Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].Cl[C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:9]=[C:8]([S:24][CH3:25])[N:7]=1>CO>[CH3:2][O:3][C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:9]=[C:8]([S:24][CH3:25])[N:7]=1
Reactant: C[O-]
Reactant: CSc1nc(Cl)cc(CN2C(=O)c3ccccc3C2=O)n1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(CN2C(=O)c3ccccc3C2=O)nc(SC)n1

Procedure:
To 100 ml of methanol was added 1.55 g (67.4 mmole) of sodium metal to prepare 67.4 mmole of sodium methoxide. To this solution was added 20.0 g (62.6 mmole) of 4-chloro-2-methylthio-6-phthalimidomethylpyrimidine (from Example 2) and the mixture was heated at reflux for 16 hours. The mixture was cooled, and the solid was then separated by filtration. This solid was washed sequentially with methanol and water to provide 4-methoxy-2-methylthio-6-phthalimidomethylpyrimidine as a white solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[C:34]([C:40]#[N:41])[CH:35]=[C:36]([CH3:39])[CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C1COCC1.CO.[Li+].[OH-].Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[C:34]([C:40]#[N:41])[CH:35]=[C:36]([CH3:39])[CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1cccc2c(C#N)cc(C)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1cccc2c(C#N)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(5-cyano-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (18 mg, 0.032 mmol) in 2:1 THF/MeOH (3 mL) at room temperature was added LiOH (2.0 N in water, 0.265 mL, 0.530 mmol). The mixture was stirred at room temperature for one hour. The mixture was acidified with 2.0 N HCl (aq) and diluted with EtOAc. The organic layer was washed twice with water, dried over sodium sulfate, filtered, then concentrated to afford the title product as a white solid. LC1 1.59 min. [M+H]+ 538.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH:10]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])=[CH2:11]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([CH:10]=[CH2:11])[CH:13]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: C=Cc1cccc(N)c1
Product: C=Cc1cccc(Nc2nc(Cl)ncc2C)c1
Yield: 39 %

Procedure:
This compound was prepared according to the procedure of Example A1, step A, using 2,4-dichloro-5-methylpyrimidine and 3-vinylaniline as the starting materials in 39% yield. LCMS calculated for C13H13ClN3 (M+H)+: m/z=246.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:32])[CH:24]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1cccc2c1cc(C)n2Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture bromo-phenyl-acetic acid methyl ester (0.24 mL, 1.512 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford 8 (0.3 g, 62%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:12]=1.C(OCC)(=O)C>[C].[Pd].CO>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:12]=1
Reactant: Cc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(CCc2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the obtained tert-butyl 4-((E)-2-(2,3-dimethylphenyl)vinyl)-2-(4-fluoroanilino)benzoate were added ethyl acetate 1.5 mL, methanol 1.5 mL and 10% palladium-carbon 27 mg sequentially, and it was stirred under hydrogen atmosphere at room temperature for 3 hours and 20 minutes. The solvent was removed under reduced pressure after insoluble matter was filtrated. Dichloromethane 1.0 mL and trifluoroacetic acid 7.5 mL were added to the obtained residue, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-(2-(2,3-dimethylphenyl)ethyl)-2-(4-fluoroanilino)benzoic acid 17 mg of a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CCOCC>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ccccc32)CC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1COc2ccccc2N1C1CCNCC1
Yield: 135.1 %

Procedure:
4-(3-Oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (17 g, 51 mmol) and 1:1 TFA/CH2Cl2 (40 mL) were combined and set stirring. After 45 min the mixture was evaporated to give a clear brown oil. The oil was set stirring and Et2O was added (300 mL). A solid formed and was filtered, washed with Et2O and air dried to give 16 g (90%) of a light beige solid. MS (electrospray): exact mass calculated for C13H16N2O2, 232.12. m/z found, 233.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.44 (dd, J=6.5, 1.4 Hz, 1H), 7.20-7.7.10 (m, 3H), 4.58 (s, 2H), 4.55-4.45 (m, 1H), 4.65-4.55 (m, 2H), 3.27 (dt, J=13.0, 2.3 Hz, 2H), 3.05 (dd, J=12.3, 4.1 Hz, 2H), 2.15 (d, J=13.8 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCOCC2)c(C)c1
Yield: 83.8 %

Procedure:
BINAP (0.67 g; 1.1 mmol; 0.05 eq.) and palladium acetate (0.24 g; 1.1 mmol; 0.05 eq.) were added to a suspension methyl 4-bromo-3-methylbenzoate (5 g; 21.8 mmol; 1 eq.), Cs2CO3 (10.65 g; 32.7 mmol; 1.5 eq.) and morpholine (2.3 g; 26 mmol; 1.2 eq.) in dioxane (100 mL) and the reaction mixture was refluxed for 15 hours. After filtration through a pad of CELITE, the solution was concentrated in vacuo and the residue purified by column chromatography (petroleum ether/ethyl acetate, 80/20) to afford the title compound (4.3 g, 84%) as a yellow solid.
Reaction SMILES: C[C@@:2]1([C:40]([OH:42])=O)[CH2:6][C@@H:5]([O:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[N:11]=[C:10]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)[CH:9]=2)[CH2:4][N:3]1C(=O)[C@@H](NC(NC(C)(C)C)=O)C(C)(C)C.FC(F)(F)C(O)=O.[NH2:50][C@@H](CCC)C(O)C(NC1CC1)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([O:7][CH:5]3[CH2:4][NH:3][CH:2]([C:40]([NH2:50])=[O:42])[CH2:6]3)=[CH:9][C:10]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[N:11]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(O[C@H]3CN(C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)[C@](C)(C(=O)O)C3)cc(-n3cccn3)nc2c1
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(OC3CNC(C(N)=O)C3)cc(-n3cccn3)nc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl-(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxo-3-ylcarbamate (48 mg, 0.165 mmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (3.0 mL) was added. After stirring for 1 hour at room temperature, the reaction mixture was evaporated to dryness to give (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide trifluoroacetic acid salt as a white solid. A solution of (2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylic acid in dichloromethane/N,N-dimethylformamide (1:1, 6.0 mL) was added to the (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide trifluoroacetic acid salt, followed by O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (75 mg, 0.198 mmol) and diisopropylethylamine (0.1 mL, 0.7 mmol). After 24 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl, sodium bicarbonate, and brine. The ethyl acetate layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude product was then dissolved in dry dichloromethane (10.0 mL) and Dess-Martin periodinane (112 mg, 0.264 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was quenched with 0.26M sodium thiosulfate in saturated sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layers were then washed with saturated sodium bicarbonate and brine. Purification by preparative HPLC gave (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((S)-1-cyclopropylamino)-1,2-dioxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide in >99% purity by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:11][CH2:10][C:9]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:8]1=2)C.[C:25]([OH:30])([C:27]([OH:29])=[O:28])=[O:26].O=C(C(=O)O)O>O>[C:27]([OH:29])(=[O:28])[C:25]([OH:30])=[O:26].[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2([CH2:6][CH2:5][CH2:4][NH:2][CH3:1])[C:8]3[C:9](=[CH:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=3)[CH2:10][O:11]2)=[CH:23][CH:22]=1
Reactant: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: O=C(O)C(=O)O
Solvent: O
Product: CNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21

Procedure:
A solution of 1-[3-(N-methyl-ammonium)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (0.70 g, 2.24 mmol) and formaldehyde (0.5 mL, 6.7 mmol, 37% aqueous solution) in 98% formic acid (5 mL) was refluxed for 4 h. After cooling, 4M HCI (2 mL) was added and the resulting mixture was evaporated. 1M NaOH (50 mL) was added to the residue and extracted with Et2O (3×100 mL). The organic extract was washed with brine, dried and evaporated. The oxalate salt was isolated from acetone (0.22 g, 30%). DSC (open chamber), Tonset=157.73, Tpeak=160.80. The NMR-spectra were identical with those obtained from citalopram oxalate prepared in example 6. Anal. (C20H21N2O, C2H2O4, ¼ H2O) calcd. C: 63.06; H: 5.67; N: 6.69. Found C: 63.24; H: 5.65; N: 6.62.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[C:6](\[F:9])/[CH:7]=[O:8].[C:10]([Mg]Br)#[CH:11].CCOCC.Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([F:9])[CH:7]([OH:8])[C:10]#[CH:11]
Reactant: O=C/C(F)=C/CCCCl
Reactant: C#C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(O)C(F)=CCCCCl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
2.35 Grams of (Z)-6-chloro-2-fluoro-2-hexenal was dissolved in 20 ml of dry tetrahydrofuran, and to the resulting solution was added dropwise a tetrahydrofuran solution of ethynylmagnesium bromide (1.5 equivalents vs. the aldehyde) with ice-cooling. After addition, the solution was stirred at room temperature for 10 hours. The reaction solution was cooled with ice, and after adding 50 ml of ether, poured into 10% hydrochloric acid. The ether layer was separated, and the aqueous layer was extracted twice with ether. The ether extracts were combined with the above ether layer, and this mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure. The residue obtained was treated by column chromatography on silica gel with an ethyl acetate/hexane (1:5) mixture as an eluent to obtain 1.72 g of 8-chloro-4-fluoro-3-hydroxy-4-octen-1-yne as a pale yellow oily product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cc2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Into a round-bottom flask, was placed a solution of tert-butyl 4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (compound 1.2, 2 g, 6.61 mmol, 1.00 equiv) in pyridine (40 mL). POCl3 (10.16 g, 66.26 mmol, 10.02 equiv) was carefully added. The resulting mixture was stirred under nitrogen overnight at room temperature and then concentrated under vacuum. The residue was taken up in 20 mL of DCM, washed with 2×20 mL of sodium bicarbonate (aq), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with PE/EtOAc (100:1-30:1) as eluent to yield 1.4 g (74%) of the title compound as a white solid.
Reaction SMILES: [ClH:1].O[C:3]1(CN)[CH2:9]OC2C=CC=CC=2O[CH2:4]1.Cl.[OH:17][C:18]1([CH:29]([NH2:31])[CH3:30])[CH2:24][O:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[O:20][CH2:19]1>>[ClH:1].[OH:17][C:18]1([CH:29]([NH:31][CH:3]([CH3:9])[CH3:4])[CH3:30])[CH2:19][O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[O:23][CH2:24]1
Reactant: NCC1(O)COc2ccccc2OC1
Reactant: CC(N)C1(O)COc2ccccc2OC1
Agent: Cl
Product: CC(C)NC(C)C1(O)COc2ccccc2OC1

Procedure:
By replacing the 3-hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin hydrochloride employed in Step F of Example 1 by an equivalent quantity of 3-hydroxy-3-(1-aminoethyl)-3,4-dihydro-2H-1,5-benzodioxepin hydrochloride and employing the same reaction conditions called for in Example 1, Step F, there is obtained 3-hydroxy-3-(1-isopropylaminoethyl)-3,4-dihydro-2H-1,5-benzodioxepin hydrochloride, M.P. 206°-211° C. It was purified by recrystallization from ethanol giving a product of M.P. 215°-7° .
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].[Cl:44][C:45]1[C:46]([CH2:51]Cl)=[N:47][CH:48]=[CH:49][CH:50]=1>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:51][C:46]3[C:45]([Cl:44])=[CH:50][CH:49]=[CH:48][N:47]=3)[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: ClCc1ncccc1Cl
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn(Cc3ncccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 3-chloro-2-(chloromethyl)pyridine. MS (m/e): 423.3 (MH+).
Reaction SMILES: C1(=O)NCCCCC1.[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:10]>O>[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:10]
Reactant: COC(=O)CCCCC=O
Agent: O=C1CCCCCN1
Solvent: O
Product: O=CCCCCC(=O)O

Procedure:
A process for preparing ε-caprolactam is described in U.S. Pat. No. 4,730,040. In this process, methyl 5-formylvalerate is first hydrolyzed (step a) in the presence of water and an acidic agent to yield 5-formylvaleric acid. In this process, the 5-formylvaleric acid is reductively aminated in water through contact with ammonia and hydrogen using a ruthenium/zirconium on alumina catalyst, a Raney Nickel catalyst or a Raney Cobalt catalyst to obtain a 6-aminocaproic acid containing reaction mixture. After separation of ammonia, the reaction mixture obtained from the reductive amination is heated to 300° C. to form ε-caprolactam by cyclization of the 6-aminocaproic acid.
Reaction SMILES: [F:1][C:2]([F:32])([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][CH:4]1[CH2:8][CH:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:5]1=[O:17].C1C=CC(S)=CC=1.[Li]CCCC.C1C[O:48]CC1>>[F:1][C:2]([F:32])([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][CH:4]([CH2:8][CH:7]([OH:48])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:6])=[O:17]
Reactant: COc1ccc(-c2ccc(C(F)(F)CC3CC(CSc4ccccc4)OC3=O)cc2)cc1
Reactant: C1CCOC1
Agent: Sc1ccccc1
Agent: [Li]CCCC
Product: COc1ccc(-c2ccc(C(F)(F)CC(CC(O)CSc3ccccc3)C(=O)O)cc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
3-[2,2-Difluoro-2-(4′-methoxy-biphenyl-4-yl)-ethyl]-5-phenylsulfanylmethyl-dihydro-furan-2-one. A solution of phenylthiol (0.65 mmol) in THF (5 mL) is treated with BuLi (0.65 mmol) at −20° C. After being stirred for 20 min at −20° C., Example 18d (0.5 mmol) in THF (5 mL) is added dropwise. The mixture is allowed to warm to 0° C. and kept at that temperature for 2 hours, then is warmed up to room temperature and stirred for 3 hours. The reaction is quenched with saturated NH4Cl, neutralized with 1N HCl and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The crude material obtained after evaporation of solvents is purified by flash chromatography (3/1 hexane/acetone) and recrystallized from hexane/acetone to give the desired compound as colorless needles: mp 117-118° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]=[O:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1.CN(C1CCCCC1)C1CCCCC1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]=[O:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:3]=1
Reactant: O=Cc1cc(Cl)cc2c(Br)n[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(Br)c2cc(Cl)cc(C=O)c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-chloro-1H-indazole-7-carbaldehyde (1.4 g, 5.4 mmol) and N-methyldicyclohexylamine (1.6 mL, 7.28 mmol) were suspended in tetrahydrofuran (6 mL), cooled to 0° C., and treated with (2-(chloromethoxy)ethyl)trimethylsilane (2.0 mL, 6.74 mmol). The ice bath was removed and stirring continued for 4 h. The reaction was poured into ethyl acetate, washed with water (3×), 1M potassium bisulfate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 1.45 g (69%) as a faint yellow oil. 1H-NMR (CDCl3, 500 MHz) δ 10.28 (s, 1H), 7.97 (d, J=1.83 Hz, 1H), 7.87 (d, J=2.14 Hz, 1H), 6.0(s, 2H), 3.48-3.51 (m, 2H), 0.80-0.83 (m, 2H), 0.10 (s, 9H).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:14][O:15][CH3:16])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].N1C(C)=CC=CC=1C.[F:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([CH3:32])[C:27]=1[C:33](F)=[O:34]>ClC1C=CC=CC=1.ClCCl>[F:1][CH2:2][CH:3]([N:14]([O:15][CH3:16])[C:33]([C:27]1[C:28]([CH3:32])=[N:29][N:30]([CH3:31])[C:26]=1[F:25])=[O:34])[CH2:4][C:5]1[C:6]([Cl:13])=[CH:7][C:8]([Cl:12])=[CH:9][C:10]=1[Cl:11]
Reactant: CONC(CF)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1nn(C)c(F)c1C(=O)F
Solvent: ClCCl
Solvent: Clc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CON(C(=O)c1c(C)nn(C)c1F)C(CF)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 130 °C
Yield: 6.7 %

Procedure:
To a stirred solution of N-[1-fluoromethyl-2-(2,4,6-trichloro-phenyl)-ethyl]-O-methylhydroxylamine (0.20 g; 0.70 mmol), prepared as described in example P6f2 in chlorobenzene (3.8 ml) was added 2,6-lutidine (85 μl; 0.74 mmol) and 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl fluoride (0.11 g; 0.70 mmol). The yellow solution was stirred at reflux (130° C.) for 22 hours. The dark brown solution was dissolved in dichloromethane (20 ml), washed with 1 M sodium hydroxide solution (20 ml), 1 M hydrochloric acid solution (20 ml), brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 9:1 to 7:3) to afford 20 mg (7% of theory) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-methoxy-amide as a brown oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OCCCCCCBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
10 g of [4-(6-bromo-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone are dissolved in 200 ml of DMF and, after the addition of 14.7 g of sodium azide, the mixture is stirred at 90° C. for 24 hours, filtered and the filtrates are concentrated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution. The organic phase is dried and concentrated. There are obtained 9.2 9 of [4-(6-azido-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone, MS: m/e 401 (M+H+, 1Br).