Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: N
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 380 mg, 47%). mp 208-210° C. 1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 2H), 7.27 (m, 2H), 7.43 (s, 1H), 7.45 (bs, 2H) 7.51 (d, J=9 Hz, 4H), 7.6 (t, 1H), 7.7 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.94 (dd, 1H), 8.25 (s, 1H). MS (DCI/NH3) m/z 474 (M+H)+, 491 (M+NH4)+. Anal. calc. for C22H14F2Cl2N3O3S.0.5H2O: C, 55.76; H, 2.98; N, 8.87. Found: C, 56.05; H, 3.42; N, 8.65.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[N:10]1[C:19]2[C:18](=O)[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:10]1[C:19]2[CH:18]([NH:5][CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[NH2:1])[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCc2cccnc21
Reactant: NCc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccccc1CNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 53.1 %

Procedure:
Using General Procedure B: To a solution of 2-aminobenzylamine (0.36 g, 2.9 mmol) and 6,7-dihydro-5H-quinolin-8-one (0.43 g, 2.9 mmol) in CH2Cl2 (15 mL) was added NaBH(OAc)3 (0.92 g, 4.4 mmol) and the mixture stirred at room temperature for 64 h. Purification of the crude material by column chromatography on silica gel (2% MeOH/CH2Cl2) gave (5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)-amine (0.39 g, 52%) as a yellow oil. 1H NMR (CDCl3) δ1.80 (m, 1H), 1.94 (m, 2H), 2.17 (m, 1H), 2.79 (m, 2H), 3.84 (m, 1H), 3.87 (d, 1H, J=11.7 Hz), 4.02 (d, 1H, J=12.0 Hz), 6.64 (d, 1H, J=7.8 Hz), 6.67 (t, 1H, J=7.8 Hz), 7.09 (m, 3H), 7.38 (d, 1H, J=3.0 Hz), 8.38 (d, 1H, J=3.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(I)cc3)c2)CC1
Yield: 116.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-iodobenzoyl chloride (61 mg, 0.229 mmol), 60.1 mg (>100%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH2:18](I)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:18][CH3:19])[C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])C=C1NCCC1Cc1ccc(Cl)nc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(Cc2ccc(Cl)nc2)C1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.5 g of 3-(2-chloropyrid-5-yl-methyl)-2-nitromethylidene-pyrrolidine, 0.3 g of ethyl iodide and 0.27 g of potassium carbonate in 3 ml of dimethylformamide is stirred at room temperature for 18 hours. The reaction mixture is poured onto water and extracted with diethyl ether. The ether phase is dried over magnesium sulfate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with ethyl acetate/hexane (2:1). The title compound having a melting point of 129-131° C. (compound 5.5) is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[S:3])[NH2:2].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCOCC1>[C:7]([C:6]1[CH:5]=[C:4]([C:1]2[S:3][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[N:2]=2)[CH:12]=[CH:11][CH:10]=1)([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1cccc(C(=O)O)c1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(-c2cccc(C(=O)O)c2)nc1C
Temperature: 90 °C
Yield: 63.5 %

Procedure:
720 mg of 3-Thiocarbamoylbenzoic acid was suspended in 10 ml of dioxane, 720 mg of ethyl 2-chloroacetoacetate was added thereto, and the mixture was heated at 90° C. for 18 hours. After the reaction mixture was cooled, the resulting crystal was collected from the suspension by filtration and recrystallized from 20 ml of ethanol and a small amount of water to give 735 mg of ethyl 2-(3-carboxyphenyl)-4-methyl-5-thiazolecarboxylate (yield: 63%). 290 mg of the crystal was dissolved in 5 ml of 1N sodium hydroxide, and the mixture was heated at 60° C. for one hour. After the completion of the reaction, the reaction mixture was neutralized with 1N hydrochloric acid. The resulting crystal was collected by filtration and recrystallized from a 80% aqueous ethanol solution to give 258 mg of 2-(3-carboxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 83%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].[OH:14]/[N:15]=[C:16](\[NH2:18])/[CH3:17].C(N(CC)CC)C>ClCCl>[NH2:18]/[C:16](=[N:15]\[O:14][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3])/[CH3:17]
Reactant: COC(=O)c1ccnc(C(=O)Cl)c1
Reactant: C/C(N)=N/O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccnc(C(=O)O/N=C(/C)N)c1

Procedure:
To a solution of methyl 2-(chlorocarbonyl)isonicotinate in dichloromethane (500 mL) was added (Z)-N′-hydroxyacetimidamide and triethylamine, keeping the temperature at 25-30° C. for 1 day. The reaction was concentrated in vacuo to afford (Z)-methyl 2-((1-aminoethylideneaminooxy)carbonyl)isonicotinate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)=[O:23])[CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2sc(C(=O)C3CCN(CC(=O)c4ccc5c(c4)NC(=O)CO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (83 mg, 0.3 mmol) and 6-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one (68 mg, 0.3 mmol) in DMF (1 ml) was treated with DIPEA (50 μl, 0.3 mmol) and the mixture was stirred at RT overnight. The mixture was poured on water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Crystallisation from ether gave 113 mg (81%) of title compound as a beige solid.
Reaction SMILES: [Cl:1]C([O-])=O.[N:5]([CH2:12][CH2:13][OH:14])([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8]>C(OCC)(=O)C>[CH2:6]([N:5]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])[CH2:7][OH:8].[ClH:1]
Reactant: O=C([O-])Cl
Solvent: CCOC(C)=O
Solvent: OCCN(CCO)CCO
Product: Cl
Reaction time: 2 h

Procedure:
100 g of a polyether acrylate (Laromer® LR 8812) were admixed with 5.75 g of chloroformate of the formula III and 3.3 g of triethanolamine at room temperature. 300 ml of ethyl acetate were then added. After 2 hours, the triethanolammonium chloride formed was washed out using distilled water in a separating funnel. After removal of the aqueous phase, the ethyl acetate was distilled off. (Viscosity of the end product: 928 mPas).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c([N+](=O)[O-])ccc(F)c1F
Yield: 106.7 %

Procedure:
20 g (0.114 mole) of 2,3-difluoro-6-nitrophenol (VI) were dissolved in 700 ml of acetone. 18.9 g (0.137 mole) of potassium carbonate and 34.1 g (0.24 mole) of methyl iodide were added to the solution, and the mixture was heated under reflux for 20 hours, whilst stirring. The solvent was then removed from the mixture by evaporation under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to give 23.0 g of 3,4-difluoro-2-methoxy-1-nitrobenzene (VII) as a yellow oil [Step (B1)].
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12](OC)=O)=[CH:4][NH:3]1.[C-]#[N:17].[Na+].CS(C)=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12]#[N:17])=[CH:4][NH:3]1
Reactant: [C-]#N
Reactant: COC(=O)Cc1c[nH]c(=O)c2ccoc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1c[nH]c(=O)c2ccoc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
Combine methyl (4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)acetate (4.42 g, 21.3 mmol), sodium cyanide (5.22 g, 106 mmol), and dimethylsulfoxide (44 mL) and heat at 80° C. for 1 hour. Cool to room temperature, pour into ethyl acetate, wash sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure to provide the desired compound (3.63 g, 63%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:16](=[O:18])[CH3:17])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:16]([C:5]1[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[CH:7]=[C:3]([CH2:2][O:1][C:25]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:26])[N:4]=1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)N1CCCCC1
Reactant: CC(=O)c1nc(CO)cn1COCC[Si](C)(C)C
Product: CC(=O)c1nc(COC(=O)N2CCCCC2)cn1COCC[Si](C)(C)C

Procedure:
In analogy to Step (4) of Example 48, but using 1-(4-hydroxymethyl-1-(2-trimethylsilylethoxymethyl)-1H-imidazol-2-yl)ethanone (1.50 g) and piperidine-1-ylcarbonyl chloride (0.763 mL), the title compound (1.93 g) was afforded.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[NH2:34].Cl>C(O)C.C(OCC)C>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([NH:34][C:33]3[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:31]([O:30][CH3:29])[CH:32]=3)[N:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Cc1ccc(C(=O)c2ccccc2Nc2nc(S(C)(=O)=O)ncc2C#N)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(Nc2ncc(C#N)c(Nc3ccccc3C(=O)c3ccc(C)cc3)n2)cc(OC)c1OC
Temperature: 180 °C
Yield: 36.6 %

Procedure:
To a mixture of 4-{[2-(4-methylbenzoyl)phenyl]amino}-2-(methylsulfonyl) pyrimidine-5-carbonitrile (54 mg, 0.138 mmol) and 3,4,5-trimethoxyaniline (26 mg, 0.142 mmol) in absolute ethanol (3 ml) was added 1N HCl in diethyl ether (3 drops). The reaction was facilitated using microwave irradiation. The reaction was heated at 180° C. for 600 sec. using Personal Chemistry SmithSynthesizer. On cooling a crude yellow solid was collected by filtration. Pure sample was obtained after chromatography to give 4-{[2-(4-methylbenzoyl)phenyl]amino}-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-5-carbonitrile (25 mg, %) as a canary yellow solid. 1H NMR (DMSO-d6): δ 10.0 (s, 1H), 9.39 (br s, 1H), 8.39 (s, 1H), 8.04 (d, 1H, J=8.4 Hz), 7.58-7.48 (m, 4H), 7.28 (t, 1H, J=7.6 Hz), 7.22 (d, 2H, J=7.9 Hz), 6.91 (s, 1H), 3.65 (s, 3H), 3.61 (s, 6H), 2.35 (s, 3H); ES-MS m/z 496 (M+H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])=[CH:35][CH:36]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2-methylpropyl)-nicotinamide (Intermediate 30, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2-methylpropyl)-3-pyridinecarboxamide 1 oxide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].Cl.[CH3:15][O:16][NH2:17].O.Cl>N1C=CC=CC=1>[CH3:15][O:16][NH:17][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 87.5 %

Procedure:
2-nitrobenzene sulfonyl chloride (28.8 g, 130 mmol) was added within 30 min to a solution of O-methylhydroxylamine hydrochloride (11.7 g, 141 mmol) in pyridine (100 ml) accompanied by stirring and water cooling. After the addition the mixture was stirred for a further 30 min at room temperature (RT), mixed with ice (200-300 g) and acidified with concentrated HCl to pH 2-3. The still-cold suspension was sucked out, the precipitate carefully washed with ice water and dried. 26.4 g (87%) of the sulfamide 1 was obtained as a yellowish solid with a melting point of 133-136° C. 1H-NMR (DMSO-D6, 300 MHz): δ=3.67 (s, 3H), 7.92-8.06 (m, 4H), 11.05 (s, 1H) ppm.
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH:9]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH2:23])[O:10][CH2:2][C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8]
Reactant: CCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Product: NCCCCCCCCCCCCC1OC[C@@H](O)[C@@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 15 g of D-ribose and 18 g of dodecylamine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:3]=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:28][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:4]2[N:3]=[N:2][NH:1][CH:5]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(Cc2c[nH]nn2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCC2)cc1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
5 g of 4-[1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -60° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour at -70° with 2.4 g of cyclopentanone, and heated to 25°. Then the mixture is combined with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.1 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile.
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[I:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(I)c(N)nc3=O)C[C@@H]2O)cc1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of 5-iodo-2'deoxycytidine (17.65g, 50.00 mmol) in 250 ml of dry pyridine at 0° (ice bath) is added p-toluenesulfonyl chloride (11.50g, 60.00 mmol). The reaction mixture is stirred at 0° for 1 h and then stored at 3° in the dark with stirring for an additional 23 h. At the end of the reaction a clear solution is obtained, to which 15 ml of methanol is added. After standing for 30 min, the solvent is removed under diminished pressure at room temperature to afford a syrup which is coevaporated several times with methanol. The residue is triturated with icecooled water to give a crystalline mass which is broken down to the fine particles with a spatula. The solid material is collected by filtration, washed thoroughly with water, a small amount of ice-cooled ethanol, ether, and dried in vacuo to yield 20.24 g (80%) of the desired product.
Reaction SMILES: C12N([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])=[O:27])[CH2:20]2.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([N:21]1[CH2:22][CH:23]2[CH:19]([CH2:25][N:24]2[C:9]2[CH:18]=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:20]1)=[O:27]
Reactant: COc1ccccc1C(=O)N1CC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Clc1cnc2ccccc2n1
Product: COc1ccccc1C(=O)N1CC2CN(c3cnc4ccccc4n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 22 and 2-chloro-quinoxaline as staring materials. MS (ESI) mass calcd. for O21H20N4O2, 360.42; m/z found, 361.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([CH:18]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][CH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([CH2:18][N:22]([CH3:23])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(C=O)C1
Agent: Cl
Product: CN(C)CC1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Yield: 91 %

Procedure:
Reductive amination of 3-formyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (160 mg) with dimethylamine hydrochloride (67 mg) according to General Procedure C followed by an aqueous work-up and purification on silica gave 3-dimethylaminomethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (160 mg). This was treated with 2M HCl to give desired (1-methanesulfonyl-piperazin-2-ylmethyl)-dimethyl-amine dihydrochloride (140 mg).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([O:41]C)=[O:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.[OH-].[Na+].CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1>CC(C)=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)OC
Agent: Cc1cc(O)c(C(C)C)cc1C1(c2cc(C(C)C)c(O)cc2C)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
1.15 g. (1.6 mmoles) of Z-Tyr-D-Ala-Gly-Phe-Nle-OMe (3rd step of Example 1) are suspended in a mixture of 4 ml. of methanol and 2 ml. of acetone, then saponified with 0.5N sodium hydroxide in the presence of thymolphthalein as indicator. When the alkali consumption becomes slower, the mixture is diluted with 10 ml. of water and shaken with 3×5 ml. of ethyl acetate. On evaporating the ethyl acetate phases 0.3 g. (26%) of protected pentapeptide ester is recovered. The aqueous phase is acidified with 0.5N sulphuric acid, the precipitated substance (Rf2 0.25-0.35) suspended in 50 ml. of 80% acetic acid and hydrogenated in the presence of palladium catalyst. In the course of the reaction the substance is dissolved. At the end of the reaction the catalyst is filtered off, the solution evaporated and the residue rubbed with about 4 ml. of cold water. The formed crystalline substance is filtered, washed with cold water and dried. Yield: 0.47 g. (70%) of the named product; Rf4 0.19-0.23. Aminoacid analysis: Gly=1.0, Ala=1.02; Nle=1.02; Tyr=0.98; Phe=1 (reference basis).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([NH2:17])[C:10]([NH2:16])=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2].[F:18][C:19]([F:24])([F:23])[C:20](O)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[O:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]3[NH:16][C:20]([C:19]([F:24])([F:23])[F:18])=[N:17][C:9]3=2)[CH2:14][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2ccc(N)c(N)c2O1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2ccc3[nH]c(C(F)(F)F)nc3c2O1
Yield: 65 %

Procedure:
A solution of ethyl-7,8-diamino-chroman-2-carboxylate (927 mg, 3 mmol) in trifluoroacetic acid (20 mL) was heated to reflux for 6 hours and then concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and then washed with saturated NaHCO3 solution (30 mL) and water (2×30 mL), dried over anhydrous Na2SO4. Purification by flash chromatography (30% CH2Cl2-hexanes) afforded 612 mg (65% yield) of the title compound as white solid: mp 134° C.; 1H NMR (400 MHz, CDCl3):[tautamer a]: δ:1.19 (t, J=7.1, 3H), 2.22 (m, 2H), 2.40 (m, 1H), 2.70 (m, 1H), 4.15 (q, J=7 Hz, 2H), 5.14 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 14.09 (bs, 1H). [tautamer b]: δ1.19 (t, J=7.1, 3H), 2.22 (m, 2H), 2.40 (m, 1H), 2.70 (m, 1H), 4.15 (q, J=7 Hz, 2H), 5.03 (m, 1H), 7.07 (s, 2H), 13.77 (bs, 1H); IR 3450, 3250, 2980, 2600, 1730, 1600, 1500, 1230 cm−1.