Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH3:10])[CH2:3][NH:4][CH2:5][C:6]([OH:8])=[O:7].S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[CH3:15][O:7][C:6](=[O:8])[CH2:5][NH:4][CH2:3][CH:2]([OH:1])[CH2:9][CH3:10]
Reactant: CO
Reactant: CCC(O)CNCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCC(O)CNCC(=O)OC
Product: Cl
Reaction time: 8 h

Procedure:
2.85 g of (2-hydroxybutylamino)acetic acid in 100 ml of methanol are cooled in an ice-acetone cooling bath, then 7.27 ml of thionyl chloride is added dropwise within 20 minutes. The reaction mixture is left overnight to come back to ambient temperature and then evaporated to dryness. Methanol is added several times to the residue and this is then concentrated by evaporation. The crude product is reacted further without any more purification. Yield: 3.83 g (100% of theory); Rf value: 0.85 (reversed phase ready-made TLC plate (E. Merck), methanol/5% sodium chloride solution=6:4); mass spectrum (ESI+): m/z=162 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([S:23][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(3-bromopropoxy)-3,4-dihydro-carbostyril (m.p. 111°-118° C.) and thiophenol.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[NH2:20].C(O)(=O)C.C([BH3-])#N.[Na+].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO.O1CCCC1>[CH2:29]([NH:20][C@H:3]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([CH2:18][CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:9][CH2:8]3)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](N)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCc3ccccc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5α-Androstan-17β-amine (10.946 g), glacial acetic acid (2.39 g), sodium cyanoborohydride (0.50 g), benzaldehyde (0.84 g) and tetrahydrofuran (50 ml) were added to methanol (25 ml). The resulting mixture was stirred at room temperature for 48 hours. Excess solvent was removed under reduced pressure. Water was added and made basic (pH 9) with 50% aqueous NMaOH. The mixture was extracted with ether (3X). The combined extracts were dried, filtered and concentrated to a solid. The solid was mixed with 20 g of flash silica gel and dissolved in ethyl acetate. The solvent was removed at reduced pressure and the silica gel was poured on top of the chromatographic column. The compound was eluted with 5% triethylamine-ethylacetate. 6 fractions (200 ml) were collected. An oil was obtained and was dissolved in hot methanol. The solution was cooled giving colorless crystals, mp 85.5°-87.5° C. (PLA2, diabetes)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33](Cl)=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1>CC(N(C)C)=O.C(OCC)(=O)C>[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCOC2)c1
Yield: 82.5 %

Procedure:
A solution of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (2.5 g, 10.5 mmol), potassium carbonate (2.9 g, 21.0 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (2.9 g, 12.6 mmol) in DMA (25 mL) was heated at 120° C. for 5 hours. The solution was diluted with ethyl acetate (150 mL), washed with water (3×50 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with 20-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (3.75 g). 1H NMR δ (CDCl3): 2.13-2.29 (m, 2H), 2.38 (quin, 2H), 3.85-4.04 (m, 4H), 3.90 (s, 3H), 4.19-4.37 (m, 4H), 4.96-5.00 (m, 1H), 6.91 (t, 1H), 7.42-7.45 (m, 2H), 8.14 (d, 1H), 8.25 (d, 1H); m/z 433 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[N+:13]([O-:15])=[O:14].[CH2:16]([O:18][C:19]([P:24]([O:27][CH2:28][CH3:29])([CH3:26])=[O:25])([O:21][CH2:22][CH3:23])[CH3:20])[CH3:17].C(=O)=O.CC(C)=O.C([Li])CCC.CCCCCC>O1CCCC1>[CH2:22]([O:21][C:19]([P:24]([CH2:26][CH:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:12][N+:13]([O-:15])=[O:14])([O:27][CH2:28][CH3:29])=[O:25])([O:18][CH2:16][CH3:17])[CH3:20])[CH3:23]
Reactant: Cc1ccc([N+](=O)[O-])cc1/C=C/[N+](=O)[O-]
Reactant: CCOC(C)(OCC)P(C)(=O)OCC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C)(OCC)P(=O)(CC(C[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1C)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Adapting literature known protocols (U.S. Pat. No. 8,344,028; and Baylis, Tetrahedron Lett., 1995, 36(51), 9385-9388), 2-[1-[(1,1-diethoxyethyl(ethoxy)phosphoryl)-methyl]-2-nitro-ethyl]-1-methyl-4-nitro-benzene (19b) is prepared from 1-methyl-4-nitro-2-[(E)-2-nitrovinyl]benzene (19a) through 1,4-conjugate addition of lithiated commercial 1-[1-ethoxy-1-(ethoxy(methyl)phosphoryl)ethoxy]ethane (Baillie, et al., U.S. Pat. No. 4,339,443 (1982). To a solution of [1-ethoxy-1-(ethoxy(methyl)phosphoryl)ethoxy]ethane (2.65 mL, 2.69 g, 12.0 mmol) in anhydrous tetrahydrofuran (THF) (15 mL) and under a nitrogen atmosphere and at a temperature of about −78° C. (dry ice/acetone bath) is dropwise added a solution of n-butyllithium (nBuLi) in hexane (12.0 mL, 12.0 mmol). After about 30 min, the solution of the lithiated compound is added via a cannula within about 5 minutes to a cooled solution (−78° C.; dry ice/acetone bath, nitrogen atmosphere) of (19a) (2.08 g, 10.0 mmol) in anhydrous tetrahydrofuran (THF) (15 mL). The reaction is stirred at this temperature for about 30 minutes followed by gradual warming to about 0° C. (ice/water bath). Stirring is continued at this temperature for another 30 minutes. Aqueous work-up and purification by silica gel column chromatography using ethyl acetate (EtOAc) and hexanes mixtures afford the title compound (19b).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14](O)=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([Cl:20])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(CC(=O)O)c(=O)oc2cc(N)ccc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(CC(=O)Cl)c(=O)oc2cc(N)ccc12

Procedure:
The reaction was carried out in a 500 ml two-necked reaction flask, containing 50 ml toluene, 7-amino-4-methylcoumarin-3-acetic acid (prepared as per Example 1 above), 699 mg (3 mmol) and thionyl chloride, 0.278 ml (446 ng, 3.75 mmol, BDH Chemicals, U.K.). Nitrogen was passed through the mixture during the reaction. The mixture was refluxed for 2 hours on an oil bath (temperature 130°-150° C.). The solvent was removed by rotatory evaporation and the precipitate was dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Product: O=C(NCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol using methods similar to Example 563 to provide a grey solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.79 (m, 8 H), 2.21 (t, J=6.31 Hz, 2 H), 2.82-2.87 (m, 1 H), 3.20-3.24 (m, 2 H), 3.37 (t, J=7.23 Hz, 2 H), 3.45-3.56 (m, 4 H), 4.17-4.25 (m, 3 H), 4.26-4.32 (m, 1 H), 7.09-7.15 (m, 2 H), 7.35-7.40 (m, 2 H), 7.86 (s, 1 H), 8.53 (s, 1 H), 10.29 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[CH2:36]([N:38]([CH2:46][CH3:47])[C:39]1C=CC=C[C:40]=1[NH2:45])[CH3:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:45][CH2:40][CH2:39][N:38]([CH2:46][CH3:47])[CH2:36][CH3:37])=[S:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: S=C(Cl)Cl
Reactant: CCN(CC)c1ccccc1N
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 6.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, N,N-diethylphenylenediamine (50 mg) was added to thereto, and the mixture was further stirred at room temperature for 14 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (5 mg, yield 5%).
Reaction SMILES: C[Si](C)(C)Cl.[SH:6][C:7]1N(C)N=NN=1.[CH2:13]([N:15]([CH:19]([CH3:21])C)[CH:16]([CH3:18])C)C.CN(C)C=[O:25]>C(OCC)(=O)C>[S:6]1[C@@H:16]2[CH2:18][C:13](=[O:25])[N:15]2[CH2:19][CH:21]=[CH:7]1
Reactant: Cn1nnnc1S
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2SC=CCN12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.049 ml (0.388 mmol) of trimethylchlorosilane, 0.585 g (5.05 mmols) of 5-mercapto-1-methyltetrazole and 0.935 ml (5.43 mmols) of N-ethyl-N,N-diisopropylamine are added to a solution of 2.93 g (3.82 mmols) of 7β-(D-α-tert.butoxycarbonylamino-α-phenyl-acetylamino)-3-(p-toluenesulphonyloxy)-3-cephem-4-carboxylic acid diphenylmethyl ester in 11 ml of dimethylformamide. The red-brown solution is stirred for 16 hours at room temperature under nitrogen, diluted with ethyl acetate and purified by shaking with water, saturated aqueous sodium bicarbonate solution, 1 M sulphuric acid and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated in vacuo. After drying the residue in a high vacuum, a mixture consisting of 7β-(D-α-tert.butoxycarbonylamino)-α-phenyl-acetylamino) 3-(1-methyl-5-tetrazolylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester and the corresponding isomeric 2-cephem compound results and shows 2 spots in a thin layer chromatogram: silica gel (toluene/ethyl acetate, 2:1): Rf=0.13 (3-cephem compound); Rf=0.07 (2-cephem compound); IR spectrum of the crude product (CHCl3): characteristic bands at 3400, 1780, 1730-1690 (broad), 1495 and 1370 cm-1.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]([O-:10])([O-])=[O:8].[K+].[K+].C(O)(=O)[CH2:14][C:15]([CH2:20]C(O)=O)([C:17](O)=O)O>O.CO>[C:15]([O:10][C:7]([NH:1][C@H:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:8])([CH3:20])([CH3:17])[CH3:14]
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a suspension of D-alanine (1 g, 11.22 mmol) in water (5.6 mL)/MeOH (2.80 mL) (2:1) K2CO3 (1.55 g, 11.22 mmol) was added at 0-5° C., followed by a solution of Boc2OO (2.61 mL, 11.22 mmol) in MeOH (2.80 mL) over 5 min. The resulting suspension was stirred for 23 h at rt. The reaction mixture was poured into water and acidified to pH=3 with aqueous citric acid solution. The white cloudy solution was extracted with DCM (3×). Organic layers were combined, washed with brine, dried over MgSO4, filtered and the solvent removed to yield 1.78 g, 9.43 mmol (R)-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [OH-:1].[Ba+2:2].[OH-].[C:4](=[O:6])=[O:5].[I:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[Na+]>>[I:7]([O-:10])(=[O:9])=[O:8].[Ba+2:2].[I:7]([O-:10])(=[O:9])=[O:8].[I:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[Ba+2:2].[I:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[C:4](=[O:1])([O-:6])[O-:5].[Ba+2:2]
Reactant: [OH-]
Reactant: O=C=O
Agent: [Ba+2]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: O=C([O-])[O-]
Product: [O-][I+2]([O-])[O-]
Reaction time: 0.5 h

Procedure:
The diol 16-mer (1 nmol.) is dissolved in sodium metaperiodate solution (20 ul, 20 mM, pH 4.5) and allowed to stand at room temperature for 30 min. Barium hydroxide (3.3 ul of a 150 mM solution) is added and the solution cooled on ice for 5 min. A small crystal of dry ice is then added and the solution is vortexed and centrifuged. The supernatant (22 ul) containing aldehyde 16-mer is removed, leaving behind the precipitate of barium iodate, barium periodate, and barium carbonate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:12]([CH2:13][C:14](=[O:18])[NH:15]OC)[N:11]=[C:10]([N+:19]([O-:21])=[O:20])[N:9]=1)=[O:7].N(CCO)[CH2:23][CH2:24][OH:25].[O:29]1CCO[CH2:31][CH2:30]1>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:12]([CH2:13][C:14](=[O:18])[N:15]([CH2:31][CH2:30][OH:29])[CH2:23][CH2:24][OH:25])[N:11]=[C:10]([N+:19]([O-:21])=[O:20])[N:9]=1)=[O:7]
Reactant: COCCNC(=O)c1nc([N+](=O)[O-])nn1CC(=O)NOC
Reactant: OCCNCCO
Reactant: C1COCCO1
Product: COCCNC(=O)c1nc([N+](=O)[O-])nn1CC(=O)N(CCO)CCO

Procedure:
To 530 mg of 1-methoxycarbamoylmethyl-3-nitro-1,2,4-triazole-5-carboxylic acid methoxyethylamide dissolved in 3 ml of dioxane is added 1 g of diethanolamine.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1([Li])C=CC=CC=1.C1CCCCC1.C(OCC)C>C(OCC)C>[C:8]1([CH2:14][N:15]2[CH2:16][CH2:17][NH:18][CH:19]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:20]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1cccnc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: c1ccc(CN2CCNC(c3cccnc3)C2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of 5.0 g (0.0515 mol) of 3-fluoropyridine and 43.5 ml of 1-(phenylmethyl)piperazine in 300 ml of anhydrous diethylether was added dropwise, at boiling temperature, within 2.5 hours, 56 ml (0.112 mol) of a 2 molar solution of phenyl-lithium in a cyclohexane-diethylether mixture (7/3 v/v) and the resulting mixture was then kept at reflux temperature for a further 4 hours. The crude reaction product obtained as an oil after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM1/cyclohexane (7/3 v/v) as eluant. 12.0 g (92% of theory) of a colourless oil were obtained, Rf 0.52 (FM4; Macherey-Nagel, POLYGRAM® SIL G/UV254 Pre-coated plastic sheets for TLC).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.O1CCC[CH2:43]1>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH:31]([CH3:32])[CH3:43])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(CC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-ethylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (392 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-isopropylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (229 mg) as yellow crystals.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)[OH:4].[Na+].[Na+].[Na+].[C:17]([OH:38])(=[O:37])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33]CCC>C(O)C>[OH:4][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][C:17]([OH:38])=[O:37]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)C=CC=CCC=CCCCC(=O)O
Reaction time: 0.17 h

Procedure:
Eight ml of blood was gathered from the abdominal aorta of a rat (JcI: Wistar, male, 12-15 weeks age) subjected to abdominal incision under anesthesia by the use of 3.2% sodium citrate (1 volume of sodium citrate solution to 9 volume of whole blood). The blood was centrifuged at 800 rpm for 10 minutes at room temperature to gather PRP (platelet rich plasma), and the residual blood was further centrifuged at 3000 rpm for 10 minutes to gather PPP (platelet poor plasma). The platelet number in PRP was measured and the PRP was adjusted by diluting with PPP so that the concentration of platelet was one million/μl. To 0.25 ml of the PRP, 125 μg of arachidonic acid and the test compound (the final concentration of 100 μM, 10 μM, 1 μM and 0.1 μM) were added, and the mixture was incubated at 37° C. for 15 minutes. After the reaction, 1.1 ml of ethanol was added, well shaken and centrifuged at 2000 rpm for 10 minutes to separate the supernatant. To 1 ml of the supernatant 1 ml of water was added and subjected to high performance liquid chromatography to determine HHT. The absorption at 240 nm due to HHT was measured by an ultraviolet absorption monitor. The inhibition rate of HHT formation calculated from the peak area is shown in Table 2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][NH2:11].[OH-].[Na+].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]1>C(#N)C.O>[CH3:9][C:4]1[N:5]=[C:6]([NH:11][CH3:10])[N:7]=[C:2]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)[N:3]=1
Reactant: CN
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(C)nc(N2CCC(C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
2,4-dichloro-6-methyl-1,3,5-triazine (5 g, 31 mmol) was dissolved in a 1:1 mixture of acetonitrile and water and treated with an aqueous solution of methyl amine (0.88 mL, 31 mmol) at a low temperature maintained by immersing the reaction flask in an ice bath. The pH of the reaction mixture was adjusted to 9-10 with 1M NaOH and the reaction was stirred for 30 minutes. Then, 4-piperidinecarboxylic acid (5 g, 39 mmol) was added and the pH was maintained between 9 and 10 with additions of 1M NaOH as needed. The reaction was allowed to warm to room temperature and stirred for one hour. The reaction mixture was then concentrated and purified by preparative HPLC to provide 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (31 mmol, 100%) as a white solid. MS (ES) m/e 252 [M+H]+. 1H NMR (400 MHz, methanol-D4) 4.7 (m, 2H), 3.3 (s, 2H), 3.0 (s, 3H), 2.7 (m, 1H), 2.4 (s, 3H), 2.0 (m, 2H), 1.7 (m, 2H)
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(O)=O>ClCCCl>[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C1CN(C2CCC3(CC2)OCCO3)CCO1
Temperature: 12 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Sodium triacetoxyborohydride (382 g, 1.8 mol) was added in one portion to a mixture of 1,4-dioxaspiro[4.5]decan-8-one (200.0 g, 1.28 mol), morpholine (111.4 g, 1.28 mol) and glacial AcOH (73.2 mL, 1.28 mol) in 1,2-dichloroethane (4 L). A slightly exothermic reaction occurred accompanied by increase in temperature by 12° C. Then the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 10% aqueous NaOH (1.8 L) over a period of 20 min. The organic layer was separated, washed with brine (1 L), dried over MgSO4 and concentrated to afford 7 (237.66 g) as white solid. The aqueous layer was extracted with EtOAc (4×300 mL). Combined extracts were washed with brine (1 L), dried over MgSO4 and concentrated to furnish additional portion of 7 (44 g) as an off-white solid. Total yield of 7 (281.66 g, 97%). 1H NMR data identical with the data obtained earlier.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[NH:10][C:11]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:27][N:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:29]=2)[CH2:31][CH2:32]1)=[O:18]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nc2ccccc2[nH]1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nc2ccccc2[nH]1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 11.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1H-benzimidazol-2-ylcarbamate (228 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3.5 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column-chromatography (hexane:ethyl acetate=2:8) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 35.6 mg (11.9%) of the desired product as a solid.