Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:24]=[C:23]([N:25]3[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]3=[O:37])[C:22]([F:38])=[CH:21][C:20]=2[N+:39]([O-:41])=[O:40])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
A mixture of 1.71 g of 4-benzyloxyphenol and 4.0 ml of N,N-dimethylformamide was added dropwise into a mixture of 0.34 g of sodium hydride and 8.5 ml of N,N-dimethylformamide while cooling with ice, and the mixture was stirred for 20 minutes. A mixture of 3.0 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene (described later, produced in Intermediate Production Example 4) and 7.0 ml of N,N-dimethylformamide was added dropwise at the same temperature, and stirred for 1 hour. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed once with IN hydrochloric acid and once with saturated saline and dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.[Cu][C:15]#[N:16].CN(C)C=O.Cl>[Fe](Cl)Cl.O>[OH:12][CH2:11][CH:9]1[CH2:8][CH2:7][C:6]2[CH:13]=[C:2]([C:15]#[N:16])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: N#C[Cu]
Reactant: OCC1CCc2cc(Br)ccc2O1
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCC(CO)O2
Yield: 49.3 %

Procedure:
A mixture of 297 parts of 6-bromo-3,4-dihydro-2H-1-benzopyran-2-methanol and 108 parts of copper (I) cyanide in 450 parts of N,N-dimethylformamide was stirred and refluxed for 4 hours. The reaction mixture was poured onto a solution of 600 parts of iron chloride in 180 parts of hydrochloric acid and 1000 parts of water. The whole was stirred for 20 minutes at 60° C. The aqueous phase was extracted with methylbenzene. The extract was filtered over Hyflo. The filtrate was washed successively with 10% hydrochloric acid, water, 10% sodium hydroxide and again with water, filtered again, dried and evaporated, yielding 112 parts (49.3%) of 3,4-dihydro-2-(hydroxymethyl)-2H-1-benzopyran-6-carbonitrile; mp. 85° C. (intermediate 2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[O:24]([CH2:31][CH:32]1[CH2:34][O:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][CH:32]([OH:33])[CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Br)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(c3cc(Br)ccc3n2CC(O)COc2ccccc2)C1
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of tert-butyl 8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (449.7 mg, 1.28 mmol) and powdered potassium hydroxide (86.9 mg, 1.54 mmol) in acetone (4.0 ml) was stirred for 15 minutes before the addition of 2-(phenoxymethyl)oxirane (254 mg, 1.69 mmol). After 1 h the reaction was condensed, diluted with EtOAc and washed twice with water and then brine. The organic layer was then dried over Na2SO4, filtered and condensed. The crude mixture was purified by silica gel chromatography (1% MeOH/CH2Cl2+0.1% Et3N). Yield=21%. ESI (m/z): 546.6 (M+CHCOO−).
Reaction SMILES: [N:1]1([NH2:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.CO[C:17](OC)([CH3:19])[CH3:18]>C(#N)C.C(O)(=O)C.C(Cl)(Cl)Cl>[N:1]1([N:14]=[C:17]([CH3:19])[CH3:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: Nn1cnc2cnc3ccccc3c21
Reactant: COC(C)(C)OC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)=Nn1cnc2cnc3ccccc3c21
Temperature: 100 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution of 1H-imidazo[4,5-c]quinolin-1-amine (2.86 g, 15.5 mmol) in 60 mL of acetonitrile and 15 mL of glacial acetic acid was treated with 2,2-dimethoxypropane (9.53 mL, 77.5 mmol) and heated to 100° C. under an atmosphere of nitrogen. After 18 h, the reaction mixture was concentrated under reduced pressure to give a brown oil. The oil was dissolved in 100 mL of CHCl3 and washed with 5% Na2CO3 solution (2×30 mL), water (30 mL) and brine (30 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3.48 g of N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine as a brown oil.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]>C1COCC1>[C:5]([Si:2]([CH3:4])([CH3:3])[CH3:1])#[C:6][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH2:8]
Reactant: C=CCCCCCCBr
Reactant: C#C[Si](C)(C)C
Solvent: C1CCOC1
Product: C=CCCCCCCC#C[Si](C)(C)C
Temperature: 0 °C
Yield: 16.2 %

Procedure:
A 250-mL round-bottom flask equipped with a stir bar and a water-jacketed reflux condenser was charged with trimethylsilylacetylene (6.00 mL, 42.0 mmol). THF (50 mL) was added, and the mixture was allowed to cool to 0° C. (ice-bath). nButyllithium (29.0 mL, 42.0 mmol, 1.46 M solution in hexanes) was added dropwise by a syringe, and the ice-bath was removed following the addition. The mixture was allowed to warm to 22° C. as it stirred for 1 h, at which point 8-bromo-1-octene (3.50 mL, 21.0 mmol) was added, and the mixture was allowed to reflux for 12 h. The mixture was allowed to cool to 0° C., quenched by addition of 50 mL water, washed with CH2Cl2 (5×50 mL). The combined organic layers were washed in brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting brown oil was filtered through a plug of silica gel (eluted in pentane), the filtrate was concentrated and the resulting brown oil distilled under vacuum (1.0 torr). The resulting yellow oil was re-distilled under vacuum (1.0 ton) to afford dec-9-en-1-ynyltrimethylsilane (0.700 g, 3.40 mmol, 14.0% yield) as a colorless oil. IR (neat): 3078 (w), 2929 (m), 2857 (w), 2175 (m), 1641 (w), 1461 (w), 1325 (w), 1248 (m), 1032 (w), 994 (w), 910 (m), 837 (s), 758 (s), 725 (w), 697 (w), 638 (m), 575 (w), 450 (w); 1H NMR (400 MHz, CDCl3): δ 5.86-5.76 (1H, m), 4.99 (1H, dd, J=17.2, 2.0 Hz), 4.93 (1H, dd, J=10.0,0.8 Hz), 2.21 (2H, t, J. 7.2 Hz), 2.05 (2H, app q, J=7.1 Hz), 1.55-1.48 (2H, m), 1.40-1.28 (6H, m), 0.14 (9H, s); 13C NMR (100 MHz, CDCl3): δ 139.2, 114.4, 107.8, 84.4, 33.9, 28.9, 28.8, 28.7, 28.7, 20.0, 0.3; HRMS (ESI+) [M+H]+ calcd for C13H25Si: 209.1726, found: 209.1719.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:25])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:5])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc(Cl)c(Cl)c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with 3,4-dichlorophenylsulphonyl chloride to give 2-(3,4-dichlorophenylsulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide as a gum (0.17 g, 27%);
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH:33]([OH:37])[C:34](O)=[O:35])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH:33]([OH:37])[C:34]([NH:16][CH2:15][CH2:14][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:35])=[CH:38][CH:39]=1
Reactant: O=C(O)C(O)COc1ccc(Cl)cc1
Reactant: C#CCOc1ccc(CCN)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(O)COc2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (5.0 g, 20 mmol) and N,N-diisopropylethylamine (10 g, 78 mmol) are dissolved in 70 ml of N,N-dimethylformamide. To this solution 3-(4-chloro-phenoxy)-2-hydroxy-propionic acid (4.3 g, 20 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (9.5 g, 22 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 6:4) to give 3-(4-chloro-phenoxy)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-propionamide (Compound E1.24).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37].N1C=CC=CC=1>C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[S:36]([NH:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:37])=[O:38]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(N)cc2ccoc12
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(CN2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)c2occc2c1
Yield: 47.8 %

Procedure:
tert-Butyl trans-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-1-carboxylate (0.037 g, 0.1 mmol; obtained in Step 3) was dissolved in DCM and reacted with 2-methoxy-5-methylbenzenesulfonyl chloride (0.045 g, 0.2 mmol) and pyridine (0.024 g, 0.3 mmol) overnight. The mixture was washed with 1 M HCl and the organic layer was dried (MgSO4) and evaporated. The crude was purified using flashtube (10% MeOH in DCM) and afforded the title product (0.026 g, 48%). HPLC 93% RT=2.01 min (System A; 10-97% MeCN over 3 min), 93% RT=1.85 min (System B; 10-97% MeCN over 3 min). MS (ESI+) m/z 544.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:26])[C@@H:16]([NH:19]C(=O)C(F)(F)F)[CH2:17][CH3:18].O1CCCC1.CO.[OH-].[Na+]>ClCCl>[NH2:19][C@@H:16]([CH2:17][CH3:18])[C:15]([NH:14][CH2:13][CH2:12][CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:26]
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](N)C(=O)NCCCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 20 mL cintillation vial was charged with N-(3-(1-methyl-1H-indol-2-yl)propyl)-2-(S)-(2,2,2-trifluoro-acetylamino)butanamide (57.0 mg, 0.154 mmol), tetrahydrofuran (0.77 mL), and methanol (0.20 mL). 3N Sodium hydroxide (0.15 mL, 0.450 mmol) was added and the resulting mixture stirred at room temperature for 18 h. The resulting mixture was then diluted with dichloromethane and extracted with 1 N HCl. The aqueous layer was neutralized to pH 8 and extracted with dichlormethane. The organic layer was dried with MgSO4, filter, and concentrate in vacuo. The resulting solid was taken up in water and lyophilized to yield (S)-2-amino-N-(3-(1-methyl-1H-indol-2-yl)propyl)butanamide. 1H NMR (300 MHz, CD3OD) δ 7.42 (d, J=7.7 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.05-7.11 (m, 1H), 6.94-7.02 (m, 1H), 6.23 (s, 1H), 3.60-3.75 (m, 4H), 3.31-3.46 (m, 2H), 2.69-2.86 (m, 2H), 1.91-2.03 (m, 2H), 1.71-1.89 (m, 2H), and 1.02 (t, J=7.4 Hz, 3H); MS (ES+) 274 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14](OS(C(F)(F)F)(=O)=O)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.[CH2:30]([N:37]([CH3:41])[CH2:38][C:39]#[CH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(NCC)C.[ClH:47]>C(Cl)Cl.CO.C(OCC)(=O)C.C(Cl)Cl.[Cu]I>[ClH:1].[ClH:47].[CH2:30]([N:37]([CH2:38][C:39]#[C:40][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[N:11][N:10]=[C:9]2[CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:29])[CH3:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C#CCN(C)Cc1ccccc1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Agent: [Cu]I
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCN(C)Cc1ccccc1
Yield: 83 %

Procedure:
A suspension under N2 of trifluoro-methanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (5 g, 10.68 mmoles), prepared as described in example 73, benzyl-methyl-prop-2-ynyl-amine (2.16 ml, 12.82 mmoles) and diethylamine (100 ml) was added under stirring with bis(triphenylphosphine)PdCl2 (150.2 mg, 0.214 mmole) and CuI (40.75 mg, 0.214 mmole). The mixture was refluxed for 6 hours, brought to dryness and the residue flash chromatographed (eluent: ethyl acetate) to give a solid which was dissolved in CH2Cl2/CH3OH 1:1 (50 ml), acidified with a solution of HCl in ethyl acetate and brought to dryness. The residue was dissolved in CH2Cl2 (100 ml), brought to dryness again, triturated in ethyl acetate (150 ml), filtered and dried in oven under vacuum at 40° C. to give 5.22 g of the title compound (yield: 83%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([O:21]CC)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24]NCCNC.C[Al](C)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[O:21])[CH3:24])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CNCCNC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 112 °C

Procedure:
General Procedure O. To a solution of ethyl 5,6-diphenylpyridine-2-carboxylate (Compound 21, 246 mg, 0.81 mmol) in toluene (5 ml) was added N,N′-dimethylethylenediamine (DMEDA, 78.7 mg, 0.89 mmol) and trimethylaluminum (1.2 ml, 2.44 mmol, 2 M in toluene) dropwise under argon at room temperature. After the mixture was refluxed at 112° C. for 2.5 hours, it was quenched with water, and the products were extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over Na2SO4. The filtered solvents were concentrated in vacuo, and the residue was purified by silica gel chromatography (15% ethyl acetate in hexane) to give title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][C@@H:13]([O:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([N:47]3[CH2:53][CH2:52][C:51]4[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=4[NH:49][C:48]3=[O:58])[CH2:43][CH2:42]2)=[O:40])[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][N:25](C(OCC4C=CC=CC=4)=O)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:3]=1.[H][H]>CO.[Pd]>[O:58]=[C:48]1[N:47]([CH:44]2[CH2:45][CH2:46][N:41]([C:39]([O:38][C@H:13]([CH2:12][C:4]3[CH:3]=[C:2]([CH3:1])[C:7]4[O:8][CH2:9][CH2:10][O:11][C:6]=4[CH:5]=3)[C:14](=[O:15])[N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:18][CH2:17]3)=[O:40])[CH2:42][CH2:43]2)[CH2:53][CH2:52][C:51]2[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=2[NH:49]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)cc2c1OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc2c1OCCO2

Procedure:
35 mg (0.04 mmol) benzyl 4-(1-{(R)-3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazin-1-carboxylate (Example 6.12) were dissolved in 10 mL MeOH and combined with 50 mg 10% Pd/C. The mixture was hydrogenated at 50° C. and 3 bar hydrogen pressure until the theoretical hydrogen uptake had occurred (for 3 h). Then the catalyst was filtered off, the filtrate was evaporated to dryness i.vac., the residue was taken up in 2 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.C(#N)C>O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:12][CH:11]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: CCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C(=O)Nc2ccc3ccc(OC)nc3n2)cc1
Temperature: 4 °C
Yield: 67.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-ethoxybenzoic acid (8 g), N,N'-carbonyldiimidazole (7.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (5.6 g). The product produced by precipitation in water (9.4 g; m.p. 74° C.) is dissolved in boiling acetonitrile (94 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 30° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-4-ethoxybenzamide (7 g) is produced, m.p. 145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:30](=[O:31])[CH2:29][NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
9 g of Nα -benzyloxycarbonyl-L-lysine, 5.6 g of tert.-butyloxycarbonylglycine, 3.2 g of triethylamine, 4.9 g of 1-hydroxybenzotriazole and 7.9 g of N,N'-dicyclohexylcarbodiimide are stirred in 100 ml of THF/DMF (7:3) for 1 hour at 0° C. and over night at ambient temperature. After the urea has been filtered off the mixture is concentrated by evaporation, the residue is taken up in ethyl acetate, extracted with saturated KHSO4 solution, washed with water, dried over MgSO4 and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with methylene chloride/ethyl acetate/methanol (10:1:1). 12.5 g (100% of theory) are obtained in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[Ca+2].[Cl-].CO.[OH-].[K+].Cl>CO>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCCCCCCCCCCC=O
Agent: Cl
Agent: O=Cc1cc(Cl)c(O)cc1O
Agent: [Ca+2]
Solvent: CO
Product: CCCCCCCCCCCC(O)c1c(O)c(Cl)cc(C=O)c1O
Reaction time: 24 h
Yield: 46 %

Procedure:
5-Chloro-2,4-dihydroxybenzaldehyde (493 mg, 2.86 mmol), dodecanal (641 mg, 3.48 mmol) and calcium chloride dehydrate (3.02 mg, 2.03 mmol) were dissolved in methanol (6 ml), added with a potassium hydroxide methanol solution (1.0 M, 4.0 ml) at 0° C. and stirred for 24 hours. The reaction mixture was made acidic with 1 M hydrochloric acid and extracted with ethyl acetate, and after post-treatment, the crude product (1.18 g) was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to obtain 5-chloro-2,4-dihydroxy-3-(1-hydroxydodecyl)benzaldehyde (colorless solid 475 mg, yield 46%) and 5-chloro-2,4-dihydroxybenzaldehyde (209 mg, recovery 42%).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[CH:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH3:5][C:4]([CH3:6])=[CH:3][CH2:2][C:8]1([CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])[CH:7]=[CH:11][CH:10]=[CH:9]1
Reactant: CC(C)=CCBr
Reactant: C1=CCC=C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCC1(CC=C(C)C)C=CC=C1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 16.8 %

Procedure:
A 1.0 L double-walled reactor, provided with baffles, condenser, top stirrer, thermometer and dropping funnel equipped with a nitrogen inlet was charged with ALIQUAT 336 (4.0 g, 10 mmol), 4-bromo-2-methyl-2-butene (30.0 g, 0.20 mol) and freshly cracked cyclopentadiene (6.6 g, 0.10 mol). A 50 wt. % NaOH aqueous solution (84 g) was then added via the dropping funnel to the turbulently stirred reaction mixture. The reaction mixture was cooled with water during the addition of the base. After 5.5 hours of stirring at room temperature, the stirring was stopped, the layers separated and the product was distilled at reduced pressure. After vacuum distillation, 3.4 g of di-(3-methyl-2-butenyl)-cyclopentadiene were obtained. Characterizaton of the product took place with the aid of GC, GC-MS, 13C- and 1H-NMR.