Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:33])[NH:7][C@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O[C:39]([NH:41][C@@H:42]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[C:48]=1[O:57][CH3:58])C(O)=O)=[O:40])(C)(C)C.[C:59]1([CH2:65][CH2:66]C(O)=O)[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>>[CH3:11][CH:9]([CH3:10])[C@H:8]([NH:7][C:6](=[O:33])[C@@H:42]([NH:41][C:39](=[O:40])[CH2:66][CH2:65][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[C:48]=1[O:57][CH3:58])[C:12]([NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:29])[CH3:30])[O:20]1)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:32]
Reactant: O=C(O)CCc1ccccc1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1ccc(C[C@H](NC(=O)CCc2ccccc2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)c(OC)c1OC

Procedure:
The title compound is prepared from {(S)-2-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-propyl}-carbamic acid tert-butyl ester by reiteration of the 2-step (deprotection/coupling) procedure described in example 1 but using (S)-2-(tert-butyloxycarbonyl-amino)-3-(2,3,4-trimethoxy-phenyl)-propionic acid and 3-Phenyl-propionic acid (Fluka, Buchs, Switzerland) as the partners in each coupling reaction (step B, example 1), respectively.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:46](C(OC(C)C)=O)=NC(OC(C)C)=O.N>O1CCCC1.CO.CC(C)=O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][NH:46][C:21](=[O:26])[O:20][CH2:24][C:23]([NH2:22])=[O:25])=[CH:16][CH:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=C1COC(=O)N1
Reactant: OCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)=O
Product: NC(=O)COC(=O)NCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A solution of 1.0 g (4 mmol) of [4-(4-phenyl-1H-imidazol-1-yl)phenyl]methanol, prepared in step 12.1., 0.485 g (4.80 mmol) of 1,3-oxazolidine-2,4-dione and 1.15 g (4.38 mmol) of triphenylphosphine in 16 ml of tetrahydrofuran, cooled by a bath of acetone and ice, is admixed dropwise with 0.80 g (4 mmol) of diisopropyl azodicarboxylate in solution in 2 ml of tetrahydrofuran. The mixture is subsequently warmed to ambient temperature again and stirred overnight. 9 ml of the solution are taken, to which are added 12 ml of a 7N ammonia solution (84 mmol) in methanol. The mixture is left to react overnight, admixed with 4 g of silica and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 95/5 then 93/7 and 90/10 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of methanol and diisopropyl ether, to give 0.429 g of product in the form of white crystals.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1.[N:53]12CCCN=C1CCCCC2>C(OCC)(=O)C.O1CCCC1.CS(C)=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:53][C:4](=[O:7])[O:5][N:46]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:23][CH2:24]2)=[O:18])=[CH:15][CH:16]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)c3ccc(OC)cc3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](C(=O)c3ccc(OC)cc3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[(4-methoxyphenyl)carbonyl]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. 25% Sulfuric acid (5 mL) and ethanol (15 mL) were added to the obtained residue, and the mixture was stirred at 100° C. for 16 hr. The precipitated solid was collected by filtration to give the title compound as a colorless amorphous solid (0.24 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[CH2:4][C:5](=[O:45])[CH2:6][CH:7]([O:37][Si](C(C)(C)C)(C)C)[CH:8]=[CH:9][C:10]1[N:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:12]=[C:13]([C:18](=[O:29])[N:19]([CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[CH:15]([CH3:17])[CH3:16].CCOC(C)=O>CC#N.O>[CH3:1][O:2][C:3](=[O:46])[CH2:4][C:5](=[O:45])[CH2:6][CH:7]([OH:37])[CH:8]=[CH:9][C:10]1[N:11]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:12]=[C:13]([C:18](=[O:29])[N:19]([CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)CC(=O)CC(C=Cc1c(C(C)C)c(C(=O)N(C)Cc2ccccc2C)nn1-c1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CC(=O)CC(O)C=Cc1c(C(C)C)c(C(=O)N(C)Cc2ccccc2C)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxy)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3-oxo-hept-6-enoic acid methyl ester (2.48 g, 3.82 mmol) in MeCN (40 mL) at 25° C. was added HF (2.5 mL of 48% in water). Reaction was stirred at 25° C. for 16 hrs. Subsequently, EtOAc (100 mL) and water (100 mL) were added and the organic layer was separated, dried and concentrated. Product was purified by column chromatography (30%-50% EtOAc-Hex) to afford 7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-5-hydroxy-3-oxo-hept-6-enoic acid methyl ester (2.03 g, 98.0%): MS(APCI+) 536.4 m/z (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].[F:22][C:23]([F:47])([F:46])[C:24]([F:45])([F:44])[C:25]([F:43])([F:42])[O:26][C:27]([F:41])([C:32]([F:40])([F:39])[O:33][C:34]([F:38])=[C:35]([F:37])[F:36])[C:28]([F:31])([F:30])[F:29]>O1CCCC1>[F:37][C:35]([F:36])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:34]([F:38])[O:33][C:32]([F:39])([F:40])[C:27]([F:41])([O:26][C:25]([F:42])([F:43])[C:24]([F:44])([F:45])[C:23]([F:22])([F:46])[F:47])[C:28]([F:31])([F:30])[F:29]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
In a dry box, tetrahydrofuran (THF, 1000 mL) and dimethyl 5-hydroxyisophthalate (42.00 g, 0.20 mol) were added to an oven dry round bottom reaction flask equipped with a stirrer to form a reaction mixture. Potassium t-butoxide (6.16 g, 0.055 mol) was added to the reaction flask. 1,1,1,2,2,3,3-Heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2trifluorovinyloxy)propan-2-yloxy)propane (216 g, 0.50 mol) was then added via the addition funnel to the reaction mixture, and the reaction allowed to stir at room temperature. After 24 hour the reaction was terminated via the addition of 80 mL of 10% HCl. The reaction mixture was concentrated at reduced pressure, diluted with dichloromethane, washed with 10% HCl (2×100 mL) and then with water (2×100 mL), to form an aqueous phase and an organic phase. The separated organic phase was dried over anhydrous sodium sulfate and was then concentrated at reduced pressure to form a crude product. The crude product was purified by column chromatography to give 86.07 g (67.32%) yield of the desired material, dimethyl 5-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)isophthalate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:12])[CH2:10][NH2:11].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH:11][CH2:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][CH:2]=3)[F:12])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: NCC(F)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(F)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-2-fluoroethanamine (0.126 g, 0.606 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.114 g, 0.303 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.0412 g, 0.303 mmol) in DMF (2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0697 g, 0.363 mmol. The reaction was stirred for 16 hours at ambient temperature. It was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was on a Biotage SP1 system eluting with a linear gradient of 5-50% EtOAc in hexanes to yield 161 mg of the title compound (93.8% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:25](=[S:27])=[S:26].Br[CH2:29]Br>CS(C)=O.O>[S:26]1[CH2:29][S:27][C:25]1=[C:11]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:18]
Reactant: BrCBr
Reactant: O=C(Cc1ccncc1)c1cccc([N+](=O)[O-])c1
Reactant: S=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(C(=C1SCS1)c1ccncc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 1-(3-nitro-phenyl)-2-pyridin-4-yl-ethanone (5 g, 20.64 mmol) in dry DMSO (80 mL) under nitrogen atmosphere solid potassium carbonate (8.56 g, 61.92 mmol, 3 eq) was added at room temperature, followed by carbon disulfide (3.73 mL, 61.92 mmol, 3 eq) and dibromomethane (4.35 mL, 61.92 mmol, 3 eq). The reaction mixture was stirred at room temperature for 1 hour and then poured into stirred iced water (600 mL). The orange precipitate was filtered, washed with water and dried at 60° C. under reduced pressure for 1 hour. The crude product was purified by silica gel chromatography (SP1, eluant: n-hexane/ethyl acetate 2:8) to obtain 5.2 g of yellow solid (76%).
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].CC(O)CCCCCC.[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCCC(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 2-octanol was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 100 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.11 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 75.2%) and 10.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.2%) were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:8]3[CH:9]=[C:10]([C:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncnn2c(C3=CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 41 h
Yield: 112 %

Procedure:
To a solution of tert-butyl 4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3,6-dihydropyridine-1(2H)-carboxylate (564 mg, 1.08 mmol) in MeOH (4 mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred at rt for 41 h. The mixture was concentrated and the residue was dissolved in 3:1 CHCl3/isopropanol (25 mL). The mixture was washed with saturated, aqueous NaHCO3 (25 mL), brine, dried (Na2SO4) and concentrated to dryness to afford 510 mg (96%) of the desired product, which contained trace impurities. 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.58 (s, 1 H), 7.92 (s, 1 H), 7.80 (d, 1 H), 7.61 (s, 1 H), 7.27-7.37 (m, 5 H), 7.14 (dd, 1 H), 7.01-7.06 (m, 1 H), 6.75 (s, 1 H), 5.65 (s, 2 H), 3.40-3.48 (m, 2 H), 2.92 (t, 1 H), 2.42-2.49 (m, 2 H); ES-MS m/z 422.06 [M+H]+, HPLC RT (min) 1.03 min.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].C(=O)([O-])OC1C(CCOCCC2C=CC=CC=2)=CC=CN=1.[CH2:35]([O:43][CH2:44][CH2:45][O:46][C:47](N1C=CC=CC1=O)=[O:48])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:47]([O:46][CH2:45][CH2:44][O:43][CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:48])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: O=C(OCCOCCc1ccccc1)n1ccccc1=O
Agent: O=C([O-])O
Agent: O=C([O-])Oc1ncccc1CCOCCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](NC(=O)OCCOCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a stirred mixture of D-threonine (0.15 g, 1.25 mmol) and NaHCO3 (0.16 g, 1.25 mmol) in H2O (3.0 mL), the crude isomeric mixture containing 2-phenethyloxyethyl-2-pyridyl carbonate and 2-phenethyloxyethyl-2-oxopyridine-1-carboxylate (0.54 g, 1.89 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.38 g, 94%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 312 [M−H]+; (ESI) m/z: 310 [M−H]−. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.4 Hz, 3H), 2.81 (t, J=7.1 Hz, 2H), 3.55-3.66 (m, 4H), 3.93 (dd, J=3.4, 8.9 Hz, 1H), 4.00-4.15 (m, 3H), 6.83 (d, J=8.9 Hz, 1H), 7.14-7.32 (m, 5H), 12.20 (s, 1H).
Reaction SMILES: C(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].F[C:16](F)(F)[C:17](O)=O.[NH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1.[OH-].[Na+]>ClCCl.O.C(OCC)C>[CH2:2]([N:22]1[C:23]2=[CH:27][CH2:26][S:25][C:24]2=[CH:23][C:24]2[S:25][CH:26]=[CH:16][C:17]1=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccsc1
Reactant: CCCCCCCCCCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCN1C2=CCSC2=Cc2sccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 263.9 %

Procedure:
A solution of tridecanal (25.00 g, 126.04 mmol) and trifluoroacetic acid (2.00 g) in anhydrous dichloromethane (200 mL) was added dropwise to a solution of 3-aminothiophene (21.00 g, 211.78 mmol) in anhydrous dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at room temperature for 1.5 h. Trifluoroacetic acid (24.15 g, 211.78 mmol) was added and the reaction mixture was then heated at reflux for 24 h. The solution was cooled and diethyl ether (300 mL) and water (100 mL) were added. The aqueous layer was basified with 0.5 N aqueous sodium hydroxide solution. The organic layer was separated. The aqueous layer was again extracted into diethyl ether (2×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (eluent: dichloromethane) afforded 4-dodecyldithieno[3,2-b:2′3′-e]pyridine (16.74 g, 22%) as a red oil: δH(CDCl3, 300 MHz) 7.76 (2H, d, 3JHH=6 Hz), 7.60 (2H, d, 3JHH=6 Hz), 3.15 (2H, t, 3JHH=7.5 Hz), 1.90 (2H, m), 1.25-1.50 (18H, m), 0.88 (3H, t, 3JHH=7.5 Hz); δC(CDCl3, 75 MHz) 155.8, 140.0, 130.3, 129.4, 125.3, 34.5, 31.9, 29.7, 29.6, 29.5, 29.4, 28.0, 22.7, 14.1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([CH3:13])[N:6]2[C:7](=[O:9])[CH:8]=1.ClCC1N(C)N=C(C)N=1.[Cl:23][C:24]1[C:25]([O:47][CH3:48])=[CH:26][C:27]([O:45][CH3:46])=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[CH2:33]2)[CH:29]=1>>[Cl:23][C:24]1[C:25]([O:47][CH3:48])=[CH:26][C:27]([O:45][CH3:46])=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[C:35]([CH2:2][C:3]3[N:4]=[C:5]4[S:12][CH:11]=[C:10]([CH3:13])[N:6]4[C:7](=[O:9])[CH:8]=3)=[C:34]([OH:39])[CH2:33]2)[CH:29]=1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1nc(CCl)n(C)n1
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3cc(=O)n4c(C)csc4n3)C(=O)O2)cc1Cl
Yield: 18 %

Procedure:
The title compound was prepared as described in Example B(53), using 7-(chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 18%.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>O1CCCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[C:14](=[O:15])[N:5]=[C:2]([CH3:3])[N:4]=2)=[CH:18][CH:19]=1
Reactant: CC(=N)N
Reactant: COc1ccc(C(Cl)C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)=NC2=O)cc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 11.8 grams (0.10 mole) of acetamidine hydrochloride in 200 mL of tetrahydrofuran is cooled to about 15° C., and 41.8 grams (0.30 mole) of potassium carbonate is added portionwise. To this is then added portionwise 21.8 grams (0.10 mole) of 2-chloro-2-(4-methoxyphenyl)acetyl chloride. Upon completion of addition, the reaction mixture is stirred for 15 minutes at 15° C., then it is warmed to reflux where it stirred for about four hours. The reaction mixture is then cooled and filtered to collect the by-product potassium chloride. The filtrate is concentrated under reduced pressure, yielding 4-(4-methoxyphenyl)-2-methylimidazol-5-one.
Reaction SMILES: [OH:1][P:2]([OH:5])([OH:4])=[O:3].[NH3:6]>O>[P:2]([O-:5])([O-:4])([O-:3])=[O:1].[NH4+:6].[NH4+:6].[NH4+:6].[NH3:6]
Reactant: O=P(O)(O)O
Agent: N
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [NH4+]

Procedure:
A process for producing solid ammonium phosphates which process comprises reacting in the liquid phase and at a pressure of from -0.1 to +1.5 kg/cm2 in a first stage phosphoric acid containing from 35 to 60% by weight of P2O5 and up to 20% by weight of H2SO4 with gaseous ammonia, the major part of said ammonium gas having been obtained from a source outside the process, so as to produce a fluid ammonium phosphate having an NH3 :H3PO4 molar ratio which varies from 0.1:1 to 1.45:1 and a water content of from 10 to 45% by weight, passing this reaction product from the first stage to a second stage where it is reacted with gaseous ammonia at a pressure of from 0.5 to 3.5 kg/cm2 to form a fluid ammonium phosphate having an NH3 :H3PO4 molar ratio of from 0.95:1 to 1.85:1 and containing from 4 to 20% by weight of water; and discharging this fluid ammonium phosphate into a zone of lower pressure to form a solid ammonium phosphate containing from 2 to 11% by weight of water.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[CH3:15]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH3:15])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3ccccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyridyl)piperazine instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as white crystals.