture was treated with a saturated solution of sodium carbonate, then extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulphate, and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a 3:1-mixture of heptane and ethyl acetate as the eluent. The 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester was obtained as a white solid (216 mg, 70% of theory). MS (ISP): m/z=236.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:24]([O-])=O)=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]>[Pd].C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([NH2:24])=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1N
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A suspension of ethyl 3-methoxy-4-(3-morpholinopropoxy)-6-nitrobenzoate (132.2 g, 359 mmol) and 10% palladium on carbon (3.0 g) in a mixture of ethanol (200 ml) and ethyl acetate (2000 ml) was stirred under an atmosphere of hydrogen for 18 hours. Removal of the catalyst by filtration, followed by solvent evaporation in vacuo yielded ethyl 3-methoxy-4-(3-morpholinopropoxy)-6-aminobenzoate (122 g, 100% yield) as a brown oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([C:14]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH2:35][C:36]([F:38])([F:39])[F:37])[CH2:26][CH2:27]2)=[O:16])=[C:12]([CH3:17])[O:11][N:10]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)O
Reactant: NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Yield: 75 %

Procedure:
The title compound was synthesised according to the procedure described in Example 1 but using 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylic acid instead of 3-phenyl-5-methyliso-xazole-4-carboxylic acid and Compound 12B instead of Compound 1B. Extraction with diethyl ether followed by purification by flash chromatography (chloroform-2 N ammonia in methanol 100:3) afforded the title compound (75%) as an oil.