Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[Cl:14]C1C=CC(OS([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=O)=CC=1.CN(C)C=O>N1C=CC=CC=1>[ClH:14].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:12])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(C(=O)O)CC1
Reactant: O=S(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(C(=O)Oc2ccc(Cl)cc2)CC1
Yield: 70.5 %

Procedure:
A mixture of 1.5 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 8.8 g of bis-(p-chlorophenyl)sulfite was stirred at room temperature for 1 hour in a solution of 14 ml of dry dimethylformamide and 7 ml of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed twice with dry ether. Acetone was added to the residue to give crystals. The crystals were washed with ether and then with ethyl acetate and recrystallized from methanol-ether to obtain 1.62 g (yield: 70.4%) of p-chlorophenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 196° to 198° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:5][CH:6]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:19]2([CH3:20])[CH:14]([CH:15]([O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])=[CH2:4].C(O)(=O)C(C(C(O)=O)O)[OH:36]>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[O:1]1[C@@:3]([CH2:4][OH:36])([CH2:5][CH:6]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:7][CH2:8][C@H:9]([C@@H:11]2[C@:19]3([CH3:20])[CH:14]([CH:15]([O:21][Si:22]([CH3:23])([CH3:24])[CH3:25])[CH2:16][CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH3:10])[CH2:2]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: C=C(CO)CC(CC[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C)O[Si](C)(C)C(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: C[C@H](CCC(C[C@@]1(CO)CO1)O[Si](C)(C)C(C)(C)C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -20 °C
Yield: 94 %

Procedure:
A 20 ml amount of dichloromethane was placed in a 200 ml eggplant-shaped flask, 1.36 ml of titanium tetraisopropoxide was added, then the solution was cooled to -20° C. and stirred. Thereafter, 1.05 g of D(-)-diethyl tartrate dissolved in 5 ml of dichloromethane and the solution stirred at -25° C. for 20 minutes was placed and then, 2.14 g of the compound (4-10), (7R)-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octene, dissolved in 10 ml of dichloromethane, was added, then the solution was stirred for 30 minutes. Further, 4.3 ml of t-butyldiperoxide was added and the solution was stirred at the same temperature for 30 minutes. The reaction solution was poured into 20 ml of a 10% aqueous solution of tartaric acid, the solution was stirred at that temperature for 30 minutes and at room temperature for 1 hour, then separation was performed and extraction performed from the aqueous layer by dichloromethane. The organic layer was washed by a 10% aqueous solution of tartaric acid and saturated saline and was dried over anhydrous magnesium sulfate. After filtration by Celite, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 50 ml of ether, 18 ml of 1N sodium hydroxide was added, then the solution was stirred under ice cooling for 1 hour. After separation, extraction was performed from the aqueous layer by ether. The organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate, then filtered by Celite. The filtrate was concentrated under reduced pressure to obtain 2.40 g of a crude product. This was purified by a silica gel column (IR-60, 200 g, hexane/ethyl acetate=15/1 to 4/1) to obtain the desired product (4-11), (7R, 2R)-1,2-epoxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octane in an amount of 2.08 g (yield 94%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[N:12]1([C:17]2[CH:33]=[CH:32][C:20]([O:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>CO>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:24]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:32][CH:33]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1ccc(CNCCOc2ccc(-n3ccnc3)cc2)cc1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Product: OC(COc1ccccc1)CN(CCOc1ccc(-n2ccnc2)cc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3.2 mL (23.9 mmol) 1,2-epoxy-3-phenoxypropane in 20 mL MeOH, add 6.99 g (23.9 mmol) 2-[4-(1H-imidazol-1-yl)phenoxy]-N-(phenylmethyl)ethanamine as the free base described above. Stir at room temperature under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1). At the completion of the reaction, evaporate the solvents. The resulting oil is chromatographed on a silica gel column using (petroleum ether :acetone, 8:2). Collect the appropriate fractions and remove the solvents to give the title compound.
Reaction SMILES: [NH:1]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:2]([NH2:4])=[S:3].C(N(CC)C(C)C)(C)C.Br[CH:23]([CH:26]=O)[CH:24]=[O:25]>C1COCC1>[CH:24]([C:23]1[S:3][C:2]([NH:1][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:4][CH:26]=1)=[O:25]
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)OC(=O)CNC(N)=S
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the crude product from Example 1 in anhydrous THF (200 mL) is added N,N-diisopropylethylamine (25 mL, 143 mmol) followed by 2-bromomalonaldehyde (18.5 g, 123 mmol). The resulting mixture is allowed to stir at room temperature for 18 h, heated to 70° C. for 6 h, and then stirred at room temperature for an additional 18 h. The solvent is removed in vacuo and the residue is partitioned between EtOAc (400 mL) and water (350 mL). The water layer is back extracted with EtOAC (300 mL), the organic layers are combined, washed with brine (1×200 mL), dried over Na2SO4, filtered and the solvent removed in vacuo. The residue is purified by BIOTAGE® Silica gel chromatography on a 300 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 45% EtOAc/CH2Cl2 over 8 column volumes to give 3.5 g (17%, 2 steps) of the title compound as a tan solid. LC/MS (Condition A): ret. T=2.66 min, (M+Na) 265.09. 1H NMR (500 MHz, chloroform-d) δ ppm 9.73 (1 H, s), 7.86 (1 H, s), 4.05 (2 H, s), 1.49 (9 H, s).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10](I)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C@@:20]12[O:28][CH2:27][O:26][N:22]([CH2:23][C@H:24]1[CH3:25])[C:21]2=[O:29].C(=O)([O-])[O-].[K+].[K+].N>CN1CCCC1=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:22]2[CH2:23][C@:24]3([O:26][CH2:27][O:28][C@@:20]3([CH3:19])[C:21]2=[O:29])[CH3:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(I)nc1Cc1ccccc1
Reactant: C[C@@H]1CN2OCO[C@@]1(C)C2=O
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCOc1ccc(N2C[C@@]3(C)OCO[C@@]3(C)C2=O)nc1Cc1ccccc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 54.5 %

Procedure:
3.6 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine (Production Example 12), 1.5 g of (3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinone synthesized by a method known in literature (J. Org. Chem., 1969, 34, 675), 1.1 g of cuprous iodide and 3.3 g of potassium carbonate were suspended in 20 ml of 1-methyl-2-pyrrolidinone, followed by heating stirring at 140° C. for 20 minutes in an oil bath in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate anhydride and the solvent was removed. The residue was subjected to silica gel column chromatography using 20-50% ethyl acetate/hexane as an eluent for separation and purification, to give 2 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][C:30]([CH:32]=[CH2:33])=[CH:31][C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][C:30]([CH2:32][CH3:33])=[CH:31][C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=Cc1ccc2c(c1)CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc2c(c1)CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of the product of example 164 (100 mg) and Pd-C (20 mg) in ethanol(2 ml) stirred under a hydrogen balloon at room temperature for 1 hour. The mixture was filtered through the celite and distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with chloroform-methanol (15:1) to give the titled compound (50 mg).
Reaction SMILES: [CH2:1]([OH:5])[C:2](=[CH2:4])[CH3:3].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].N1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][C:7](=[O:8])[O:5][CH2:1][C:2]([CH3:3])=[CH2:4])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: C=C(C)CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methallyl alcohol [CAS No. 513-42-8] (5 g) and 4-nitrophenyl chloroformate [CAS No. 7693-46-1] (12.6 g) were dissolved in THF (70 mL), and pyridine (6.69 mL) was added to the resulting mixture under ice-cooling, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture, ice and saturated aqueous ammonium chloride solution were added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (10.5 g).
Reaction SMILES: [C:1]1([C:7]([S:13][CH:14](O)[C:15]([O:17][CH3:18])=[O:16])(O)[C:8]([O:10]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC)(=O)[C:21](OC)=[O:22].[Na]>>[OH:22][C:21]1[C:8]([OH:10])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(O)SC(O)(C(=O)OC)c1ccccc1
Reactant: COC(=O)C(=O)OC
Agent: [Na]
Product: COC(=O)c1sc(-c2ccccc2)c(O)c1O
Yield: 43.4 %

Procedure:
Prepared by the method described in Example 15 from dimethyl α-phenyl-thiodiglycolate (9.0 g, 35 mmoles), dimethyl oxalate (6.1 g, 52 mmoles) and sodium (2.5 g, 109 mmoles). The product is obtained as a beige powder (3.8 g); mp 143°-144° C.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C(O)C>O.[OH-].[Na+]>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1cccs1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N=C(NCc1cccs1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide and 3.39 g. of 2-(aminomethyl)thiophene in 25 ml. of absolute ethanol is heated under reflux for 16 hours, diluted with water and excess 10N sodium hydroxide is added. After standing, crystallization occurs, and filtration gives 3.50 g. of nearly colorless crystals. Recrystallization from aqueous ethanol gives the desired product as colorless crystals, m.p. 135°-137° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].BrC[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]([O:21][CH2:22]C)=O)[CH:10]=1.Cl>CO.O>[CH3:22][O:21][CH2:19][C:11]1[N:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=[C:9]([C:1]([OH:2])=[O:4])[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCc1cc(C(=O)O)nc(C(F)(F)F)n1
Reaction time: 2 h

Procedure:
Potassium carbonate (1.2 g, 8.7 mmol) was added to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.65 g, 1.2 mmol, prepared in the manner outlined in Example 47, Step A) in methanol (10 mL). After stirring for 2 hours, the reaction was then treated with 1N HCl to achieve pH 4, was diluted with water and extracted with six portions of 10% isopropanol in chloroform. The combined extracts were dried over sodium sulfate and concentrated to afford product as an oil which was used without further purification (0.25 g, 88%). 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 4.74 (s, 2H), 3.58 (s, 3H); LCMS (M+H)+: 237.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C=O>[N:15]([CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc2[nH]cc(CCCBr)c2c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCc1c[nH]c2ccc(F)cc12
Yield: 91 %

Procedure:
A solution of 3-(3-bromopropyl)-5-flouro-1H-indole (0.95 g, 3 mmol) and sodium azide (0.59 g, 9 mmol) in anhydrous dimethyl formamide is stirred at 60° C. for 18 h, poured into water and extracted with methylene chloride. The extracts are combined, washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to afford the title product as a clear oil, 0.98 g (91% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Mg+2].[Cl-].[Cl-].O>CN(C)C(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:14]=[CH:15][C:16]([C:19]3[NH:24][N:23]=[N:22][N:20]=3)=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 150 °C

Procedure:
The product from Example 4A (300 mg, 1.08 mmol) in N,N-dimethylacetamide (10 mL) was treated with NaN3 (0.7 g, 10.8 mmol) and MgCl2 (1.03 g, 10.8 mmol). The mixture was heated at 150° C. for 16 hours, allowed to cool to room temperature, and poured into H2O (50 mL). The mixture was filtered and the filter cake air-dried to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 1.29 (s, 9H); MS (ESI+) m/z 322 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](O)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:54][CH:55]([F:66])[O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][NH2:62])=[CH:59][C:58]=1[F:65]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:29])[NH:62][CH2:61][C:60]2[CH:63]=[CH:64][C:57]([O:56][CH:55]([F:54])[F:66])=[C:58]([F:65])[CH:59]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1ccc(OC(F)F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)F)c(F)c2)C1
Yield: 109.2 %

Procedure:
To a solution of the compound (1.83 g) obtained in Example 783, Step 2 in N,N-dimethylformamide (10 ml) were successively added, with stirring under ice-cooling, 1-hydroxybenzotriazole hydrate (677 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (847 mg) and a solution of 4-difluoromethoxy-3-fluorobenzylamine (806 mg) in N,N-dimethylformamide (3 ml). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (2.76 g).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[N:10]=[C:9](Cl)[N:8]=[C:7]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:6]=1.O>C(O)C>[Cl:4][C:5]1[N:10]=[C:9]([NH:3][CH2:1][CH3:2])[N:8]=[C:7]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:6]=1
Reactant: CCN
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Solvent: CCO
Solvent: O
Product: CCNc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 12 h

Procedure:
15 g of a 70% aqueous ethylamine solution is added to 28.9 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (prepared according to Example 1) in 250 ml of ethanol at room temperature. The temperature climbs rapidly to about 35°. The mixture is subsequently stirred at 55° for 12 hours, 25 ml of water are added and the mixture is cooled to 5°. The resulting precipitate is filtered off, washed with 200 ml of water and dried. 2-Chloro-4-ethylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained by crystallization from acetonitrile as colorless crystals having a melting point of 148°.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:34]=2)[N:31]=1.O>N1C=CC=CC=1>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([N:32]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1nc2ccc(Cl)nn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 38.8 %

Procedure:
563 mg of 4-(diphenylmethoxy)-1-piperidinepropanamine and 442 mg of tert-butyl (6-chloro[1,2,4]triazolo[1,5-b]pyridazin-2-yl)carboxylate were dissolved in 5 ml of pyridine, followed by stirring at 80° C. for 13.5 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized by the addition of ethyl acetate, collected by filtration, washed with ethyl ether and dried to yield 365 mg of the title compound.
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4]>>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:4])=[O:1])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
From N-Boc-D-cHyp(Tosyloxy)-OMe (5.27 mmol, 2.50 g), powdered KOH (13.2 mmol, 0.74 g), and 4-nitrophenol (13.2 mmol, 1.83 g), held at reflux for 6 days, the 4-nitrophenyl ether of D-trans-hydroxyproline methyl ester (0.39 g, 20%, m.p. 154-155° C.) was obtained after purification by column chromatography (silica gel, ethyl acetate/hexane mixtures). Impure fractions (1.14 g) accounted for the low yield relative to L-hydroxyproline derivatives above. Elemental analysis for C17H22N2O7: Calculated C, 55.74; H, 6.05; N, 7.65. Found: Calculated C, 55.71; H, 6.08; N, 7.69.
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]2[C:27]([CH2:28][OH:29])=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[CH2:31]O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)Cl>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:21][CH:22]([C:23]3[CH:24]=[CH:25][C:26]([OH:30])=[C:27]([CH2:28][OH:29])[CH:31]=3)[O:2][CH2:1]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1ccc(O)c(CO)c1CNCCCCCCOCCCCc1ccccc1
Reactant: C=O
Solvent: ClCCl
Product: OCc1cc(C2CN(CCCCCCOCCCCc3ccccc3)CO2)ccc1O

Procedure:
With stirring, 0.18 ml 36.5% aqueous formaldehyde are added at room temperature to a suspension of 0.589 g of (RS)-α1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-4-hydroxy-1,3-dihydroxymethylbenzene (racemic mixture of R- and S-enantiomers) in 14 ml of methylene chloride. The mixture is stirred for 1 hour, diluted with methylene chloride and stirred for 14 hours at room temperature. The solution is washed with water (2×10 ml), dried over magnesium sulfate and concentrated by evaporation at 20 mbar and 30° C. The residue is dried at 0.1 mbar at 30° C. for 4 hours, giving the racemate of (SR)-3-[6-(4-phenylbutoxy)hexyl]-5-(4-hydroxy-3-hydroxymethylphenyl)oxazolidine in the form of a crystalline powder; m.p. 72°-75° C. [1H-NMR (400 MHZ, CD2Cl2)]: identical with the spectrum of the compound of Example 1.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([NH:26][NH2:27])[N:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:2](=[O:4])[NH:27][N:26]=[C:24]3[CH:25]=2)=[CH:18][CH:19]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)ncn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)ncn12
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of triphosgene (2.86 g, 9.66 mmol) in THF (10 mL) at room temperature under argon was added a suspension of 4-(4-chlorophenyl)-6-hydrazinylpyrimidine (825 mg, 3.22 mmol) in THF (10 mL). The reaction mixture was stirred overnight. Analysis by HPLC/MS indicated that no starting material remained. Solvent was removed under reduced pressure and water (50 mL) was added. After stirring for 30 min, the solid precipitate was collected and further washed with water (3×10 mL), then methanol (3×5 mL). The title compound (793 mg) was obtained as an off-white solid. HPLC/MS: retention time=2.74 min, [M+H]30 =247.