Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([O:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45]O)=[CH:41][N:40]=1)[CH2:32][CH2:33][CH3:34]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:45][C:42]1[CH:41]=[N:40][C:39]([O:38][CH2:37][CH2:36][O:35][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:44][CH:43]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCCCOCCOc1ccc(CO)cn1
Product: CCCCOCCOc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1
Yield: 49.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 142 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) and 2-(2-butoxyethoxy)-5-(hydroxymethyl)pyridine (0.30 g) as starting materials, 5-benzyloxy-N-{[6-(2-butoxyethoxy)pyridin-3-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.40 g) was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13]C)=O)[N:2]=1.[NH2:15][NH2:16]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:15][NH2:16])=[O:13])[N:2]=1
Reactant: COC(=O)c1cc2ccccc2cn1
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1cc2ccccc2cn1
Yield: 86 %

Procedure:
To a solution of methyl isoquinoline-3-carboxylate (10 g, 53.42 mmol) in ethanol (100 mL) was added hydrazine (17.1 g). The reaction mixture was refluxed for 30 min and concentrated under high vacuum to remove hydrazine. The resulting residue was triturated with ethanol (20 mL) to give isoquinoline-3-carbohydrazide (8.6 g, 86%). LRMS (M+H+) m/z 188.1.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=[O:9])=[O:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([O:9][C:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH:1]=[O:2])=[O:10])[CH3:13]
Reactant: CCI
Reactant: O=Cc1ccsc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sccc1C=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Formyl-2-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.76 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours and poured into water. The mixture was extracted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 3-formyl-2-thiophenecarboxylic acid ethyl ester (2.91 g). 3-Formyl-2-thiphenecarboxylic acid ethyl ester (1.84 g) in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.45 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 3 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-difluoromethyl-2-thiophenecarboxylic acid ethyl ester (1.58 g). 3-Difluoromethyl-2-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (11 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced ppressure to give 3-difluoromethyl-2-thiophenecarboxylic acid (1.12 g) as crystals.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12](C(=O)C)[CH:11]=[CH:10]2>Cl>[ClH:6].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[C:10]2[CH2:2][C:1]([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: CC(=O)N1C=Cc2cc(Cl)ccc2C1
Agent: Cl
Product: O=C(O)Cc1cncc2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Glyoxylic acid (1.37 g, 9.28 mmol) is added to mixture of 1-(6-chloro-1H-isoquinolin-2-yl)-ethanone [J. Org. Chem, 1980, 45, 1950] (1.44 g, 5.90 mmol) in 6N HCl (24 ml). The reaction is heated at 100° C. for 3 hours, cooled to RT, washed with ether and evaporated to 10 ml volume. After overnight refrigeration, the solid is collected by filtration and dried to afford (6-chloro-isoquinolin-4-yl)-acetic acid hydrochloride. 1H NMR (400 MHz, DMSO) δ: 4.45 (s 2H), 8.18 (d J 9 1H), 8.52 (s 1H), 8.70 (d J 8 1H), 8.83 (s 1H), 9.96 (s 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.Cl[C:14]1[N:19]=[C:18](Cl)[N:17]=[C:16]([Cl:21])[N:15]=1.Cl.[OH-].[Na+].Cl.Cl[CH2:27][CH2:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30]>O>[NH2:12][C:4]1[CH:3]=[C:2]([NH:1][C:18]2[N:17]=[C:16]([Cl:21])[N:15]=[C:14]([NH:34][CH2:33][CH2:32][S:29]([CH:28]=[CH2:27])(=[O:31])=[O:30])[N:19]=2)[CH:7]=[CH:6][C:5]=1[S:8]([OH:11])(=[O:9])=[O:10]
Reactant: NCCS(=O)(=O)CCCl
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CS(=O)(=O)CCNc1nc(Cl)nc(Nc2ccc(S(=O)(=O)O)c(N)c2)n1

Procedure:
18.8 parts of 1,3-diaminobenzene-4-sulfonic acid are dissolved in 100 parts of water under neutral conditions. This solution is added dropwise in the course of 10 minutes to a mixture of 200 parts of ice and water, 18.5 parts of 2,4,6-trichloro-1,3,5-triazine and 10 parts of 37% hydrochloric acid. The reaction mixture is held at pH 1.5 until the condensation has ended by the continuous addition of 2N sodium hydroxide solution. After the addition of 22.9 parts of β-(β-chloroethylsulfonyl)-ethylamine hydrochloride, the temperature of the reaction mixture is gradually raised from 5° C. to 20° C. while the reaction mixture is initially held at pH 6.5 and then at pH 8.0 by the continuous addition of 2N sodium hydroxide solution. After the condensation and elimination reaction has ended, this reaction mixture is used directly for the acid coupling in Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([OH:10])[OH:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O>[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:10])([OH:9])[OH:11])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(P(=O)(O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(P(=O)(O)O)cc1
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a suspension of (4-aminophenyl)phosphonic acid (Aldrich, 0.00058 mol) in water (1.5 mL) was added sufficient sodium bicarbonate to make a clear solution. To the mixture, acetic anhydride (0.2 mL, 0.002 mol) was added and stirred for 0.5 h. Again, acetic anhydride (0.2 mL, 0.002 mol) was added and stirred for 0.5 h. The mixture was let stand at room temperature for 2 h and then concentrated hydrochloric acid (0.5 mL) was added. Fine white needles separated out which were collected by filtration, washed with water and dried to give 0.048 g (38.5%) of the title compound, mp 228° C. (rep. mp 229° C.--Bauer, H. J. Am. Chem. Soc. 1947, 63, 2137-2138).
Reaction SMILES: B.[CH2:2]([O:9][CH2:10][C:11]1[O:16][CH2:15][CH2:14][CH2:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:17].[Na+].OO>O1CCCC1>[CH2:2]([O:9][CH2:10][C@H:11]1[C@H:12]([OH:17])[CH2:13][CH2:14][CH2:15][O:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: C1=C(COCc2ccccc2)OCCC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 1M solution of borane in 29.3 ml of tetrahydrofuran was added dropwise to a solution of 9.00 g of 6-benzyloxymethyl-3,4-dihydro-2H-pyran (prepared as described in Preparation 1) dissolved in 30 ml of tetrahydrofuran at a temperature, whilst maintaining the temperature in the range from -5° C. to 0° C. The reaction mixture was then stirred at room temperature for 3 hours, after which a 10% w/v aqueous solution of sodium hydroxide was added dropwise. 10.8 ml of 30% v/v aqueous hydrogen peroxide were then added, whilst keeping the temperature in the range from 32° to 40° C. The mixture was then stirred for a further 1 hour at room temperature, after which the organic layer was separated, washed wth water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue (10.5 g) was purified by column chromatography through 250 g of silica gel. 8.82 g of the title compound were obtained from those fractions eluted with a 1:20 by volume mixture of ethyl acetate and methylene chloride. It boiled at 130°-135° C. (bath temperature)/1 mmHg (133 Pa).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([OH:25])([C@H:16]([O:18]C1CCCCO1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:25])([C@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 55 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
A mixture of (3R)-2-(2,5-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (43.9 g, 0.124 mol) and PPTS (15.6 g, 62.1 mmol) in EtOH ( 400 ml ) was stirred at 55° C. for 5 hrs. The mixture was was evaporated to remove solvent down to 100 ml. The residue was poured into ice-aqueous NaHCO3 (500 ml). The whole was extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silicagel (CH2Cl2: MeOH=20:1) to give (2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (18.0 g, 54%).
Reaction SMILES: C([O:4][C@H:5]([C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:8]=1)[CH3:6])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:18][C:16]1[CH:15]=[C:14]([C:19]([F:21])([F:20])[F:22])[CH:13]=[C:12]([C:9]2[N:8]=[C:7]([C@@H:5]([OH:4])[CH3:6])[O:11][N:10]=2)[CH:17]=1
Reactant: CC(=O)O[C@@H](C)c1nc(-c2cc(F)cc(C(F)(F)F)c2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](O)c1nc(-c2cc(F)cc(C(F)(F)F)c2)no1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (1S)-1-{3-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-yl)}ethyl acetate (900 mg, 2.83 mmol) in methanol (4 ml) at −15° C. was added an aqueous solution of potassium carbonate (10M, 10 ml). The mixture was stirred for 20 minutes, and the mixture allowed to warm to room temperature, stirring for 1 hour. The mixture was extracted with ethyl acetate (3×20 ml), and the combined organic phase washed with water (10 ml), brine (2×20 ml). Removal of the solvent under reduced pressure provided (1S)-1-{3-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-yl)}ethane-1-ol, which was crystallized from hexane to yield a white solid, LCMS 277.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([O:17][CH2:18][CH2:19][OH:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:20][CH2:19][CH2:18][O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: OCCOc1ccccc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCCOc2ccccc2)cc1
Yield: 87 %

Procedure:
1-Chloro-4-nitrobenzene is reacted in dimethylsulphoxide, in the presence of a base, with ethylene glycol monophenyl ether: 1-nitro-4-(2-phenoxy-ethoxy)-benzene is obtained in 87% yield.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O)=[O:6])[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].[NH2:25][NH:26][C:27]([NH2:29])=[O:28]>CO>[CH2:1]([O:4][C:5]([NH:7][CH:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6])[CH:2]=[CH2:3]
Reactant: NNC(N)=O
Reactant: C=CCOC(=O)NC(C=O)CCC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)NC(C=O)CCC(=NNC(N)=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 207a (2.39 g, 8.8 mmol), in MeOH (20 ml) was added sodium acetate (0.72 g, 8.8 mmol) and semicarbazide (0.98 g, 8.8 mmol) stirred overnight, concentrated and diluted with CH2Cl2 (100 ml), washed with water, dried and concentrated. Flash chromatography (2% MeOH in CH2Cl2) afforded 208a (2.10 g, 73%) as an oil: [α]D20 −21 (c 2.55°, CH2Cl2); 1H NMR (CDCl3) δ9.98 (1H, s), 7.27 (1H, d), 5.8 (1H, m), 5.5 (1H, d), 5.35-5.19 (2H, m), 4.58 (2H, m), 4.14 (1H, m), 2.37 (2H, t), 2.09 (1H, m), 2.0-1.75 (2H, m); Anal. Calcd for C14H24N4O5: C, 51.21; H, 7.37; N, 17.06. Found: C, 50.2; H, 7.3; N, 16.1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH:13][C:14]([NH:16][C:17]1[S:21][N:20]=[C:19]([CH2:22]Cl)[N:18]=1)=[O:15].ClCCl>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH:13][C:14]([NH:16][C:17]1[S:21][N:20]=[C:19]([CH2:22][O:7][CH2:6][CH2:5][O:4][CH3:3])[N:18]=1)=[O:15]
Reactant: COCCO
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCOCc1nsc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 0 °C

Procedure:
Sodium hydride (4 eq, 2.66 mmol, 0.13 g of a 50 wt-% suspension in oil) was suspended in THF (2 mL) and cooled to 0° C. 2-methoxy ethanol (3 eq, 1.99 mmol, 0.15 g) and 15-crown-5-ether (1 drop) were added. 1-(3-Fluorobenzyl)-3-(3-(chloromethyl)-1,2,4-thiadiazol-5-yl)urea (Intermediate XXV) was added and the mixture was stirred over night with temperature allowed to rise to room temperature. Dichloromethane (50 mL) was added. The mixture was washed with water (2×10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material (0.2 g of an oil) was further purified by preparative HPLC to give 0.101 g. 1H-NMR (300 MHz, CD3OD): δ 7.34 (m, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 6.99 (m, 1H), 4.58 (s, 2H), 4.45 (s, 2H), 3.70 (t, 2H), 3.56 (t, 2H), 3.30 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]=[CH:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]4[NH:21][CH2:22][CH2:23][CH2:24][C:25]=4[CH:26]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: COC(=O)C=Cn1ccc2cc(CCc3cc4cccnc4nc3C)ccc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCn1ccc2cc(CCc3cc4c(nc3C)NCCC4)ccc21
Yield: 0.6 %

Procedure:
3-{5-[2-(2-Methyl-[1,8]naphthyridin-3-yl)-ethyl]-indol-1-yl}-acrylic acid methyl ester (230 mg, 6.1 mmol) was stirred in methanol (5 mL) under a hydrogen atmosphere in the presence of 10% palladium on carbon (10% w/w) (20 mg) for 3 days. After removal of solvent, the crude product was purified by flash chromatography on silica gel with methylene chloride/methanol (95/5) to give the title product (14 mg, 6% yield). 1H NMR (CDCl3) δ 7.40 (1H), 7.33 (1H), 7.23 (1H), 7.10 (1H), 7.00 (d, 1H), 6.65 (br, 1H), 6.45 (1H), 4.45 (t, 2H), 3.67 (s, 3H), 3.40 (br, 2H), 2.85 (4H), 2.30 (s, 3H), 2.70 (m, 2H), 1.90 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C23H28N3O2 378.2 (M+H); found 378.3.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH2:10]([NH2:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[K+]>CC(C)=O>[CH2:10]([NH:18][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([NH:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:4]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCCCNc1nc(Cl)nc(NCCCCCCCC)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
37 g (0.2 mol) of cyanuric chloride was dissolved in 80 ml of hot acetone and the solution was rapidly added to 120 ml of ice water (crushed ice:water=1:1) with vigorous stirring. The temperature reached 0° to 5° C. 56.8 g (0.44 mol) of n-octylamine was gradually added dropwise while maintaining the temperature at 10° C. or below. Then, the temperature was raised to 40° C. by heating and the mixture was heated on a water bath for 1 hour. Since the pH of the reaction solution turned into the acid region (pH<2), granules of potassium hydroxide was gradually added to maintain the pH around neutral (the time required was 1 hour). The product deposited in the reaction solution was cooled and separated by filtration. The crystals were thoroughly washed with water and dried. The crude crystals were recrystallized from ethanol to obtain 48 g of Intermediate A having a melting point of 171°-172° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[N:19]=[C:18]([Cl:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc2ccccc2c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 25 g of 2-(1-methyl-5-nitro-2-imidazolyl)-4-quinazolinone and 26.2 g of phosphorus pentachloride in 150 ml of phosphorus oxychloride is boiled for 3 hours and then evaporated in vacuo (12 Torr). The residue is taken up in methylene chloride and stirred with water for one hour at room temperature. The mixture is made alkaline with sodium bicarbonate and extracted by dropwise addition of methylene chloride. The mixture is dried with magnesium sulphate and treated with animal charcoal, filtered and evaporated in vacuo (12 Torr) at 30° C. The residue is mixed with ether, filtered and washed pure with ether to obtain the heading compound, m.p. 178°-181° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(-c2cc(F)cc(F)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of the compound obtained from step b above (0.79 g) in a mixture of ethyl acetate (˜10 mL), 10% Palladium on charcoal (0.2 g) was added and stirred under hydrogen atmosphere at 30 psi for 2.5 hours. The reaction mixture was filtered through a celite pad washed with ethyl acetate and the filtrate was concentrated under reduced pressure to obtain the title compound (0.77 g) as white solid which was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[O:7])[N:4]([CH:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)[C:3]1=[O:27]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]([N:5]1[C:2]([CH3:1])([CH3:28])[C:3](=[O:27])[N:4]1[CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2)=[O:7]
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 4,4-dimethyl-1-[(2-nitrophenyl)carbonyl]-2-(adamantan-2-yl)-1,2-diazetidin-3-one (16.7 mg, 0.0436 mmol) prepared in Example 124 in ethanol-tetrahydrofuran was added with 10% palladium carbon (catalyst amount), and under a hydrogen atmosphere, the resultant was stirred at room temperature for 1 hour. The reaction solution was filtered using celite and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (14.8 mg, 96.1%) was obtained as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][CH:28]([CH3:44])[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]2[O:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36](=[O:42])[C:35]=2[CH:43]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(C)C>[CH3:41][C:38]1([CH3:40])[NH:37][C:36](=[O:42])[C:35]2[CH:43]=[C:31]([O:30][CH2:29][CH:28]([N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH:17]([OH:19])[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][CH:13]=3)[CH3:44])[CH:32]=[CH:33][C:34]=2[O:39]1
Reactant: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)NCc1ccccc1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Solvent: CC(C)O
Product: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)N(Cc1ccccc1)CC(O)COc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 15.4 g of benzyl [4-(2,3-epoxypropoxy)phenyl]ether and 17.0 g of 6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one in 100 ml of isopropanol is refluxed for 24 hours, filtered and concentrated by evaporation. Trituration of the residue with approximately 200 ml of ether results in crystallisation of 1-[N-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylethyl]benzylamino]-3-(4-benzyloxyphenoxy)propan-2-ol having a melting point of 149°-160° (in which the enantiomer pair A is present in greater amount).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7]C[CH2:5][CH2:4]1)=O.S(Cl)([Cl:11])=[O:10].[CH2:13]([Cl:15])Cl>C1(C)C=CC=CC=1>[Cl-:11].[Cl:15][CH:13]=[N+:3]1[CH2:4][CH2:5][O:10][CH2:7][CH2:8]1
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Reactant: O=CN1CCCCC1
Solvent: Cc1ccccc1
Product: ClC=[N+]1CCOCC1
Product: [Cl-]
Temperature: 56 °C

Procedure:
Under dry nitrogen, N-formyl piperidine (124 gm, 1.10 mol), rapidly stirring at -4° C., is treated dropwise over the course of 30 minutes with thionyl chloride (144 gm, 1.21 mol), the temperature being maintained below 0° C. with ice-methanol cooling. The resulting solution is warmed slowly to 56° C. over 80 minutes with the application of vacuum (at about 30 mm). A mixture of methylene chloride 10 ml and toluene (40 ml) is added, and the resulting slurry is concentrated to dryness (37° C., about 30 mm vacuum). This stripping procedure is repeated, and final concentration is accomplished by the application of higher (about 5 mm) vacuum (30°-42° C., 30 min), to yield solid N-(chloromethylene)-morpholinium chloride.