Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:14]([NH2:21])(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(C)C=CC=CC=1>O>[C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:21][C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCCCCC(N)=O
Reactant: O=C1CCCCC1C1=CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC(=O)NC1=C(C2=CCCCC2)CCCC1

Procedure:
2-(1-Cyclohexenyl)cyclohexanone (17.8 g., 0.1 mole), hexanamide (11.5 g., 0.1 mole), 5.0 g. of a highly acidic resin, Amberlyst 15, and toluene (150 ml) are mixed, stirred and heated at reflux for 16 hours. The water formed in the course of the reaction is azeotroped from the reaction mixture. The hot solution is decanted from the Amberlyst catalyst, the catalyst washed with toluene (200 ml.), and the toluene fractions are combined. Pentane (300 ml.) is added to the toluene solution, the mixture chilled in ice and filtered to remove 3.65 g. of unreacted hexanamide. The orange filtrate is stripped to yield 24 g. of crude product, an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:36](Cl)=[O:37]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:36](=[O:37])[C:35]2[CH:34]=[C:33]([Cl:32])[CH:41]=[C:40]([Cl:42])[CH:39]=2)[C@H:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCN[C@H](Cc3ccc4ccccc4c3)C2)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-1-benzyl-3-(2-naphthylmethyl)piperazine (3.23 g) and triethylamine (4.3 ml) in dichloromethane (60 ml) was added a solution of 3,5-dichlorobenzoyl chloride (6.0 g) in dichloromethane (10 ml) at 0° C. After stirring at room temperature for 3 hours, the mixture was quenched with water and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was triturated with a mixture of dichloromethane and hexane to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(2-naphthylmethyl)piperazine.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH2:18]Cl)=O)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[S:30])[NH2:29])[CH2:24][CH2:23]1)=O.[OH-].[K+]>C(O)C.O>[C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[N:29]=[C:28]([N:25]4[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]4)[S:30][CH:18]=3)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)N1CCN(C=O)CC1
Reactant: O=C(CCl)Cc1ccc(S(=O)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(c1ccccc1)c1ccc(Cc2csc(N3CCNCC3)n2)cc1
Yield: 83.7 %

Procedure:
A solution of 14.6 g of 1-(4-phenylsulfinylphenyl)-3-chloroacetone and 8.7 g of 1-formyl-4-thiocarbamoyl piperazine, melting (Kofler) at 228° C., in 250 ml of ethanol at 90%, was boiled for one hour. There was added to the hot solution a solution of 9.3 g of KOH at 85% in 10 ml of water, and the mixture was refluxed for three hours, in order to hydrolyze the formyl protecting group. Then the solvent was evaporated off under reduced pressure, and the oily residue was taken up with 200 ml of a N hydrochloric acid solution. The insoluble matter was extracted with ether. The acid solution was alkalized with K2CO3, and the resulting base was extracted thrice with, each time, 50 ml of chloroform. The chloroform part was washed with water, then the solvent was evaporated off. There was obtained 16 g of 1-[4-(4-phenylsulfinylbenzyl)-2-thiazolyl]piperazine, as raw base, M.P. of its dihydrochloride: 158°-160° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH3:17])([S:15][CH3:16])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:41][C:42]1[N:46]2[C:47](=[O:56])[N:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:49][C:45]2=[CH:44][N:43]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:14][C:13]([S:15][CH3:16])([CH3:17])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:53]1[CH2:52][CH2:51][CH:50]([N:48]2[CH2:49][C:45]3=[CH:44][N:43]=[C:42]([CH3:41])[N:46]3[C:47]2=[O:56])[CH2:55][CH2:54]1)=[O:12]
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Reactant: CSC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CSC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Yield: 74.9 %

Procedure:
To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-3-methyl-3-(methylthio)butanoic acid (T. Fukami et al., J. Med. Chem., 39, 2313 (1996); 1.3 g) and HOBt (1.14 g) in acetonitrile (30 ml) was added WSC (1.42 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (1.43 g), DBU (1.47 ml) and triethylamine (2.2 ml) in acetonitrile (10 ml) was added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound as colorless powder (1.7 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:27])[CH2:7]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(F)cc1

Procedure:
Example 17 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-fluoro-4-isocyanatobenzene (15.5 μl) to give the title compound (0.031 μg). LC-MS (System A): Rt 2.30 mins, Mass Spectrum m/z 421 [MH+].
Reaction SMILES: Cl.[OH:2][CH:3]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:2][CH:3]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:8]1)[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C(O)C1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 2-hydroxy-2-(piperidin-3-yl)acetic acid hydrochloride (1.956 g; 10 mmoles) in 2.7 (w/w) % aqueous sodium hydroxide solution is added 1.72 ml (1.2 equivalents) of benzyloxycarbonylchloride. After 2 hours, the reaction mixture is washed twice with ether, adjusted to pH 1 to 2 with 10% hydrochloric acid, and extracted thrice with methylene chloride. The extract is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to yield 2.650 g of oily 2-hydroxy-2-(1-benzyloxycarbonylpiperidin-3-yl) acetic acid in 90.4% yield.
Reaction SMILES: [CH:1]#[C:2][CH3:3].Cl[C:5]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][N:6]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>[C:1]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[C:2][CH3:3]
Reactant: Clc1ccnc(Cl)n1
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC#Cc1ncccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
Using a high pressure tube, propyne (5 mL) was condensed in a mixture of 2,4-dichloro-pyrimidine (1.71 g, 11.47 mmol), CuI (228 mg, 1.20 mmol), Pd(PPh3)2Cl2 (0.57 mmol), and Et3N (50 mL) at −78° C. The mixture was slowly warmed up and stirred at room temperature for 12 h. After this period, the mixture was quenched with aqueous NH4Cl. The aqueous phase was thoroughly extracted with hexanes. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4; and concentrated under reduced pressure. The residue was purified by silica gel chromatography with 5%-15% EtOAc/hexanes to give 19 (1.64 g, 94%).
Reaction SMILES: [C:1](/[C:3](/[CH3:11])=[C:4](\[O-])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[K+].FC(F)(F)C(O)=O.Cl.Cl.[CH2:22]([O:24][C:25]1[CH:33]=[C:32]([F:34])[C:28]([CH2:29][NH:30][NH2:31])=[C:27]([F:35])[CH:26]=1)[CH3:23]>O1CCOCC1>[NH2:2][C:1]1[N:30]([CH2:29][C:28]2[C:27]([F:35])=[CH:26][C:25]([O:24][CH2:22][CH3:23])=[CH:33][C:32]=2[F:34])[N:31]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]=1[CH3:11]
Reactant: CCOc1cc(F)c(CNN)c(F)c1
Reactant: CCOC(=O)/C([O-])=C(\C)C#N
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(N)c1C
Reaction time: 0.17 h

Procedure:
2.01 g potassium (2Z)-3-cyano-1-ethoxy-1-oxobut-2-en-2-olate (10.9 mmol, 1.0 eq.) were dissolved in dioxane at rt and 1.34 mL trifluoroacetic acid (17.4 mmol, 1.6 eq.) were added within 2 minutes. The slurry was stirred for 10 minutes and 3.00 g (4-ethoxy-2,6-difluorobenzyl)hydrazine dihydrochloride (10.9 mmol, 1.0 eq.) were added. The reaction mixture was stirred at 130° C. for 3 hours. The resulting solid was filtered off and washed rinsed with dioxane. The filtrate was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate three times. The collected organic solutions were washed with brine, dried over a silicon filter, concentrated in vacuo and purified by flash chromatography: 1.10 g (2.42 mmol, 22%) of a 71% pure target compound.
Reaction SMILES: O.[CH:2]([C:4]1[CH:13]=[N+:12]([O-:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:15])=[O:3].[N+:16]([CH3:19])([O-:18])=[O:17]>CO.C(N(CC)CC)C>[OH:3][CH:2]([C:4]1[CH:13]=[N+:12]([O-:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:15])[CH2:19][N+:16]([O-:18])=[O:17]
Reactant: O=Cc1c[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=[N+]([O-])CC(O)c1c[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C

Procedure:
2-Formylquinoxaline-1,4-dioxide hydrate 2 g (0.01 mole) was dissolved in 100 ml of warm methanol. Ten drops of triethylamine were added with stirring and 1.3 g of nitromethane was added incrementally. The heat source was removed and the reaction mixture was allowed to cool to room temperature. The methanol was removed by evaporation and the residue was recrystallized from water, 1 g/75 ml. There was obtained 2-(1-hydroxy-2-nitroethyl)quinoxaline-1,4-dioxide, m.p. 202°-204° C. with decomposition. This compound was dissolved in an excess of warm acetyl chloride. The mixture was heated to boiling for about 30 minutes, then allowed to cool. The solids which separated were isolated by filtration, rinsed with ether and dried. A sample was purified by recrystallization from a mixture of dimethylsulfoxide and methanol (1 g/5 ml/45 ml respectively). There was obtained 2-(1-acetoxy-2-nitroethyl)quinoxaline-1,4-dioxide, m.p. 201°-204° C. It analyzed as follows:
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.O.[CH2:7]([CH:9]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][NH:11][CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:8]>>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][N:11]([CH2:1][CH:3]1[CH2:4][O:5]1)[CH2:10][CH:9]([CH2:7][CH3:8])[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:19]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: ClCC1CO1
Solvent: O
Product: CCCCC(CC)CN(CC(CC)CCCC)CC1CO1
Temperature: 25 °C

Procedure:
A mixture of epichlorohydrin (111 g, 1.2 mol), and water (0.27 g, 0.015 mol) was vigorously stirred at room temperature. Bis(2-ethylhexyl)amine (241.4 g, 1.0 mol) was added slowly by an addition funnel. The mixture was slowly heated to 70° C. and then stirred at 70° C. for 6 hours. The mixture was washed with aqueous potassium carbonate, K2CO3, (20%, 200 ml). Sodium hydroxide, NaOH, (36%, 200 ml) was added to the oil phase and the mixture was stirred at 70-90° C. for 18 hours. The phases were separated and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried over magnesium sulfate, MgSO4, and the solvent removed by rotary evaporation.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([OH:21])[CH:20]=1)[CH:16]=[O:17]>>[CH2:2]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:20]=1)[CH:16]=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOc1cc(C=O)cc(OCCCCCCCCCC)c1

Procedure:
The title compound was prepared according to the method described in Example 9 above from 1-bromodecane and 3,5-dihydroxy-benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]=O.[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:18][NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=1[F:20]
Reactant: O=Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Reactant: Nc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: O=c1c2sccc2nc(CNc2ccccc2F)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine-2-carboxaldehyde (0.435 g, 1.5 mmol), 2-fluoroaniline (0.121 mL, 1.25 mmol), and anhydrous sodium sulfate (2.1 g 15 mmol) in glacial acetic acid (10 mL) was stirred overnight at ambient temperature. Sodium triacetoxyborohydride (0.795 g, 3.75 mmol) was added in one portion and the reaction was stirred for four hours. The reaction was carefully poured into saturated aqueous sodium bicarbonate and repeatedly extracted with methylene chloride. The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The residue was flash chromatographed on silica gel eluting with 2:1 hexane/ethyl acetate. After elution of a 50 mL forerun, 15 mL fractions were collected. Fractions 3-12 were combined and concentrated to afford 0.190 g (39%) of 3-(2-chloro-phenyl)-2-[(2-fluoro-phenylamino)-methyl]-3H-thieno[3,2-d]pyrimidin-4-one as a tan solid which had: mp 175-176° C.; 1H NMR δ 7.84 (d, J=5.5 Hz, 1H), 7.66 (dd, J=1.5, 8 Hz, 1h), 7.53 (sym m, 2H), 7.42 (d, J=5.5 Hz, 1H), 7.37 (dd, J=2, 7 Hz, 1H), 6.97 (ddd, J=1.5, 8, 11.5 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H), 6.63 (sym m, 1H), 6.40 (dt, J=1.5, 9 Hz, 1H), 5.17 (br s, 1H), 3.96 (dd, J=5.5, 17 Hz, 1H), 3.87 (dd, J=5, 17 Hz, 1H). Analysis calculated for C19H13ClFN3OS: C, 59.15; H, 3.40; N, 10.89. Found: C, 58.96; H, 3.41; N, 11.17.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[CH2:5][CH2:6][CH2:7][N:8]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:9](=O)[O:10]C1C=CC=CC=1>C(O)C>[NH2:2][N:3]1[CH2:5][CH2:6][CH2:7][N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]1=[O:10]
Reactant: NN
Reactant: O=C(Oc1ccccc1)N(CCCCl)c1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: NN1CCCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (5.3 mL) was added to a solution of 3-(4-fluorophenylamino)propan-1-ol (2.37 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added to the residue, followed by extraction with ethyl acetate (100 mL). Heptane (100 mL) was added to the resulting extract, and the solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1) to obtain (3-chloropropyl)-(4-fluorophenyl)amine. Triethylamine (5.4 mL) and phenyl chlorocarbonate (1.9 mL) were added to a solution of (3-chloropropyl)-(4-fluorophenyl)amine (2.40 g) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (3.93 g). Hydrazine monohydrate (0.40 mL) was added to a solution of phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (500 mg) in ethanol (10 mL) at room temperature. The reaction solution was stirred at room temperature for one hour, stirred at 60° C. for one hour and heated under reflux for seven hours. Hydrazine monohydrate (0.40 mL) was added to the reaction solution, and the reaction solution was heated under reflux for 13 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 265 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])=[O:15])[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]([CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])[OH:15])[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCN(CC(=O)c1ccccc1Br)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CCCN(Cc1ccccc1)CC(O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The 131.9 g of product obtained in Step 1 are dissolved in 300 ml of methanol and then added dropwise to 39.9 g of sodium borohydride in 300 ml of methanol. The temperature is maintained at 0° C. throughout the period of addition; the reaction mixture is then left at ambient temperature overnight and is subsequently evaporated to dryness, taken up in dichloromethane and washed with water. After concentrating under reduced pressure, chromatography on silica gel (dichloromethane) allows 94 g of expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.N1C=CN=N1.OC1(C=CC=CC1)C(O)=O.[OH:27][CH2:28][C:29]([NH2:32])([CH3:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl.O>[OH:27][CH2:28][C:29]([NH:32][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[O:2][CH3:1])([CH3:31])[CH3:30]
Reactant: COc1ccccc1C(=O)O
Reactant: CC(C)(N)CO
Agent: O=C(O)C1(O)C=CC=CC1
Agent: c1c[nH]nn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
15.2 g (100 mmol) of 2-methoxy-benzoic acid are dissolved in 300 ml of methylene chloride and the solution is stirred with 14.2 g (105 mmol) of 1-hydroxy-benzoic acid triazole×1 H2O and 21.66 g (105 mmol) of N,N-dicyclohexylcarbodiimide at 0° C. The suspension thus obtained is stirred at room temperature for 0.5 hour, cooled to 0° C. again, and a solution of 9.89 g (111 mmol) of 1-hydroxy-2-methyl-2-propylamine and 12.65 g (125 mmol) of triethylamine in 300 ml of methylene chloride is added. The reaction is complete after 1 hour. The reaction mixture is washed with 1M of hydrochloric acid and saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated in vacuo. The crude product is stirred with petroleum ether, filtered off with suction, subsequently rinsed with the solvent and dried under a high vacuum.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][NH:11][CH2:10]1)C1C=CC=CC=1.C(O[C:22](=[O:24])[CH3:23])(=O)C>N1C=CC=CC=1>[C:9]([O:15][CH:14]1[CH:13]([CH2:16][O:17][C:14](=[O:15])[CH3:13])[CH2:12][N:11]([C:22](=[O:24])[CH3:23])[CH2:10][CH:9]1[OH:8])(=[O:8])[CH3:10]
Reactant: OC[C@H]1CNC[C@@H](OCc2ccccc2)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CN(C(C)=O)CC(O)C1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
(3R,4R,5R)-3-Benzyloxy-5-hydroxymethyl4-piperidinol (0.1 g, 0.4 mmol) was dissolved in pyridine (0.5 ml) at 0° C. by and acetic anhydride (0.5 ml) was added dropwise over 1 min. Stirring at room temperature for 20 h and evaporation to dryness gave a crude product which was purified on silica gel using ethanol as eluent (yield 55%). The purified 3-benzyloxy-3-acetoxy-5-acetoxymethyl-1-acetylpiperidine (75 mg) was debenzylated in methanol at room temperature using 10% Pd/C as catalyst. Filtration and evaporation to dryness gave 50 mg of crude 4-acetoxy-5-acetoxymethyl-1-acetyl-3-piperidinol which was dissolved in dry methanol (4 ml) containing 50 μl of a 1% sodium methoxide in methanol. After stirring at room temperature for 4 days the solution was evaporated to dryness to give (3R,4R,5R)-1-acetyl-5-hydroxymethyl-3,4-piperidinediol (Yield: 35 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[C:22]1(=O)[CH:27]=[CH:26][C:25](=[O:28])[CH:24]=[CH:23]1.B(F)(F)F>>[CH3:1][O:2][C:3]([C:4]1[N:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([CH3:19])[CH3:20])=[CH:15][CH:16]=2)[C:22]2[C:27]([C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:21]
Reactant: O=C1C=CC(=O)C=C1
Reactant: COC(=O)/C=C(\Nc1ccc(OC(C)C)cc1)C(=O)OC
Agent: FB(F)F
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12

Procedure:
The sub-title compound was prepared from N-(4-isopropoxyphenyl)aminofumaric acid dimethyl ester (1.57 g, 5.40 mmol), p-benzoquinone (0.60 g, 5.6 mmol) and BF3 etherate (0.83 m L, 5.8 mmol), see procedure in GDR No. 61800 (1967). Yield 1.40 g (71%).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[C:5]([O:9][C:10](=[O:23])[NH:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)([CH3:15])[CH:13]=[O:14])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.[NH4+].[Cl-]>[C:5]([O:9][C:10](=[O:23])[NH:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)([CH3:15])[CH:13]([OH:14])[C:1]#[CH:2])([CH3:6])([CH3:7])[CH3:8]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)C(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Ethynylmagnesium bromide 0.5 M in THF (23.89 mL, 11.94 mmol) was added dropwise to a solution of rac-[1-(3-bromo-phenyl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (1.96 g, 5.97 mmol) in THF (60 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 15 minutes and at room temperature for 30 minutes. The mixture was diluted with NH4Cl (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield rac-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-but-3-ynyl]-carbamic acid tert-butyl ester (2.11 g, 99% yield) as an oil, which was used in the next step without further purification.