Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[NH3:12]>CCO>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: N
Solvent: CCO
Product: Nc1cccc(F)c1[N+](=O)[O-]
Temperature: 75 °C
Yield: 85 %

Procedure:
To a solution of 1,3-difluoro-2-nitro-benzene (30 g, 0.188 moles) in EtOH (300 mL) was added 25% aq. ammonia solution (300 mL) and the resulting mixture was heated to 75° C. for 16 h then cooled and concentrated in vacuo. The residue was dissolved in EtOAc, washed with water and brine solution, dried (Na2SO4), filtered and concentrated to afford 25 g (85%) of 3-fluoro-2-nitro-phenylamine (138) as a brown solid which was used without any further purification.
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].CI.[C:17](OCC)(=O)C>O1CCCC1>[CH3:17][CH:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
9.91 Gram (95%, 56.9 mmol) of tert-butyl methyl malonate was dissolved in 120 mL of tetrahydrofuran (THF), and the resulting solution was added dropwise to a suspension containing 2.28 g (60 wt %, 56.9 mmol) of sodium hydride (NaH) and 120 mL of THF at 0° C. over 0.5 hours, followed by stirring for 0.5 hours. Thereafter, a solution containing 8.08 g (56.9 mmol) of methyl iodide (MeI) and 20 mL of TI-IF was added dropwise over 0.5 hours, and the resulting mixture was stirred at 0° C. for 0.5 hours and further stirred at 25° C. for 5 hours. After adding 200 of ethyl acetate, the organic layer was washed, in order, twice with saturated brine and twice with water, and dried over sodium sulfate, and the solvent was concentrated to obtain 13.0 g of 1-tert-butyl 3-methyl 2-methylmalonate as a colorless transparent oil. Subsequently, 45.9 g of an aqueous formalin solution was added to 13.0 g of the oil, and resulting mixture was cooled to 0° C. Furthermore, 7.81 g of potassium carbonate was added, and the mixture was stirred at 0° C. for 1 hour and further stirred at 25° C. for 3 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in order, three times with an aqueous saturated sodium hydrogensulfite solution and twice with water, and dried over sodium sulfate. The solvent was concentrated, and the residue was dissolved in 50 mL of pyridine. The resulting solution was cooled to 0° C., and 21.7 g of p-toluenesulfonyl chloride was added thereto. The obtained mixture was stirred at 0° C. for 2 hours and then stirred at 60° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in order, three times with an aqueous saturated ammonium chloride solution and twice with water, and dried over sodium sulfate. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate=4/1) to obtain 15.8 g of the objective Compound (I-31) as a colorless transparent oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[C:25]3[C:20](=[CH:21][C:22]([C:27]4[N:28]=[N:29][C:30]([O:33]C)=[CH:31][CH:32]=4)=[C:23]([F:26])[CH:24]=3)[CH2:19][NH:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15].Br>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[C:25]3[C:20](=[CH:21][C:22]([C:27]4[CH:32]=[CH:31][C:30](=[O:33])[NH:29][N:28]=4)=[C:23]([F:26])[CH:24]=3)[CH2:19][NH:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COc1ccc(-c2cc3c(cc2F)C(c2ccc(Cl)c(Cl)c2)CNC3)nn1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc(-c2cc3c(cc2F)C(c2ccc(Cl)c(Cl)c2)CNC3)n[nH]1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline, trifluoroacetate salt (20 mg, 0.04 mmol, product of Step B in Example 21) and hydrobromic acid (aqueous, 48%) was heated to reflux for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was purified by semi-preparative HPLC followed by lyophilization to give 4 6-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one, trifluoroacetate salt (16 mg, 80%) as a white solid: 1H NMR (CD3OD, 500 MHz) δ 7.84 (dd, J=9.9, 2.1 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.24 (dd, J=8.3, 2.0 Hz, 1H), 7.04 (d, J=9.9 Hz, 1H), 6.78 (d, J=11.7 Hz, 1H), 4.67-4.49 (m, 3H), 3.81 (dd, J=12.6, 6.0 Hz, 1H), 3.50 (dd, J=11.3, 11.3 Hz, 1H); ESI MS m/z 390 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Si:15]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1NCCCC1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC1CCCNC1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.00 g (38.7 mmol) of 3-hydroxymethylpiperidin-2-one in 40 ml of N,N-dimethylformamide is admixed successively with 3.16 g (46.5 mmol) of imidazole, and dropwise with 11 ml (42.6 mmol) of tert-butyl(diphenyl)silyl chloride. After stirring at RT for 3 hours, the mixture is admixed with approx. 400 ml of water and extracted three times with ethyl acetate. The combined organic extracts are washed successively with saturated ammonium chloride solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture is filtered and the filtrate is freed of the solvent under reduced pressure. The resulting residue is purified by suction filtration through silica gel with 20:1→1:1 cyclohexane/ethyl acetate as the eluent. This affords 9.43 g (66% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[O:16][CH3:17].B(OB=O)=O.[CH2:23]([N:25]([CH2:38][CH3:39])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28]([O:34][CH2:35][O:36][CH3:37])[CH:27]=1)[CH3:24].B(OCCCC)(OCCCC)OCCCC.C(N)CCC>C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:38]([N:25]([CH2:23][CH3:24])[C:26]1[CH:33]=[CH:32][C:29](/[CH:30]=[CH:13]/[C:12](=[O:14])[CH2:11][C:10](=[O:15])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:16][CH3:17])[CH:4]=2)=[C:28]([O:34][CH2:35][O:36][CH3:37])[CH:27]=1)[CH3:39]
Reactant: COc1cc(C=CC(=O)CC(C)=O)ccc1O
Reactant: CCN(CC)c1ccc(C=O)c(OCOC)c1
Agent: CCCCOB(OCCCC)OCCCC
Agent: O=BOB=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCN
Product: CCN(CC)c1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)c(OCOC)c1
Reaction time: 1 h
Yield: 159.5 %

Procedure:
6-(4-Hydroxy-3-methoxyphenyl)hex-5-ene-2,4-dione (20 mg, 0.085 mmol) and boron trioxide (11 mg, 0.16 mmol) were placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring solution at 80° C. was added a solution of 4-diethylamino-2-(methoxymethoxy)benzaldehyde (26 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol) in 0.7 mL of ethyl acetate. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The resulting mixture was diluted with 25 mL of brine, and the solution was extracted with 50 mL of ethyl acetate. The extract was dried over MgSO4, filtered, and concentrated in vacuo to give a crude solid of (1E,6E)-1-[4-diethylamino-2-(methoxymethoxy)phenyl]-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (61.5 mg).
Reaction SMILES: [CH:1]1([C:16]([O:18]CC)=[O:17])[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[OH-].[Na+]>C(O)C.O>[C:12]([O:11][C:9]([N:6]1[CH2:5][CH2:4][C:3]2([CH:1]([C:16]([OH:18])=[O:17])[CH2:2]2)[CH2:8][CH2:7]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C1CC12CCN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2C(=O)O
Temperature: 15 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
To the solution of 165c (500 mg, 1.76 mmol) in ethanol (8 mL) was added sodium hydroxide (212 mg, 5.3 mmol) in water (4 mL). See FIG. 6. The mixture was stirred at 15° C. for 12 h. The solvent was evaporated under reduced pressure. The aqueous solution was acidified with dilute hydrochloride acid (0.5 M) slowly under ice bath until pH˜4, and extracted with EtOAc (10 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid 165d (390 mg, 83%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 3.52-3.42 (m, 3H), 3.38-3.35 (m, 1H), 1.75-1.72 (m, 2H), 1.58-1.56 (m, 1H), 1.46-1.43 (m, 11H), 1.23-1.21 (m, 1H), 1.02-1.01 (m, 1H).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:23])[N:9]3[C:14](=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=2)[C:13]2[S:20][CH:21]=[CH:22][C:12]=2[CH:11]=[CH:10]3)=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:34]1(C)C=CC=C[CH:35]=1>C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:8](=[O:23])[N:9]3[C:14](=[C:15]([C:17]([O:19][CH2:34][CH3:35])=[O:18])[CH:16]=2)[C:13]2[S:20][CH:21]=[CH:22][C:12]=2[CH:11]=[CH:10]3)=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccc(-c3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccc(-c3ccccc3)cc2)c(=O)n2ccc3ccsc3c12

Procedure:
From 8-(biphenyl-4-yl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 in toluene and ethanol.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][NH:11][C:12]([NH2:14])=[S:13].[NH4+].[OH-]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1cccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1nnc(-c2cccnc2)s1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 50.7 %

Procedure:
5-pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine was prepared as described by Turner et al. J. Med. Chem. 1988, 31, 898. Nicotinic acid (30 g, 0.24 mol) was added in portions to polyphosphoric acid (60 mL) under mechanical stirring. After stirring for 5 minutes, thiosemicarbazide (22.2 g, 0.24 mol) was added in portions. The reaction mixture was heated to 90° C. for 6 hours, cooled to room temperature over 14 hours, and re-heated to 40° C. to melt the solid yellow cake. Water was added (50 mL) dropwise via Pasteur pipette while stirring. The solution was cooled to 0° C., NH4OH (29% solution, approx 250 mL) was added dropwise over 2.5 hours to bring the pH to 14. The solids were collected by filtration, washed with water (150 mL) and dried in vacuo at 65° C. for 16 hours to afford the title compound as a beige-colored solid (21.7 g, 50%): mp 201-211° C.; IR (KBr thin film) 1508 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J=2.1 Hz, 1H), 8.62 (dd, J=4.5, 0.9 Hz, 1H), 8.14 (dt, J=8.4, 1.5 Hz, 1H), 7.51 (dd, J=8.1, 1.5 Hz, 1H); ESIMS m/z 179 ([M+H]+).
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.O.S(=O)(=O)(O)O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(Cl)(Cl)Cl>[C:4]1(=[O:13])[N:5]([CH:6]2[CH2:7][CH2:8][C:9](=[O:12])[CH2:10][CH2:11]2)[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reaction time: 3 h

Procedure:
95 g (0.388 Mol) of 4-(phthalimido)-cyclohexanol are dissolved in 600 ml of chloroform and, after the addition of 450 ml of water and 120 ml of sulfuric acid, 90 g (0.3 Mol) of potassium dichromate are added in batches. The internal temperature of the mixture is maintained at between 25° and 30° C. by slight cooling. The mixture is stirred for a further 3 hours, then the chloroform phase is separated off and the mixture extracted twice more with chloroform. After drying and concentration of the extracts 82 g (86.9% of theory) are obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].[O-:34][C:35]#[N:36].[K+]>CN(C)C=O.O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][C:35]([NH2:36])=[O:34])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:26])[F:27])=[N:11]2)=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCN)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethanamine hydrochloride obtained by Example 74 (400 g) and sodium acetate (159 g) was dissolved in a mixture of N,N-dimethylformamide (1.4 L) and water (0.52 L) at 50° C. A solution of potassium cyanate (157 g) in water (520 ml) was added dropwise to the solution over 15 min at 38–40° C. The whole solution was stirred at 50° C. for 2 hrs.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.S([O:16][CH3:17])(OC)(=O)=O.C(#N)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH3:4])[C:17](=[O:16])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cnc(Cl)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cn(C)c(=O)cc1Br
Temperature: 25 °C

Procedure:
A solution of 4-bromo-2-chloro-5-methoxypyridine (1 g, 4.5 mmol) in dimethyl sulfate (1.9 mL, 19.5 mmol) was stirred at 120° C. for 16 h in a sealed tube. After cooling, acetonitrile and a saturated aqueous NaHCO3 solution were added and the mixture was stirred at rt over week-end. DCM was added and extracted. The organic layer was dried (Na2SO4), filtered and concentrated to give the title compound. tR: 0.57 min (LC-MS 2); ESI-MS: 218.0/220.0 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([C:6](=[CH:12][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccccc1)C(=O)OCC
Yield: 68.9 %

Procedure:
A mixture of ethyl 2-butyryl-3-ethoxyacrylate (95 g, 0.4 mol) and aniline (36 ml, 0.4 mol) was heated at reflux for 30 minutes, then cooled, diluted with petroleum ether, and left to crystallise at -20° overnight. Filtration and washing gave ethyl 2-butyryl-3-(phenylamino)acrylate (72 g, 60%) as a mixture of E and Z isomers.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)[CH:32]=[CH:31][C:30]=1[F:47])=[O:27])[CH2:22][C:23]([OH:25])=O)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(N(C)C)=O>[CH2:10]([O:17][C:18]([NH:20][C@H:21]1[CH2:22][C:23](=[O:25])[N:28]([C:29]2[CH:34]=[C:33]([CH2:35][C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39](=[O:46])[NH:38][N:37]=3)[CH:32]=[CH:31][C:30]=2[F:47])[C:26]1=[O:27])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(N[C@H]1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.289 g, 0.9 mmol) and diisopropylethylamine (0.193 g, 1.5 mmol) were added sequentially to a stirred solution of (S)-3-benzyloxycarbonylamino-N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]succinamic acid (0.35 g, 0.68 mmol) in dimethylacetamide (3 ml), the mixture was stirred at ambient temperature for 24 hours, then it was added dropwise to stirred, ice-cold water (30 ml). The mixture was stirred for 1 hour, then the resulting solid was collected by filtration and dried in vacuo to give (S)-3-benzyloxycarbonylamino-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]pyrrolidine-2,5-dione (0.238 g) as an off white solid, m.pt. 121–127° C. (softens 102° C.); m/z (M+H)+. 501, 96% purity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][CH:14]([CH2:15]2)[C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([N:12]1[C:13](=[O:17])[CH:14]2[CH2:15][C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)([CH2:16]2)[C:11]1=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.92 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 70 ml of dimethylformamide and, under a nitrogen atmosphere, 1.2 g of sodium hydride (pract. Fluka) are added. After stirring for 30 minutes at room temperature, the mixture is cooled to 0°, and a solution of 4.5 g of benzyl bromide in 10 ml of dimethylformamide is added dropwise thereto. After the addition is complete, the mixture is stirred at room temperature for 4 hours. The excess sodium hydride is destroyed by the addition of methanol, and concentration by evaporation is effected in vacuo. The residue is taken up in ethyl acetate and washed with water and aqueous sodium chloride solution. After drying over magnesium sulphate, the mixture is filtered and concentrated by evaporation. Melting point 150°-152° (from ether).
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[O:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH2:6]([O:5][P:4]([C:3]([C:1]#[N:2])=[CH:27][CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)(=[O:11])[O:8][CH2:9][CH3:10])[CH3:7]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=CC1CCOCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of diethyl cyanomethylphosphonate (50.0 g, 282 mmol), ammonium acetate (9.0 g, 117 mmol), acetic acid (9 ml) in toluene (200 mL), tetrahydropyran-4-carbaldehyde (32.2 g, 282 mmol) were added. The reaction mixture was stirred at room temperature for two hours and then heated at reflux for 1.5 hours. After cooling down, the reaction mixture was washed with saturated sodium bicarbonate solution three times, and brine one time and then dried over magnesium sulfate. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield [1-cyano-2-(tetrahydropyran-4-yl)-vinyl]-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]([O-:11])=O)[CH:5]=[CH:4][CH:3]=1.[K+].C1C=CC2N(O)N=[N:25][C:23]=2C=1.C(Cl)CCl.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]([NH:25][CH3:23])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])C(c1cccc(Br)n1)N1CCOCC1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)C(c1cccc(Br)n1)N1CCOCC1
Temperature: 25 °C

Procedure:
Potassium (6-bromopyridin-2-yl)(morpholin-4-yl)acetate (533 mg, 1.57 mmol), HOBT (361 mg, 2.36 mmol), EDC (452 mg, 2.36 mmol), and methylamine hydrochloride (318 mg, 4.71 mmol) were taken up in DMF (5.0 mL) and DIEA (0.41 mL, 2.36 mmol) was added. The reaction was maintained at room temperature overnight, then diluted with water, and extracted with 5:1 CH2Cl2:MeOH (2×). The combined organic layers were dried over MgSO4, filtered, and evaporated. Silica gel chromatography (0-10% MeOH/CH2Cl2) yielded the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[CH3:27][O:26][C:24]([N:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1)=[O:25]
Reactant: COC(=O)Cl
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)n1nnnc1-c1cnc2ccccn2c1=O

Procedure:
A mixture of 1.07 g (0.005 moles) of 3-(1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine; 45 ml of dimethylformamide, 0.75 g (0.0055 moles) of anhydrous potassium carbonate and 0.76 ml (0.01 moles) of methyl chloroformate was stirred at 80°-90° C. for 6 hours. The hot reaction mixture was filtered; the crystals precipitating from the filtrate were collected to obtain 0.32 g (23.5%) of the 1:1 ratio mixture of the title compounds, which on crystallization from ethanol gave the 3-(1-methoxycarbonyl-1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, m.p.: 182°-183° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[CH2:27](OC1C(OC)=CC=CC=1C=O)[CH:28](C)C.[Br-].C(OC(C1N2C(SC=C2)=NC=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)C.[H-].[Na+]>CS(C)=O>[CH2:4]([O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[CH:20][S:19]2)[CH:1]([CH3:2])[CH3:3]
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Reactant: COc1cccc(C=O)c1OCC(C)C
Agent: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC)c2OCC(C)C)nc2sccn12

Procedure:
This compound was prepared as described in Intermediate 1 by the reaction of 2-isobutoxy-3-methoxybenzaldehyde (1.328 g, 5.984 mmol) with 5-ethyloxycarbonylimidazo[2,1-b][1,3]thiazol-6-yl-methyl(triphenyl)phosphonium bromide (3.0 g, 5.440 mmol) in the presence of sodium hydride (0.23 g, 5.984 mmol) in anhydrous DMSO (15 mL) to give 1.50 g of product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (d, J=6.9 Hz, 6H), 1.47 (t, J=6.9 Hz, 3H), 2.12-2.23 (m, 1H), 3.75 (d, J=6.6 Hz, 2H), 3.86 (s, 3H), 4.40-4.49 (m, 2H), 6.85 (d, J=7.8 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 7.28-7.33 (m, 1H), 7.76 (d, J=16.2 Hz, 1H), 8.03 (d, J=16.2 Hz, 1H), 8.07-8.11 (m, 1H); APCI-MS (m/z) 399.09 (M−H)−.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:18]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:19]=[C:20]([CH3:22])[CH:21]=1)=[O:4].[OH-].[Li+]>>[CH:14]1([CH2:13][S:10]([C@H:8]2[CH2:7][N:6]([C:17]3[N:18]([CH2:23][C:24]([F:27])([F:25])[F:26])[N:19]=[C:20]([CH3:22])[CH:21]=3)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:11])=[O:12])[CH2:15][CH2:16]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)CC3CC3)C[C@H]2C(=O)O)n(CC(F)(F)F)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-cyclopropylmethanesulfonyl-1-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=396.2 [M+H]+.