Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][CH2:11][CH:10]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CCOCC>[Si:1]([O:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][CH2:11][C:10]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2cccc(F)c2F)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H](c2cccc(F)c2F)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round-bottomed flask (t=g) was added 2-(tert-butyldimethylsilyloxy)-5-(2,3-difluorophenyl)cycloheptanol (1.73 g, 4.85 mmol) in CH2Cl2 (50 mL) to give a colorless solution. Dess-Martin Periodinane (2.264 g, 5.34 mmol) was added in one portion, and the mixture was stirred at room temperature overnight. 17 h: TLC showed complete conversion. It was diluted with Et2O and treated with 40 ml saturated Na2S2O3 and Na2HCO3 solution (1/1 mixture) until the milky solution became clear (10 min). The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried with Na2SO4, and concentrated to a colorless oil (with some solids insoluble in hexane). Purification by FCC up to 40% Et2O in hexane afforded two peaks. They were individually pooled and concentrated. The less polar major one (978 mg, 55%) was a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.02-6.90 (m, 3H), 4.34 (d, J=4.6 Hz, 1H), 2.82-2.75 (m, 2H), 2.54-2.46 (m, 1H), 2.45-2.32 (m, 1H), 2.17-1.98 (m, 2H), 1.90-1.68 (m, 3H), 0.94 (s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 213.4, 150.7 (dd, J=247.6 and 13.4 Hz), 147.8 (dd, J=245.7 and 13.4 Hz), 137.5 (d, J=11.5 Hz), 127.7, 122.2, 114.7 (d, J=17.3 Hz), 79.0, 40.0, 39.2, 33.2, 30.7, 29.4, 25.8, 18.2, −5.0. The more polar minor one solidified upon standing to a white solid (698 mg, 39%). It was re-crystallized from hexane and X-ray analysis verified the anti-stereochemistry relation. 1H NMR (500 MHz, CDCl3) δ 7.10-6.97 (m, 2H), 6.97-6.90 (m, 1H), 4.34 (dd, J=3.0 and 9.7 Hz, 1H), 3.04-2.94 (m, 1H), 2.80-2.70 (m, 1H), 2.62-2.50 (m, 1H), 2.18-1.72 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 211.0, 150.8 (dd, J=248.6 and 13.5 Hz), 148.1 (dd, J=246.7 and 12.5 Hz), 136.4 (d, J=11.5 Hz), 124.2, 122.3, 115.1 (d, J=17.3 Hz), 78.4, 40.3, 39.4, 34.3, 33.0, 30.4, 25.9, 18.5, −4.5, −5.1.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][C@@H:19]([CH2:36][CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>O.C(O)C>[CH3:18][C@@H:19]([CH2:36][CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC[C@H](C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H](C)CCCCCOc1ccc(OCc2ccccc2)cc1
Yield: 83.5 %

Procedure:
A solution of NaOH (40 g) dissolved in water (18 ml) was added to a solution of p-benzyloxyphenol (12 g, 0.060 mol) dissolved in ethanol (60 ml), followed by dropwise adding to the mixture, (S)-6-methyloctyl-p-toluenesulfonate (16.7 g, 0.055 mol) obtained above, refluxing the resulting mixture for 12 hours, distilling off ethanol after completion of the reaction, extracting the residue with toluene, washing the resulting ortanic layer with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution, further with water until the washing water became neutral, drying the layer, distilling off the organic solvent to obtain an oily product, and subjecting this product to column chromatography with activated alumina (17 g) to obtain (S)-p-benzyloxyphenyl 6-methyloctyl ether (15 g), dissolving this product (15 g, 0.046 mol) in ethanol (43 ml), subjecting the solution to hydrogenolysis in the presence of paradium-carbon (1.5 g) to obtain (S)-p-6-methyloctyloxyphenol (XII) (8.2 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:29]([N:13]1[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[CH2:10][CH:11]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:12]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: CC(C)(C)N=C=O
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)NC(C)(C)C)C2)cc1

Procedure:
62 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 20 mg (0.20 mmol, 1.0 eq.) of tert-butyl isocyanate were reacted according to General Method 4.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH:2]=C.[BH4-].[Na+].C(Cl)Cl.C[OH:36]>C(=O)=O.CC(C)=O>[OH:36][CH2:2][CH2:1][O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: C=CCOCc1cccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)c1
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2cccc(COCCO)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
3-(3′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (260 mg, 0.664 mmol) was dissolved in DCM/methanol (4:1, 7.5 mL) and was cooled to −78° C. in dry ice-acetone bath. O3 was bubbled through the solution for 15 min. Thin layer chromatography (TLC) confirmed the completion of the reaction at this stage. The DCM was evaporated in vacuo; ethanol (5 mL) was added and the solution was cooled in ice-water bath to 0° C. NaBH4 (175 mg, 7 eq.) was added and the reaction was stirred at the temperature of 0˜5° C. for one hour then at room temperature for 1.5 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution. The aqueous phase was extracted with DCM (3×8 mL), the combined organic phases were washed with brine (5 mL), dried over sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with 20˜50% ethyl acetate in hexane to give the product (134 mg, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.59 (d, 3H), 7.52 (d, 1H), 7.41 (t, 1H), 7.32 (d, 3H), 4.85 (s, 2H), 4.45 (s, 2H), 3.77 (br, 2H), 3.62 (t, 2H), 3.12 (s, 2H), 2.48 (br, 1H), 1.72 (m, 4H), 1.5 (m, 6H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH:15]C(=O)C(C)(C)C>Cl>[I:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH2:15]
Reactant: CN1CCN(c2cc(I)c(NC(=O)C(C)(C)C)cn2)CC1
Agent: Cl
Product: CN1CCN(c2cc(I)c(N)cn2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
A mixture of 2.20 g (5.47 mmol) N-[4-iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-2,2-dimethyl-propionamide (synthesis described in DE10008042) in 50 ml 3 N hydrochloric acid was stirred for 18 h at 100° C. After cooling to 0° C. the reaction mixture was washed twice with ether (50 ml). The aqueous phase was treated with 50 ml dichloromethane and basified with a 1 M solution of sodium carbonate. The organic phase was separated and the aqueous phase was extracted four times with 50 ml dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 1.60 g (92%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=N[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[NH:9][C@H:10]([C:15]([NH:43][CH2:38][C:37]#[N:36])=[O:17])[CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1)C(=O)NCC#N
Reaction time: 18 h

Procedure:
To a solution of N-{(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}-L-leucine from step 3 (76 mg, 0.17 mmol), HATU (146 mg, 0.38 mmol), aminoacetonitrile hydrochloride (52 mg, 0.56 mmol) in DMF (1.1 mL) cooled to −10° C., was added N,N-diisopropylethylamine (0.13 mL, 0.75 mmol). The reaction was allowed to proceed at room temperature for 18 h and it was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography using EtOAc and hexane as eluant to give the title compound as a colorless gum.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O-:20])=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+]>CN(C)C=O.O>[Br:1][CH2:2][CH2:3][CH2:4][O:20][C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)[O-])cccc2c1=O
Reactant: BrCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCBr)cccc2c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 69.6 %

Procedure:
30 g of 1,3-dibromopropane was added dropwise at ambient temperature to a suspension of 30 g of sodium 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150 ml of dimethylformamide and 35 ml of water. The reaction mixture was stirred at ambient temperature for 5 days. 100 ml of water was added and stirring was continued for a further 15 minutes. The precipitate was filtered off by suction, washed with water and purified by flash chromatography on silica gel, eluting with chloroform:ethyl acetate 95:5. The collected fractions were evaporated to dryness in vacuo and the residue was recrystallized from ethanol to give 27.7 g of the title compound, m.p. 114-115° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:29])[CH2:19][C@@H:20]2[OH:28])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH2:30].[BH4-].[Na+]>O1CCCC1>[OH:28][C@@H:20]1[C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:2]([OH:30])([CH3:3])[CH3:1])[CH2:17][C@@H:18]([OH:29])[CH2:19]1
Reactant: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a cooled, stirred solution of 4.05 g (10.1 mmol) of cholesta-5,24-diene-1α,3β-diol in 53 ml of tetrahydrofuran in an ice bath was added 33 ml of water followed by 4.0 g (12.5 mmol) of mercuric acetate. The bath was removed. After 2 hr., the reaction was still incomplete (tlc) so 0.4 g (1.3 mmol) of mercuric acetate was added. After 4 hr., 800 mg (21.1 mol) of sodium borohydride was added, followed after 30 min. by 190 ml of saturated brine and extraction of the resulting suspension with 5×50 ml of methylene chloride. The organic phases were backwashed with 20 ml of brine, dried (Na2SO4), filtered and evaporated. The residue was chromatographed on 400 g of silica gel. Elution with 5% methanol--chloroform and combination of fractions according to tlc (10% methanol--chloroform) afforded 3.60 g (85%) of 1α,25-dihydroxycholesterol, mp 165°- 167° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 77 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.
Reaction SMILES: [C:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].O=[C:26]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C1(C)C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[CH2:27][C:26](=[CH:5][C:1]([O:3][CH3:4])=[O:2])[CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C=C(CC(=O)OC)CC(=O)OC
Temperature: 120 °C
Yield: 77.4 %

Procedure:
Carbomethoxymethylenetriphenylphosphorane (167 g, 0.5 mol) in toluene (600 ml) was treated with dimethyl 3-oxoglutarate (87 g, 0.5 mol) and the reaction heated to 100° C. on an oil bath at 120° C. under an atmosphere of nitrogen for 36 h. The reaction was then concentrated in vacuo and the oily residue triturated with 40/60 petrol ether/diethylether 1:1, 600 ml. Triphenylphosphine oxide precipitated out and the supernatant liquid was decanted/filtered off. The residue on evaporation in vacuo was Kugelrohr distilled under high vacuum Bpt (oven temperature 180-200° C. at 0.2 torr) to give 3-(methoxycarbonylmethylene)glutaric acid dimethylester (89.08 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH2:21]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:21][CH3:20])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h
Yield: 109.6 %

Procedure:
A solution of 2 g (0.0065 mole) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1 ml (0.013 mole) of 40% aqueous monomethylamine. After stirring for 16 h the reaction mixture was diluted with 100 ml of water and the solid which precipitated was collected by filtration (2.4 g). Recrystallization from benzene/ligroin yielded 2.2 g of white crystals, mp 160°-161°.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:7](=[O:9])[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)([OH:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCN(C(=O)C(O)(c2ccccc2)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (1.0 g, 4.54 mmol) in DCM (50 mL) was added t-butoxycarbonyl-4-aminopiperidine (0.9 g, 4.5 mmol). DIPEA (2.4 mL, 1.4 mmol) and HOBt (1.0 g, 6.8 mmol) were added to the mixture, followed by EDCI (1.0 g, 5.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then washed with 1N NaOH (50 mL), 1N HCl (50 mL), and then saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed by rotary evaporation. To the crude material was added a solution of 20% TFA/DCM and the reaction was stirred for 2 hours at room temperature. The solvent was removed by rotary evaporation. DCM (50 mL) was added and the mixture was then washed with saturated sodium bicarbonate (50 mL). The organic layer was removed, dried over MgSO4 and filtered. The crude material was purified by silica gel chromatography (10% MeOH/DCM with 1% NH3 (aq)) to afford the title compound as a white powder (920 mg, 3.0 mmol).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[NH:22][NH2:23].C(N=C=NCCCN(C)C)C>ClCCl>[C:26]([O:25][C:21]([N:22]([C:7](=[O:9])[C:6]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:5]=1[NH:4][C:3]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:2]=1[F:1])[NH2:23])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(N)C(=O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a solution of 2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid (Example 5, 2.18 g, 7.6 mmol) and tert-butyl carbazate (1.57 g, 11.8 mmol) in dichloromethane (30 mL) is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.25 g, 11.77 mmol). After stirring for 16 hours at room temperature, the reaction mixture is diluted with dichloromethane and then washed with saturated NaHCO3, water, and brine. The organic layer is dried over Na2SO4, concentrated under vacuum, and purified via column chromatography (1:3 ethyl acetate/hexanes) to afford [2-(2,4-difluoroanilino)-4,5-difluorobenzoyl]-hydrazinecarboxylic acid tert-butyl ester as a solid (2.20 g). MS EI: m/z 400 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH:9]([C:13]1[CH:14]=[N:15][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:18]=1)[CH2:10][CH2:11][CH3:12])[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH:9]([C:13]1[CH:14]=[N:15][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:18]=1)[CH2:10][CH2:11][CH3:12])=[CH2:6])[CH3:2]
Reactant: CCCC(c1ccc(NC(=O)C(C)(C)C)nc1)C(C(=O)O)C(=O)OCC
Agent: C=O
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: C=C(C(=O)OCC)C(CCC)c1ccc(NC(=O)C(C)(C)C)nc1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of 2-{1-[6-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-butyl}-malonic acid monoethyl ester (712 mg, 1.95 mmol) in THF (6.5 mL) at 0° C. formaldehyde (37% in water, 0.3 mL) was added within 5 min. Stirring was continued for 10 min, then piperidine (0.26 mL, 2.63 mmol) was added dropwise within 10 min. The mixture was allowed to warm up overnight to room temperature. After 14 h the mixture was concentrated under reduced pressure to one third of its volume, then ether and water were added (15 mL each). After 2 min vigorous stirring the layers were separated, the aqueous was extracted with ether and the combined organic layers were washed with water, 4% citric acid, water and brine. Drying and concentration under reduced pressure gave 2-{1-[6-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-butyl}-acrylic acid ethyl ester (550 mg, 85%) as a colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21](I)=[CH:20][N:19]=2)[CH2:8][C@@:7]1([NH2:42])[CH2:40][CH3:41])=[O:5])[CH3:2].[SH:43][CH2:44][CH2:45][OH:46].C(O)CO.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.[Cu](I)I.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21]([S:43][CH2:44][CH2:45][OH:46])=[CH:20][N:19]=2)[CH2:8][C@@:7]1([NH2:42])[CH2:40][CH3:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](c2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@@]1(N)CC
Reactant: OCCS
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](c2ncc(SCCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@@]1(N)CC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (400 mg) is dissolved in isopropyl alcohol (2 ml), then thereto are added 2-mercaptoethanol (96 μl), copper iodide (20 mg), ethylene glycol (62 μl) and potassium carbonate (156 mg), and the mixture is stirred at 80° C. under nitrogen flow overnight. After cooling to room temperature, water is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with a saturated brine twice, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethylsulfanyl)pyrimidin-2-yl]}-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (110 mg). MS (m/z): 660 [M+H]+
Reaction SMILES: [NH2:1][C:2](=[NH:44])[N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][NH:10][C:11]([CH2:13][C@H:14]([NH:34][S:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])[C:15]([N:17]([CH:31]2[CH2:33][CH2:32]2)[CH2:18][CH2:19][NH:20]C(=O)OCC2C=CC=CC=2)=[O:16])=[O:12])[CH2:4]1.[ClH:45]>CO.[Pd]>[ClH:45].[NH2:20][CH2:19][CH2:18][N:17]([CH:31]1[CH2:33][CH2:32]1)[C:15](=[O:16])[C@@H:14]([NH:34][S:35]([N:38]1[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1)(=[O:37])=[O:36])[CH2:13][C:11]([NH:10][CH2:9][C@@H:5]1[CH2:6][CH2:7][CH2:8][N:3]([C:2]([NH2:44])=[NH:1])[CH2:4]1)=[O:12]
Reactant: N=C(N)N1CCC[C@@H](CNC(=O)C[C@H](NS(=O)(=O)N2CCOCC2)C(=O)N(CCNC(=O)OCc2ccccc2)C2CC2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)N1CCC[C@@H](CNC(=O)C[C@H](NS(=O)(=O)N2CCOCC2)C(=O)N(CCN)C2CC2)C1
Reaction time: 1.5 h

Procedure:
2.77 g of benzyl 2-[[(S)-3-[(S)-1-(amino-imino-methyl)-piperidin-3-ylmethyl-carbamoyl]-2-morpholin-4-ylsulphonylamino-propionyl]-cyclopropyl-amino]-ethylcarbamate (Example 23) are dissolved in 90 ml of methanol. After the addition of 2.13 ml of 2N hydrochloric acid and 300 mg of Pd/C (10%) the mixture is hydrogenated at room temperature for 1.5 hours, the catalyst is then filtered off and the filtrate is evaporated. The residue is dispersed with ether and the white crystals are filtered off. 2.44 g of crystalline (S)-N1-(2-amino-ethyl)-N4-[(S)-1-(amino-imino-methyl)-piperidin-3-ylmethyl]-N1-cyclopropyl-2-morpholin-4-ylsulphonylamino-succinamide hydrochloride (1:2), MS (ISP): 503.4 (M+H), are obtained.